Nanocarrier-based drug delivery system with dual targeting and NIR/pH response for synergistic treatment of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Safety analysis of fluoroquinolone drugs in elderly patients over 65 based on FAERS.

OBJECTIVE: This study investigates adverse drug event (ADE) reports from the FAERS related to FQs drugs (ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin) in patients aged 65 and older. The findings aim to guide the rational clinical use of these drugs in elderly patients. METHODS: We employed Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods to analyze ADE reports for the representative FQ drugs from Q1 2015 to Q4 2023, covering 36 quarters. RESULTS: The analysis identified 6883 ADE cases for ciprofloxacin, 5866 for levofloxacin, 1498 for moxifloxacin, and 317 for ofloxacin. Moxifloxacin showed higher incidences of Cardiac disorders and Psychiatric disorders ADEs (4.01%, 23.11%).The strongly associated ADEs were Torsade de pointes(X2:255.69),Delirium(X2:4600.04),Dysphoria(X2:11802.38),Mental disorder(X2:3584.69);Vascular disorders ADEs were similar among FQs.Ciprofloxacin and levofloxacin showed higher ADE rates in musculoskeletal and connective tissue diseases (20.18% and 26.97%) compared to moxifloxacin(3.62%) and ofloxacin(9.25%),The most frequently reported and strongly associated ADEs were tendinitis (X2: 13383.57, X2: 31499.01), tendon pain (X2: 18730.22, X2: 40313.79), and tendon disorders (X2: 9534.69, X2: 13143.72).Additionally, moxifloxacin and ofloxacin showed higher ADE rates for eye disorders (10.61% and 15.03%). Significant ADEs included iridocyclitis (X2: 10931.34) and corneal erosion (X2: 1348.35). CONCLUSION: Different FQs exhibit varying ADE profiles across cardiovascular, vascular and lymphatic, renal and urinary, psychiatric, musculoskeletal and connective tissue, and ocular systems. Patients with underlying systemic diseases should avoid FQs with higher ADE risks for their conditions. Enhanced monitoring and evaluation of FQs are crucial for promptly identifying and managing adverse reactions. Personalized medication plans for elderly patients should also be strengthened.

Safety analysis of quinolones use in minors-based on the FAERS database.

Objective: This study utilizes the FDA Adverse Event Reporting System (FAERS) to investigate adverse drug event (ADE) signals linked to quinolones use (ciprofloxacin, moxifloxacin, levofloxacin, ofloxacin) in minors, offering insights for clinical use. Methods: Minors were categorized into four age groups. ADE reports for these quinolones from the first quarter of 2015 to the third quarter of 2023 were extracted from the FAERS database. Data analysis used reporting odds ratio (ROR) and the MHRA method. Results: Most ADE cases in minors involved ciprofloxacin (575)and levofloxacin (477). In the infant group, various injury, poisoning, and procedural complication events were more frequently associated with ciprofloxacin, levofloxacin, and moxifloxacin (19.83%, 31.25%, and 100.00%, respectively). In the preschool children group, psychiatric disorders were more frequently reported with levofloxacin and ofloxacin use (59.00% and 47.62%, respectively). Ocular disorders were notably associated with moxifloxacin in the children group (62.50%), In the adolescent group, more gastrointestinal diseases occurred with ciprofloxacin (12.96%). Conclusion: ADE occurrence with quinolones in minors varies by age. Strict adherence to indications, rational use, avoiding prolonged use, and monitoring for short-term reactions are essential. Enhanced monitoring of interactions and drug education are crucial to reducing ADE.

[Research status and prospect of the application of artificial intelligence in the acupuncture and moxibustion field based on bibliometric].

