Unveiling Mechanistic Insight into Accelerating Oxygen Molecule Activation by Oxygen Defects in Co3O4-x/g-C3N4 p-n Heterojunction for Efficient Photo-Assisted Uranium Extraction from Seawater.

Photo-assisted uranium extraction from seawater (UES) is regarded as an efficient technique for uranium resource recovery, yet it currently faces many challenges, such as issues like biofouling resistance, low charge separation efficiency, slow carrier transfer, and a lack of active sites. Based on addressing the above challenges, a novel oxygen-deficient Co3O4-x/g-C3N4 p-n heterojunction is developed for efficient photo-assisted uranium extraction from seawater. Relying on the defect-coupling heterojunction synergistic effect, the redistribution of molecular charge density formed the built-in electric field as revealed by DFT calculations, significantly enhancing the separation efficiency of carriers and accelerating their migration rate. Notably, oxygen vacancies served as capture sites for oxygen, effectively promoting the generation of reactive oxygen species (ROS), thereby significantly improving the photo-assisted uranium extraction performance and antibacterial activity. Thus, under simulated sunlight irradiation with no sacrificial reagent added, Co3O4-x/g-C3N4 extracted a high uranium extraction amount of 1.08 mg g-1 from 25 L of natural seawater after 7 days, which is superior to most reported carbon nitride-based photocatalysts. This study elaborates on the important role of surface defects and inerface engineering strategies in enhancing photocatalytic performance, providing a new approach to the development and design of uranium extraction material from seawater.

Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

A modified glycosylase base editor without predictable DNA off-target effects.

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBEYE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBEYE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBEYE1 is a safe tool for gene therapy.

Synthesis of a novel magnetic calcium-rich biochar nanocomposite for efficient removal of phosphate from aqueous solution.

Phosphorus (P) scarcity and eutrophication have triggered the development of new materials for P recovery. In this work, a novel magnetic calcium-rich biochar nanocomposite (MCRB) was prepared through co-precipitation of crab shell derived biochar, Fe2+ and Fe3+. Characteristics of the material demonstrated that the MCRB was rich in calcite and that the Fe3O4 NPs with a diameter range of 18-22 nanometers were uniformly adhered on the biochar surface by strong ether linking (C-O-Fe). Batch tests demonstrated that the removal of P was pH dependent with an optimal pH of 3-7. The MCRB exhibited a superior P removal performance, with a maximum removal capacity of 105.6 mg g-1, which was even higher than the majority lanthanum containing compounds. Study of the removal mechanisms revealed that the P removal by MCRB involved the formation of hydroxyapatite (HAP-Ca5(PO4)3OH), electrostatic attraction and ligand exchange. The recyclability test demonstrated that a certain level (approximately 60%) was still maintained even after the six adsorption-desorption process, suggesting that MCRB is a promising material for P removal from wastewater.

Ultrasound-electrochemistry assisted liquid-phase co-exfoliation of phosphorene decorated by Au-Ag bimetallic nanoparticles as nanozyme for smartphone-based portable sensing of 4-nitrophenol.

The stability of black phosphorene (BP) and its preparation and modification for developing and applying devices have become a hot topic in the interdisciplinary field. We propose ultrasound-electrochemistry co-assisted liquid-phase exfoliation as an eco-friendly one-step method to prepare gold-silver bimetallic nanoparticles (Au-AgNPs)-decorated BP nanozyme for smartphone-based portable sensing of 4-nitrophenol (4-NP) in different water sources. The structure, morphology, composition, and properties of Au-AgNPs-BP nanozyme are characterized by multiple instrumental analyses. Bimetallic salts are induced to efficiently occupy oxidative sites of BP to form highly stable Au-AgNPs-BP nanozyme and guarantee the integrity of the lamellar BP. The electrochemistry shortens the exfoliation time of the BP nanosheet and contributes to the loading efficiency of bimetallic nanoparticles on the BP nanosheet. Au-AgNPs-BP-modified screen-printed carbon electrode coupled with palm-sized smartphone-controlled wireless electrochemical analyzer as a portable wireless intelligent sensing platform was applied to the determination of 4-NP in a linear range of 0.6-10 µM with a limit of detection of 63 nM. It enables on-site determination of 4-NP content in lake water, river water, and irrigation ditch water. This work will provide a reference for an eco-friendly one-step preparation of bimetallic nanoparticle-decorated graphene-like materials as nanozymes and their smartphone-based portable sensing application outdoors.

