Pharmacokinetics and safety of injected ornidazole compared to its enantiomer levornidazole in healthy Chinese subjects.

OBJECTIVE: To compare the pharmacokinetics of levornidazole and ornidazole in healthy Chinese subjects after a single intravenous injection, and to determine whether the chiral inversion of levornidazole occurs in vivo. MATERIALS AND METHODS: The study was a randomized, open-label, two-period crossover, single-dose design. A total of 12 subjects were enrolled in this study. Subjects received an intravenous injection of either levornidazole sodium chloride injection (200 mL: 0.5 g) or ornidazole sodium chloride injection (200 mL: 0.5 g) once per period. The plasma concentrations of levornidazole, ornidazole, and their metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Phenix WinNolin software (version 6.4) was used to calculate the pharmacokinetic parameters of levornidazole, ornidazole, and their metabolites. RESULTS: Dexornidazole was not detected in the plasma or urine. After a single intravenous injection of levornidazole or ornidazole, there was no significant difference in Cmax between the two drugs (p < 0.05). The AUC0-∞ and AUC0-t of levornidazole were slightly lower than those of ornidazole. Metabolites M1 and M4 were detected in the plasma of both drugs, and their pharmacokinetic parameters were similar. Metabolites M1, M2, and M4 were present in urine. The average cumulative urinary excretion rates of levornidazole and its metabolites M1 and M4 were: during 0 - 24 hours (8.14 ± 0.80%, 0.560 ± 0.072%, and 1.42 ± 0.19%) and 0 - 60 hours (10.5 ± 1.0%, 0.960 ± 0.084%, and 2.52 ± 0.20%), the average cumulative urinary excretion rates of ornidazole and its metabolites M1 and M4 were: 0 - 24 hours (8.64 ± 0.98%, 0.486 ± 0.074%, and 1.46 ± 0.21%), 0 - 60 hours (11.8 ± 1.0%, 0.888 ± 0.070%, and 2.76 ± 0.20%). The incidence of adverse reactions was similar between the two drugs. CONCLUSION: No chiral inversion of levornidazole occurred in vivo after intravenous administration of levornidazole. The pharmacokinetic parameters and cumulative excretion rates of levornidazole and ornidazole were similar. The safety results were basically consistent between the two drugs.

Effect of comprehensive nursing intervention on the efficacy of spleen aminopeptide combined with aerosol inhalation in the treatment of pediatric pneumonia.

Objective: To analyze the effect of comprehensive nursing intervention on the efficacy of spleen aminopeptide combined with aerosol inhalation in the treatment of pediatric pneumonia. Methods: This is a retrospective study. Eighty children with pneumonia admitted to Baoding children's Hospital from March 2020 to March 2021 were included and randomly divided into two groups. Children in the control group received routine treatment and nursing measures, while those in the experimental group received comprehensive nursing intervention on the basis of routine treatment in the control group. The differences in clinical effect, symptom improvement time, nursing quality score and satisfaction score between the two groups were compared and analyzed. Results: The efficacy of the experimental group was significantly higher than that of the control group (p=0.02). After comprehensive nursing intervention, the cough disappearance time, body temperature recovery time, pulmonary rales disappearance time and hospitalization time in the experimental group were significantly shorter than those in the control group, with statistically significant differences (p<0.05). The scores of nursing quality such as health guidance, nursing operation, and medication management in the experimental group were higher than those in the control group, with significant differences in the data comparison between the groups (p<0.05). The satisfaction of the experimental group was 100%, which was higher than 90% of the control group, with a statistically significant difference (p=0.04). Conclusion: Comprehensive nursing intervention boasts various significant effects in the treatment of pediatric pneumonia, such as rapid amelioration of the condition, improvement of efficacy, and enhancement of nursing quality and satisfaction.

Assessing the utility of the Xpert Mycobacterium tuberculosis/rifampin assay for analysis of bronchoalveolar lavage fluid in patients with suspected pulmonary tuberculosis.