To explore the research hotspot, development trend and existing problem of artificial intelligence (AI) application in the field of acupuncture and moxibustion by using bibliometric method. Relevant articles of AI application in the field of acupuncture and moxibustion published in CNKI, Wanfang, VIP, PubMed and Web of Science from the database establishment to September 17, 2023 were searched. Excel 2019, CiteSpace 6.2.R4 and VOSviewer 1.6.19 were used to draw visual map of the number of publication, authors, research institutions and keywords, and further analyzed the research hotspot and trend. A total of 443 Chinese articles and 68 English articles were included. The number of annual publication of Chinese articles showed an overall increasing trend, while the number of publication of English articles was less, with a growing trend from 2020. Keywords analysis showed that "Machine learning", "neural network", "deep learning", "data mining", "robot" and other AI technologies were developing around acupuncture and moxibustion diagnosis and treatment of disease, efficacy prediction, teaching and intelligent equipment development. However, the research on the application of AI in the field of acupuncture and moxibustion is in the preliminary stage of development, and in the future, it is necessary to strengthen the communication and cooperation among the teams, to further explore the AI system in line with the characteristics of acupuncture and moxibustion diagnosis and treatment, and to promote the development of the digitalisation, intellectualisation and industrialisation of acupuncture and moxibustion.

The Synergistic Inhibitory Effect of Combination Drug Treatment of Enteromorpha Prolifera Polysaccaharide and Doxorubicin Hydrochloride on A549 Cell.

BACKGROUND: As a common drug for tumor therapy, doxorubicin hydrochloride (DOX) is not yet widely used as a clinical solution. This is due to its toxicity and potential drug resistance. OBJECTIVE: This study investigated the inhibitory effect of enteromorpha prolifera polysaccaharide (EPP) combined with doxorubicin hydrochloride (DOX) on A549 cells, which fall into the cell line of human non-small cell lung cancer (NSCLC). It also explained the attenuated and synergistic effect of enteromorpha acid polysaccharide along with its synergistic effect on DOX. METHODS: To evaluate the proliferation inhibitory effect of EPP, DOX and both combined, we monitored cell growth curve and morphology using the real-time cell function analysis and imaging system-xCELLigence RTCA eSight system (eSight system). Flow cytometry was used to monitor cell apoptosis rate and cell cycle distribution. Mitochondrial function was tested by the energy metabolism analysis system. RESULTS: EPP could work with DOX to inhibit the proliferation of A549 cells. Growth curve showed that when 0.4 mg/mL of EPP was mixed with 0.2 µg/mL of DOX for 24 h, the mixure liquid had a significant inhibitory effect on the proliferation of A549 cells (p < 0.0001). The cells had lower cell adhesiveness, shrinking cell membrane, cytoplasmic aggregation, and hyperchromatic nuclei. According to the flow cytometry results, the combined drug of EPP and DOX could significantly increase the apoptosis rate of A549 cells (p < 0.0001), and block the cell cycle in the G1-S phase. Based on the results of the real-time energy metabolism, we found that the combined drug could significantly reduce A549 cells' ATP production rate and inhibit their mitochondrial respiratory function. CONCLUSIONS: The combination of EPP and DOX can block cell cycle, inhibit cell mitochondrial function, promote cell apoptosis, and enhance the killing ability of DOX on tumor cells. This study supports the antitumor activity of enterococcus acid polysaccharide and provides insights on reducing doxorubicin toxicity and drug resistance. It holds great significance for applying traditional Chinese natural medicine in clinical disease treatment.

BhrPETase catalyzed polyethylene terephthalate depolymerization: A quantum mechanics/molecular mechanics approach.

Polyethylene terephthalate (PET) is a widely used material in our daily life, particularly in areas such as packaging, fibers, and engineering plastics. However, PET waste can accumulate in the environment and pose a great threat to our ecosystem. Recently enzymatic conversion has emerged as an efficient and green strategy to address the PET crisis. Here, using a theoretical approach combining molecular dynamics simulation and quantum mechanics/molecular mechanics calculations, the depolymerization mechanism of the thermophilic cutinase BhrPETase was fully deciphered. Surprisingly, unlike the previously studied cutinase LCCICCG, our results indicate that the first step, catalytic triad assisted nucleophilic attack, is the rate-determining step. The corresponding Boltzmann weighted average energy barrier is 18.2 kcal/mol. Through extensive comparison between BhrPETase and LCCICCG, we evidence that key features like charge CHis@N1 and angle APET@C1-Ser@O1-His@H1 significantly impact the depolymerization efficiency of BhrPETase. Non-covalent bond interaction and distortion/interaction analysis inform new insights on enzyme engineer and may aid the recycling of enzymatic PET waste. This study will aid the advancement of the plastic bio-recycling economy and promote resource conservation and reuse.