Clinical, pharmacological, and qualitative characterization of drug-drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa.

BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.

Association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and kidney stone: evidence from NHANES 2007-2018.

BACKGROUND: As an innovative lipid parameter, NHHR (the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol) can serve as a valuable tool for assessing cardiovascular disease risk. Nevertheless, the relationship between NHHR and the risk of kidney stones remains unexplored. METHODS: A cross-sectional survey utilized data from the National Health and Population Survey (NHANES) database in the United States spanning from 2007 to 2018. Distinct statistical analyses were applied, including weighted logistic regression, stratified and interaction analysis and restricted cubic spline curve (RCS) models, to examine the correlation between NHHR and the incidence of kidney stones. RESULTS: This analysis encompassed 24,664 participants, with 9.63% reporting incidents of kidney stones. Following multivariate logistic regression and comprehensive adjustments, participants in NHHR quartile 4 (OR 1.34; 95% CI 1.12, 1.60, P < 0.01) exhibited a significantly increased risk of kidney stones compared to those in NHHR quartile 1 (Q1). The RCS result further illustrated a non-linear correlation between NHHR and the incidence of kidney stones. The result of subgroup analysis manifested that participants without diabetes had a higher risk of kidney stones when measured high NHHR levels compared those with diabetes (p for interaction < 0.05). CONCLUSION: Elevated NHHR levels were found to be associated with an increased risk of kidney stones. Based on these findings, NHHR appears to be a promising predictive indicator for the occurrence of kidney stones.

Application of 3D bioprinting technology apply to assessing Dangguiniantongtang (DGNT) decoctions in arthritis.

The aim of this study was to develop a three-dimensional (3D) cell model in order to evaluate the effectiveness of a traditional Chinese medicine decoction in the treatment of arthritis. Chondrocytes (ATDC5) and osteoblasts (MC3T3-E1) were 3D printed separately using methacryloyl gelatin (GelMA) hydrogel bioinks to mimic the natural 3D cell environment. Both cell types showed good biocompatibility in GelMA. Lipopolysaccharide (LPS) was added to the cell models to create inflammation models, which resulted in increased expression of inflammatory factors IL-1ß, TNF-α, iNOS, and IL-6, and decreased expression of cell functional genes such as Collagen II (COLII), transcription factor SOX-9 (Sox9), Aggrecan, alkaline phosphatase (ALP), RUNX family transcription factor 2 (Runx2), Collagen I (COLI), Osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). The created inflammation model was then used to evaluate the effectiveness of Dangguiniantongtang (DGNT) decoctions. The results showed that DGNT reduced the expression of inflammatory factors and increased the expression of functional genes in the cell model. In summary, this study established a 3D cell model to assess the effectiveness of traditional Chinese medicine (TCM) decoctions, characterized the gene expression profile of the inflammatory state model, and provided a practical reference for future research on TCM efficacy evaluation for arthritis treatment.

SlMDH3 Interacts with Autophagy Receptor Protein SlATI1 and Positively Regulates Tomato Heat Tolerance.