BACKGROUND: There is limited research assessing the utility of the Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay for the analysis of bronchoalveolar lavage fluid (BALF) in Chinese patients with suspected pulmonary tuberculosis (PTB). Thus, our objective was to determine the diagnostic accuracy of the Xpert MTB/RIF assay and evaluate its utility for the determination of rifampicin resistance. METHODS: We retrospectively analyzed BALF from 214 patients with suspected PTB between January 2018 and March 2019. Using mycobacterial culture or final clinical diagnosis as the reference standard, the diagnostic accuracy of the smear microscopy (SM), tuberculosis bacillus DNA (TB-DNA), Xpert MTB/RIF assay, and the determination of rifampicin resistance based on the Xpert MTB/RIF assay were compared. RESULTS: As compared to mycobacterial culture, the sensitivity of the Xpert MTB/RIF assay, SM, and TB-DNA were 85.5% (74.2%-93.1%), 38.7% (26.6%-51.9%), and 67.7% (54.7%-79.1%), respectively. As compared to the final diagnosis, the specificity of the Xpert MTB/RIF assay, SM, and TB-DNA were 100.0% (95.9%-100.0%), 94.3% (87.1%-98.1%), and 98.9% (93.8%-100.0%), respectively. The sensitivity and specificity of the rifampicin resistance detection using the Xpert MTB/RIF assay were 100% and 98.0%, respectively, with liquid culture as the reference. CONCLUSIONS: This study demonstrates that the analysis of BALF with the Xpert MTB/RIF assay provides a rapid and accurate tool for the early diagnosis of PTB. The accuracy of diagnosis was superior compared with the SM and TB-DNA. Moreover, Xpert is a quick and accurate method for the diagnosis of rifampicin-resistant tuberculosis and can also provide more effective guidance for the treatment of PTB or multidrug-resistant tuberculosis (MDR-TB).

Diagnosing malignant pleural effusion using clinical and analytical parameters.

BACKGROUND: Malignant pleural effusion (MPE) is common and diagnosis is often problematic. A cancer ratio (serum lactate dehydrogenases: pleural adenosine deaminase ratio) has been proposed for diagnosing MPE. However, the usefulness of this "cancer ratio" and the clinical-radiological criteria for diagnosing MPE has not been clearly determined to date. The aim of this study was to assess the performance of those parameters in the diagnosis of MPE. METHODS: We analyzed 240 patients including 120 with MPE and 120 with non-MPE (93 tuberculous and 27 parapneumonic). Patients were divided into two groups: MPE and non-MPE (eg, tuberculous and parapneumonic). We constructed two predictive models to assess the probability of MPE: (a) clinical-radiological data only and (b) a combination of clinical-radiological data, the cancer ratio, and the carcinoembryonic antigen (CEA). The performances of the predictive models were assessed using receiver operating characteristic (ROC) curves and by examining the calibration. RESULTS: The area under the ROC curves for model 1 and model 2 were excellent, 0.936 and 0.998, respectively. The overall diagnostic accuracies for model 1 and model 2 were 87.5% and 98.8%, respectively. CONCLUSION: The results confirm that both models achieved a high diagnostic accuracy for MPE; however, model 2 was superior with the addition of its simplicity of use in daily practice. This model should be applied to determine which patients with a pleural effusion of unknown origin would not benefit from further invasive procedures.

5'-AMP-Activated Protein Kinase Regulates Goat Sperm Functions via Energy Metabolism In Vitro.

BACKGROUND/AIMS: ATP is essential for mammalian sperm to survive and maintain fertilizing capacity. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The aims of the present study were to explore the localization of AMPK in goat sperm and to investigate whether and how AMPK regulates sperm functions in vitro. METHODS: Sperm were treated with AMPK modulators (AICAR, metformin and Compound C) during incubation. Sperm motility was assessed with a computer-assisted spermatozoa analysis system (CASA). Membrane integrity, acrosome reaction and mitochondrial membrane potentials were detected by SYBR-14/PI, FITC-PNA and JC-1 staining, respectively. And the lactate content, ATP content, AMPK activity, activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) were also measured with the commercial assay kits. Immunofluorescence staining was used to analyze the distribution of PK, LDH, AMPK and phospho-Thr172-AMPK in sperm. The role of AMPK was further studied during induction of capacitation and acrosome reaction. RESULTS: We found that AMPKα was localized in the entire acrosomal region, the midpiece and the flagellum, while the phospho-Thr172-AMPK was distributed in the head, the midpiece and flagellum. Activation of AMPK by AICAR and metformin significantly improved sperm motility, membrane integrity and acrosome reaction, largely maintained sperm mitochondrial membrane potentials, lactate content and ATP content, and enhanced the activity of AMPK, PK and LDH, whereas inhibition by Compound C triggered the converse effects. Moreover, PK was localized in the acrosomal area and the midpiece, while LDH was distributed in the tail. Induction of capacitation and acrosome reaction led to AMPK phosphorylation. AMPK phosphorylation regulated the activity of energetic enzymes. CONCLUSION: This study for the first time provides evidence that AMPK governs goat sperm functions through energy metabolism in vitro. This finding will help to improve assisted reproductive techniques in goats and the other species.