Sorption/desorption and degradation of long- and short-chain PFAS by anion exchange resin and UV/sulfite system.

A combined sorption/desorption and UV/sulfite degradation process was investigated for achieving efficient elimination of PFAS from water. Two gel-type resins, Purolite A532E and A600, and one macroporous resin, Purolite A860, were firstly tested for the sorption of individual PFPrA, PFHxA, PFOA, PFOS, and GenX at different concentrations. Sorption data and density functional theory (DFT) calculations revealed that electrostatic interactions predominated for short-chain PFAS sorption and hydrophobic interactions played a more significant role for long-chain PFAS than for short-chain PFAS. A600 and A860 were selected for desorption tests with 0.025% NaOH, 5% NaCl, and 5% NH4Cl solution with or without 20% ethanol (EtOH) due to their high sorption capacity for all target PFAS. The mixture of 5% NH4Cl and 20% EtOH as the desorption solution typically showed the highest desorption efficiency. PFOS was the most resistant for desorption but its desorption could be enhanced by stronger mixing conditions (in 5% NaCl + 20% EtOH). Direct degradation of studied PFAS in the desorption solution (0.025% NaOH, 5% NaCl, and 5% NH4Cl) by UV/sulfite achieved 97.6-100% degradation and 46.6-86.1% defluorination. EtOH hindered degradation and thus should be separated from the water before UV/sulfite degradation.

Biotic/abiotic transformation mechanisms of phenanthrene in iron-rich constructed wetland under redox fluctuation.

Iron-rich constructed wetlands (CWs) could promote phenanthrene bioremediation efficiently through biotic and abiotic pathways, which have gained increasing attention. However, the biotic/abiotic transformation mechanisms of trace organic contaminants in iron-rich CW are still ambiguous. Herein, three CWs (i.e., CW-A: Control; CW-B: Iron-rich CW, CW-C: Iron-rich CW + tidal flow) were constructed to investigate the transformation mechanisms of phenanthrene through Mössbauer spectroscopy and metagenomics. Results demonstrated CW-C achieved the highest phenanthrene removal (94.0 %) and bacterial toxicity reduction (92.1 %) due to the optimized degradation pathway, and subsequently achieved the safe transformation of phenanthrene. Surface-bound/low-crystalline iron regulated hydroxyl radical (·OH) production predominantly, and its utilization was promoted in CW-C, which also improved electron transfer capacity. The enhanced electron transfer capacity led to the enrichment of PAH-degrading microorganisms (e.g., Thauera) and keystone species (Sphingobacteriales bacterium 46-32) in CW-C. Additionally, the abundances of phenanthrene transformation (e.g., EC:1.14.12.-) and tricarboxylic-acid-cycle (e.g., EC:2.3.3.1) enzyme were up-regulated in CW-C. Further analysis indicated that the safe transformation of phenanthrene was mainly attributed to the combined effect of abiotic (·OH and surface-bound/low-crystalline iron) and biotic (microbial community and diversity) mechanisms in CW-C, which contributed similarly. Our study revealed the essential role of active iron in the safe transformation of phenanthrene, and was beneficial for enhanced performance of iron-rich CW.

Comparison of dynamic hip screw with anti-rotation screw and femoral neck system internal fixation for the treatment of garden II-IV type femoral neck fractures.