Autophagy, a highly conserved protein degradation system, plays an important role in protecting cells from adverse environmental conditions. ATG8-INTERACTING PROTEIN1 (ATI1) acts as an autophagy receptor, but its functional mechanisms in plants' heat stress tolerance remain unclear. In this study, using LC-MS/MS, we identified malate dehydrogenase (SlMDH3) as a SlATI1-interacting protein. Further studies showed that heat stress induced the expression of SlMDH3 and SlMDH3 co-localized with SlATI1 under both 22 °C and 42 °C heat treatment conditions. Moreover, silencing of SlMDH3 increased the sensitivity of tomato to heat stress, as evidenced by exacerbated degradation of chlorophyll; accumulation of MDA, H2O2, and dead cells; increased relative conductivity; and inhibition of stress-related gene expression. Conversely, overexpression of SlMDH3 improved tomato's heat tolerance, leading to opposite effects on physiological indicators and gene expression compared to SlMDH3 silencing. Taken together, our study suggests that SlMDH3 interacts with SlATI1 and positively regulates tomato heat tolerance.

Comprehensive analysis and experimental verification reveal the molecular characteristics of EGLN3 in pan-cancer and its relationship with the proliferation and apoptosis of lung cancer.

Background: Egl-9 family hypoxia-inducible factor 3 (EGLN3) is involved in the regulation of tumor microenvironment and tumor progression. However, its biological function and clinical significance in various cancers remain unclear. Methods: RNA-seq, immunofluorescence, and single-cell sequencing were used to investigate the expression landscape of EGLN3 in pan-cancer. The TISCH2 and CancerSEA databases were used for single-cell function analysis of EGLN3 in tumors. TIMER2.0 database was used to explain the relationship between EGLN3 expression and immune cell infiltration. In addition, the LinkedOmics database was used to perform KEGG enrichment analysis of EGLN3 in pan-cancer. siRNA was used to silence gene expression. CCK8, transwell migration assay, flow cytometry analysis, RT-PCR, and western blotting were used to explore biological function of EGLN3. Results: The results showed that EGLN3 was highly expressed in a variety of tumors, and was mainly localized to the cytosol. EGLN3 expression is associated with immunoinfiltration of a variety of immune cells, including macrophages in the tumor immune microenvironment and tumor-associated fibroblasts. Functional experiments revealed that EGLN3 knockdown could inhibit cell proliferation, migration, and promote cell apoptosis. In addition, we found that Bax expression was up-regulated and Bcl-2 expression was down-regulated in the si-EGLN3 group. Taken together, as a potential oncogene, EGLN3 is involved in the regulation of tumor malignant process, especially tumor cell apoptosis. Conclusion: We comprehensively investigated the expression pattern, single-cell function, immune infiltration level and regulated signaling pathway of EGLN3 in pan-cancer. We found that EGLN3 is an important hypoxia and immune-related gene that may serve as a potential target for tumor immunotherapy.

Engineering Corynebacterium glutamicum for the efficient production of 3-hydroxypropionic acid from glucose via the ß-alanine pathway.

3-Hydroxypropionic Acid (3-HP) is recognized as a high value-added chemical with a broad range of applications. Among the various biosynthetic pathways for 3-HP production, the ß-alanine pathway is particularly noteworthy due to its capacity to generate 3-HP from glucose at a high theoretical titer. In this study, the ß-alanine biosynthesis pathway was introduced and optimized in Corynebacterium glutamicum. By strategically regulating the supply of precursors, we successfully engineered a strain capable of efficiently synthesizing 3-HP through the ß-alanine pathway, utilizing glucose as the substrate. The engineered strain CgP36 produced 47.54 g/L 3-HP at a yield of 0.295 g/g glucose during the fed-batch fermentation in a 5 L fermenter, thereby attaining the highest 3-HP titer obtained from glucose via the ß-alanine pathway.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Prevalence and trends in overactive bladder among men in the United States, 2005-2020.