BACKGROUND: Femoral neck fractures, which are fractures occurring from the femoral head to the base of the femoral neck, are prevalent in the elderly population. With the progression of societal aging, the incidence of femoral neck fractures has been steadily increasing, making it a significant global issue that urgently needs to be addressed. OBJECTIVE: To compare the efficacy and safety of dynamic hip screw (DHS) with anti-rotation screw and femoral neck system (FNS) internal fixation for the treatment of Garden II-IV type femoral neck fractures. METHODS: A total of 90 patients with Garden II-IV type femoral neck fractures were randomly assigned to either the control group (n= 45) treated with DHS and anti-rotation screw or the experimental group (n= 45) treated with FNS. Surgical outcomes, including incision size, blood loss, operation time, fluoroscopy frequency, and fracture healing time, were compared. Postoperative complication rates, reoperation rates, Harris scores, and visual analogue scale (VAS) scores were also assessed. RESULTS: The experimental group demonstrated significantly reduced incision length, blood loss, operation time, and fluoroscopy frequency compared to the control group (P< 0.01). No significant differences were observed in fracture healing time, Garden classification, or fracture reduction outcomes between the two groups (P> 0.05). At 6 months post-treatment, both groups showed significant improvements in Harris scores and VAS scores compared to pre-treatment (P< 0.05), with no significant differences between the groups (P> 0.05). The rates of internal fixation failure, nonunion, and avascular necrosis of the femoral head, as well as overall incidence of postoperative complications and reoperation rates, showed no significant differences between the two groups (P> 0.05). CONCLUSIONS: Both DHS with anti-rotation screw and FNS internal fixation demonstrated comparable efficacy and safety profiles in the treatment of Garden II-IV type femoral neck fractures. The experimental group showed advantages in terms of reduced incision length, blood loss, operation time, and fluoroscopy frequency, while maintaining similar clinical outcomes and complication rates.

Multilayer porous Co-Fe bimetallic electrocatalyst based on multi-walled carbon nanotubes for rechargeable zinc-air batteries.

The rational design of efficient, stable, low-cost non-precious metal-based electrocatalysts with enhanced oxygen reduction reaction (ORR) activity has attracted widespread attention. In this study, a novel electrocatalyst, Fe/Co-N-MWCNT, was prepared by in-situ growth of ZIF-8 and Fe/Co-Phen on multi-walled carbon nanotubes (MWCNTs), then pyrolysis under different temperature to obtain optimal one. During the pyrolysis process, the incorporation of Fe and Co facilitated the formation of metal active sites and Fe-Co alloy, thereby promoting electron transfer and enhancing the ORR activity. Compared to Pt/C (E1/2 = 0.854V, JL = 4.90 mA cm-2), Fe/Co-N-MWCNT demonstrated a comparable half-wave potential (E1/2 = 0.812V) and an enhanced limiting current density (JL = 5.37 mA cm-2). Furthermore, Fe/Co-N-MWCNT was stable and showed no significant change after 2000 cycles, with only a negative shift of 7 mV in E1/2. Ampere response testing revealed that the current decay of Fe/Co-N-MWCNT after 10000 s was only about 7.8%, while that of Pt/C was about 18.4%. Due to its excellent catalytic stability, Fe/Co-N-MWCNT was demonstrated to be an excellent candidate for rechargeable zinc-air batteries. The outstanding electrocatalytic performance of Fe/Co-N-MWCNT can be attributed to its high pyridinic nitrogen content, the unique structure and abundant metal active sites.

Association between neural prosody discrimination and language abilities in toddlers: a functional near-infrared spectroscopy study.

BACKGROUND: Language delay affects near- and long-term social communication and learning in toddlers, and, an increasing number of experts pay attention to it. The development of prosody discrimination is one of the earliest stages of language development in which key skills for later stages are mastered. Therefore, analyzing the relationship between brain discrimination of speech prosody and language abilities may provide an objective basis for the diagnosis and intervention of language delay. METHODS: In this study, all cases(n = 241) were enrolled from a tertiary women's hospital, from 2021 to 2022. We used functional near-infrared spectroscopy (fNIRS) to assess children's neural prosody discrimination abilities, and a Chinese communicative development inventory (CCDI) were used to evaluate their language abilities. RESULTS: Ninety-eight full-term and 108 preterm toddlers were included in the final analysis in phase I and II studies, respectively. The total CCDI screening abnormality rate was 9.2% for full-term and 34.3% for preterm toddlers. Full-term toddlers showed prosody discrimination ability in all channels except channel 5, while preterm toddlers showed prosody discrimination ability in channel 6 only. Multifactorial logistic regression analyses showed that prosody discrimination of the right angular gyrus (channel 3) had a statistically significant effect on language delay (odd ratio = 0.301, P < 0.05) in full-term toddlers. Random forest (RF) regression model presented that prosody discrimination reflected by channels and brain regions based on fNIRS data was an important parameter for predicting language delay in preterm toddlers, among which the prosody discrimination reflected by the right angular gyrus (channel 4) was the most important parameter. The area under the model Receiver operating characteristic (ROC) curve was 0.687. CONCLUSIONS: Neural prosody discrimination ability is positively associated with language development, assessment of brain prosody discrimination abilities through fNIRS could be used as an objective indicator for early identification of children with language delay in the future clinical application.

Prolonged administration of the granisetron transdermal delivery system reduces capecitabine plus oxaliplatin regimen induced nausea and vomiting.

OBJECTIVE: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. DESIGN: Open-label, prospective, multi-center phase II trial. SETTING: Three institutions. PARTICIPANTS: Fifty-four patients scheduled to receive CapeOX chemotherapy. INTERVENTIONS: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. MAIN OUTCOME MEASURES: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. RESULTS: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported. CONCLUSION: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Enhancing the amination activity of meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum by modifying the crucial residue His154 for deamination.

During the deamination and amination processes of meso-diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum (StDAPDH), residue R71 was observed to display distinct functions. H154 has been proposed as a basic residue that facilitates water molecules to attack the D-chiral carbon of meso-DAP during deamination. Inspired by the phenomenon of R71, the effects of H154 during deamination and amination were investigated in this study with the goal of enhancing the amination activities of StDAPDH. Single site saturation mutagenesis indicated that almost all of the H154 mutants completely lost their deamination activity towards meso-DAP. However, some H154 variants showed enhanced kcat/Km values towards pyruvic acid and other bulky 2-keto acids, such as 2-oxovaleric acid, 4-methyl-2-oxopentanoic acid, 2-ketobutyric acid, and 3-methyl-2-oxobutanoic acid. When combined with the previously reported W121L/H227I mutant, triple mutants with significantly improved kcat/Km values (2.4-, 2.5-, 2.5-, and 4.0-fold) towards these 2-keto acids were obtained. Despite previous attempts, mutations at the H154 site did not yield the desired results. Moreover, this study not only recognizes the distinctive impact of H154 on both the deamination and amination reactions, but also provides guidance for further high-throughput screening in protein engineering and understanding the catalytic mechanism of StDAPDH.

Gut Microbiota and Its Metabolites: The Emerging Bridge Between Coronary Artery Disease and Anxiety and Depression?

The increasing studies indicated that cardiovascular diseases, such as coronary artery disease (CAD), usually induce and exacerbate psychological problems, including anxiety and depression. These psychological issues are admitted as independent risk factors of heart disease as well. The interaction between CAD and anxiety and depression deteriorates the development and prognosis of CAD, which severely threatens the quality of life of patients. Although the existing mechanisms revealed the pathological relationship between CAD and anxiety and depression, there are few studies investigating the correlation between CAD and anxiety and depression from the aspect of gut microbiota (GM) and its metabolites. Therefore, in this review, we summarized whether GM and its metabolites are the emergent bridge between CAD and anxiety and depression. The results showed that there are four kinds of jointly up-regulated bacteria (i.e., Staphylococcus, Escherichia coli, Helicobacter pylori, and Shigella) and five kinds of jointly down-regulated bacteria (i.e., Prevotella, Lactobacillus, Faecalibacterium prausnitzii, Collinsella, and Bifidobacterium) in CAD as well as anxiety and depression. In addition, in CAD and anxiety and depression, the dysbiosis of the former four kinds of bacterium frequently leads to the outburst of inflammatory response, and the dysbiosis of the latter five kinds of bacterium is usually related to the metabolic abnormality of short-chain fatty acids, bile acids, and branched-chain amino acids. Therefore, we believe that GM and its metabolites act as the emergent bridge between CAD and anxiety and depression. The findings of this review provide novel insights and approaches for the clinical treatment of patients with both CAD and anxiety and depression.

WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis.

INTRODUCTION: Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. OBJECTIVES: We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. METHODS: We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2's implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. RESULTS: In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin's protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells. CONCLUSION: Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI.

Purinergic Receptor Antagonists Inhibit Hemolysis Induced by Clostridium perfringens Alpha Toxin.