The purpose of present study was to examine the current prevalence and recent trends of overactive bladder (OAB) among US adult men and examine the correlations between OAB and several potential risk factors. The study used the nationally representative data between 2005 and 2020 from the National Health and Nutrition Examination Survey in the US. A total of 18,386 participants aged ≥ 20 years were included in the study. We divided the data into three groups: 2005-2008, 2009-2014 and 2015-2020 to investigate the trends in OAB prevalence. The weighted prevalence and corresponding 95% confidence intervals (CI) of OAB were calculated. The differences (95% CI) in prevalence between the surveys were calculated and multivariate-adjusted weighted logistic regression analysis was performed to determine the correlates of OAB. Among all US adult men, the overall prevalence of OAB increased slightly from 11.3% in 2005-2008 to 11.7% in 2009-2014 and significantly increased to 14.5% in 2015-2020 (difference, 3.2% [95% CI (1.9-4.4%)]; P < 0.05). Increases in OAB prevalence especially concentrated on those who were 40-59 years, non-Hispanic White, non-Hispanic Black and those who were overweight and obese. Older age, non-Hispanic Black, lower educational level and family poverty ratio, diabetes, depression, sleep disorder, other chronic comorbidities, less intense recreational activity, poorer health condition and unsafe food were independent risk factors of OAB. The contemporary prevalence of OAB was high, affecting 14.5% US men and the estimated overall prevalence significantly increased from 2005 to 2020. Therefore, future research should be focused to prevent and remedy this growing socioeconomic and individually troublesome malady.

Comparison of the Impact of a 6 French GlideSheath Slender® and a Conventional Sheath on Distal Radial Artery Occlusion: A Randomized Controlled Trial.

BACKGROUND: There is a lack of randomized clinical trials investigating whether the 6-Fr Glidesheath Slender (GSS) is superior to the 6-Fr conventional radial sheath (CS) with respect to the early-term incidence of distal radial artery occlusion (dRAO) in patients undergoing coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) via distal transradial access (dTRA). METHODS: This was a prospective, single-centre trial of patients who were randomized to undergo CAG and/or PCI with either a 6-Fr GSS or a 6-Fr CS. The primary endpoint was the incidence of dRAO at 24 h postoperatively, as evaluated by Doppler ultrasound. RESULTS: A total of 620 patients were included in the study. The baseline patient and procedural characteristics were similar between the two groups. For the primary endpoint, the incidence of dRAO at 24 h after the procedure was 1.0% (3/314) in the GSS group and 3.6% (11/306) in the CS group (RR= 0.266, 95% CI= 0.075-0.943, P= 0.027) according to the intention-to-treat (ITT) analysis. For the secondary endpoints, the incidence of proximal RAO was 0.3% (1/314) in the GSS group and 2.3% (7/306) in the CS group (P= 0.029). Other secondary endpoints, including the puncture success rate, procedural outcomes, other puncture-related outcomes and access-related complications, were not significantly different between the two groups. CONCLUSION: The use of a thin-walled and hydrophilic coating sheath can reduce the incidence of early-term dRAO in patients who undergo CAG and/or PCI via the dTRA.

Autophagy in erectile dysfunction: focusing on apoptosis and fibrosis.

In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.

The production of methyl mercaptan is the main odor source of chicken manure treated with a vertical aerobic fermenter.

The process of harmless treatment of livestock manure produces a large amount of odor, which poses a potential threat to human and livestock health. A vertical fermentation tank system is commonly used for the environmentally sound treatment of chicken manure in China, but the composition and concentration of the odor produced and the factors affecting odor emissions remain unclear. In this study, we investigated the types and concentrations of odors produced in the mixing room (MR), vertical fermenter (VF), and aging room (AR) of the system, and analyzed the effects of bacterial communities and metabolic genes on odor production. The results revealed that 34, 26 and 26 odors were detected in the VF, MR and AR, respectively. The total odor concentration in the VF was 66613 ± 10097, which was significantly greater than that in the MR (1157 ± 675) and AR (1143 ± 1005) (P < 0.001), suggesting that the VF was the main source of odor in the vertical fermentation tank system. Methyl mercaptan had the greatest contribution to the odor produced by VF, reaching 47.82%, and the concentration was 0.6145 ± 0.2164 mg/m3. The abundance of metabolic genes did not correlate significantly with odor production, but PICRUSt analysis showed that cysteine and methionine metabolism involved in methyl mercaptan production was significantly more enriched in MR and VF than in AR. Bacillus was the most abundant genus in the VF, with a relative abundance significantly greater than that in the MR (P < 0.05). The RDA results revealed that Bacillus was significantly and positively correlated with methyl mercaptan. The use of large-scale aerobic fermentation systems to treat chicken manure needs to focused on the production of methyl mercaptan.