Clostridium perfringens alpha toxin (CPA), which causes yellow lamb disease in sheep and gas gangrene and food poisoning in humans, is produced by all types of C. perfringens and is the major virulence determinant of C. perfringens type A. CPA induces hemolysis in many species, including humans, murines, sheep and rabbits, through its enzymatic activity, which dissolves the cell membrane. Recent studies have shown that some pore-forming toxins cause hemolysis, which is achieved by the activation of purinergic receptors (P2). However, the relationship between P2 receptors and non-pore-forming toxin hemolysis has not been investigated. In the present study, we examined the function of P2 receptors in CPA toxin hemolysis and found that CPA-induced hemolysis was dependent on P2 receptor activation, and this was also true for Staphylococcus aureus ß-Hemolysin, another non-pore-forming toxin. Furthermore, we use selective P2 receptor antagonists to demonstrate that P2X1 and P2X7 play important roles in the hemolysis of human and murine erythrocytes. In addition, we found that redox metabolism was mainly involved in CPA-induced hemolysis using metabolomic analysis. We further demonstrate that CPA activates P2 receptors and then activates NADPH oxidase through the PI3K/Akt and MEK1/ERK1 pathways, followed by the production of active oxygen to induce hemolysis. These findings contribute to our understanding of the pathological effects of CPA, clarify the relationship between P2 activation and non-pore-forming toxin-induced hemolysis, and provide new insights into CPA-induced hemolysis.

Synchronously enhanced dual oxidation pathways via engineered Co-Nx/Co3O4 for high-efficiency degradation of versatile antibiotics.

Developing efficient and eco-friendly technologies for treating the antibiotic wastewaters is crucial. At present, the catalysts with metal-nitrogen (M-Nx) coordination showed excellent Fenton-like performance but were always difficult to realize practical antibiotics degradation because of their complicated preparation methods and inferior stability. In this work, the Co-Nx configuration was facilely reconstructed on the surface of Co3O4 (Co-Nx/Co3O4), which exhibited superior catalytic activity and stability towards various antibiotics. DFT results indicated that stronger ETP oxidation will be triggered by the electron-donating pollutants since more electrons can be easily migrated from these pollutants to the Co-Nx/Co3O4/PMS complex. The Co-Nx/Co3O4/PMS system could maintain superior oxidation capacity, high catalytic stability and anti-interference due to (i) the strong nonradical ETP oxidation with superior degradation selectivity in Co-Nx/Co3O4/PMS system, and (ii) the synchronously enhanced radical oxidation with high populations of non-selective radicals generated via activating PMS by the Co-Nx/Co3O4. As a result, the synergies of synchronously enhanced dual oxidation pathways guaranteed the self-cleaning properties, maintaining 98 % of activity after eight cycles and stability across a wide pH range. Basically, these findings have significant implications for developing technologies for purifying antibiotic wastewater.

Regioselective enzymatic depolymerization of aromatic-aliphatic polyester revealed by computational modelling.

Poly(butylene adipate-co-terephthalate) (PBAT) is widely utilized in the production of food packaging and mulch films. Its extensive application has contributed significantly to global solid waste, posing numerous environmental challenges. Recently, enzymatic recycling has emerged as a promising eco-friendly solution for the management of plastic waste. Here, we systematically investigate the depolymerization mechanism of PBAT catalyzed by cutinase TfCutSI with molecular docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations. Although the binding affinities for acid ester and terephthalic acid ester bonds are similar, a regioselective depolymerization mechanism and a "chain-length" effect on regioselectivity were proposed and evidenced. The regioselectivity is highly associated with specific structural parameters, namely Substrate@O4-Met@H7 and Substrate@C1-Ser@O1 distances. Notably, the binding mode of BTa captured by X-ray crystallography does not facilitate subsequent depolymerization. Instead, a previously unanticipated binding mode, predicted through computational analysis, is confirmed to play a crucial role in BTa depolymerization. This finding proves the critical role of computational modelling in refining experimental results. Furthermore, our results revealed that both the hydrogen bond network and enzyme's intrinsic electric field are instrumental in the formation of the final product. In summary, these novel molecular insights into the PBAT depolymerization mechanism offer a fundamental basis for enzyme engineering to enhance industrial plastic recycling.