Sol-gel transition effect based on konjac glucomannan thermosensitive hydrogel for photo-assisted uranium extraction.

Exploiting the intelligent photocatalysts capable of phase separation provides a promising solution to the removal of uranium, which is expected to solve the difficulty in separation and the poor selectivity of traditional photocatalysts in carbonate-containing uranium wastewater. In this paper, the γ-FeOOH/konjac glucomannan grafted with phenolic hydroxyl groups/poly-N-isopropylacrylamide (γ-FeOOH/KGM(Ga)/PNIPAM) thermosensitive hydrogel is proposed as the photocatalysts for extracting uranium from carbonate-containing uranium wastewater. The dynamic phase transformation is demonstrated to confirm the arbitrary transition of γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel from a dispersed state with a high specific surface area at low temperatures to a stable aggregated state at high temperatures. Notably, the γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel achieves a remarkably high rate of 92.3% in the removal of uranium from the wastewater containing carbonates and maintains the efficiency of uranium removal from uranium mine wastewater at over 90%. Relying on electron spin resonance and free radical capture experiment, we reveal the adsorption-reduction-nucleation-crystallization mechanism of uranium on γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel. Overall, this strategy provides a promising solution to treating uranium-contaminated wastewater, showing a massive potential in water purification.

The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2.

Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Rapidly screening of pancreatic lipase inhibitors from Clematis tangutica using affinity ultrafiltration-HPLC-QTOFMS technique combined with targeted separation, in vitro validation, and molecular docking.

INTRODUCTION: Screening of novel pancreatic lipase inhibitors from complex natural products is a meaningful task. OBJECTIVES: Through accurately screening and separating pancreatic lipase inhibitors from Clematis tangutica (C. tangutica), to discover new leading compounds for slimming and accelerate the development and utilization of Tibetan medicine resources. METHODS: An integrated strategy that combines affinity ultrafiltration and high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (AU-HPLC-QTOFMS), targeted separation, in vitro validation, and molecular docking was developed to screen pancreatic lipase inhibitors from C. tangutica. The AU-HPLC-QTOFMS technique was performed to fish for the potential active substances. Macroporous resin, preparative liquid chromatography, and high-speed countercurrent chromatography were implemented for the accurate and targeted separation of active compounds. The inhibitory activities of target compounds to pancreatic lipase were detected by the inhibition experiments in vitro. The binding affinities and binding sites were analyzed using molecular docking. RESULTS: A total of eleven kinds of pancreatic lipase inhibitory substances were screened from C. tangutica. Seven triterpenoid saponins were screened for the first time as lipase inhibitors and successfully prepared with purities higher than 97%. Tanguticoside B, clematangoticoside J, hederoside H1, and rutin showed stronger inhibitory effects with IC50 values of 1.539 ± 0.048, 1.661 ± 0.092, 1.793 ± 0.069, and 1.792 ± 0.094 mmol/l. Moreover, they have the lowest ΔG values of -10.84, -9.97, -10.87, and -9.39 kcal/mol to pancreatic lipase. CONCLUSION: The integrated strategy using AU-HPLC-QTOFMS, targeted separation, in vitro validation, and molecular docking was feasible for rapidly screening and directionally isolating pancreatic lipase inhibitors from C. tangutica.