Comparsion analysis of data mining models applied to clinical research in traditional Chinese medicine.

OBJECTIVE: To help researchers selecting appropriate data mining models to provide better evidence for the clinical practice of Traditional Chinese Medicine (TCM) diagnosis and therapy. METHODS: Clinical issues based on data mining models were comprehensively summarized from four significant elements of the clinical studies: symptoms, symptom patterns, herbs, and efficacy. Existing problems were further generalized to determine the relevant factors of the performance of data mining models, e.g. data type, samples, parameters, variable labels. Combining these relevant factors, the TCM clinical data features were compared with regards to statistical characters and informatics properties. Data models were compared simultaneously from the view of applied conditions and suitable scopes. RESULTS: The main application problems were the inconsistent data type and the small samples for the used data mining models, which caused the inappropriate results, even the mistake results. These features, i.e. advantages, disadvantages, satisfied data types, tasks of data mining, and the TCM issues, were summarized and compared. CONCLUSION: By aiming at the special features of different data mining models, the clinical doctors could select the suitable data mining models to resolve the TCM problem.

Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study.

OBJECTIVES: This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS: In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS: All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS: HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.

Lattice Strain Engineering on Metal-Organic Frameworks by Ligand Doping to Boost the Electrocatalytic Biomass Valorization.

As an efficient and environmental-friendly strategy, electrocatalytic oxidation can realize biomass lignin valorization by cleaving its aryl ether bonds to produce value-added chemicals. However, the complex and polymerized structure of lignin presents challenges in terms of reactant adsorption on the catalyst surface, which hinders further refinement. Herein, NiCo-based metal-organic frameworks (MOFs) are employed as the electrocatalyst to enhance the adsorption of reactant molecules through π-π interaction. More importantly, lattice strain is introduced into the MOFs via curved ligand doping, which enables tuning of the d-band center of metal active sites to align with the reaction intermediates, leading to stronger adsorption and higher electrocatalytic activity toward bond cleavage within lignin model compounds and native lignin. When 2'-phenoxyacetophenone is utilized as the model compound, high yields of phenol (76.3%) and acetophenone (21.7%) are achieved, and the conversion rate of the reactants reaches 97%. Following pre-oxidation of extracted poplar lignin, >10 kinds of phenolic compounds are received using the as-designed MOFs electrocatalyst, providing ≈12.48% of the monomer, including guaiacol, vanillin, eugenol, etc., and p-hydroxybenzoic acid dominates all the products. This work presents a promising and deliberately designed electrocatalyst for realizing lignin valorization, making significant strides for the sustainability of this biomass resource.

Development and validation of a prediction model for gastric cancer: a single-center prospective study.

OBJECTIVE: This study aimed to develop and validate a novel nomogram for diagnosing gastric cancer (GC). METHODS: In this prospective analysis, 146 patients of Wenzhou Central Hospital were recruited for a GC group and a benign lesion group and were divided into a training set and an internal validation set in a ratio of 7:3. Clinical and analytical characteristics were collected and analyzed by logistic regression analysis. The performance of the predictive model was evaluated using the receiver operating characteristic curve, calibration curve, and decision curve analysis. RESULTS: There were 5 variables, namely albumin, carcinoembryonic antigen, carbohydrate antigen 125, creatinine, and small proline-rich protein 2A, that were identified as the final parameters for the developed model. In the training and internal validation sets, the area under the curve of the model was 0.968 and 0.979, respectively, showing good diagnostic performance. CONCLUSION: This study developed and validated a new nomogram based on 5 parameters. This model shows good diagnostic performance in distinguishing GC from benign lesion groups and has certain significance in clinical application.

Enhancing antitumor efficacy of oncolytic virus M1 via albendazole-sustained CD8+ T cell activation.

The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8+ T cells within the tumor, downregulated the expression of PD1 on CD8+ T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-γ, granzyme B, and tumor necrosis factor (TNF)-α. Consistently, it enhanced the in vitro tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8+ T cells, suggesting a CD8+ T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy in vivo. In summary, Albendazole can act synergistically with oncolytic viruses via CD8+ T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.

Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

[Study on method for formulating clinical practice guidelines of common Chinese patent medicines based on clinical practices].

The clinical application of Chinese patent medicines has suffered sever problems and required guidelines for clinical practices. Currently, the expert consensus method is more suitable for formulating clinical practice guidelines of Chinese patent medicines than the evidence-based method. However, there remain problems in the application of the expert consensus method. This study proposed a derivative expert consensus method--a method for formulating clinical practice guidelines of common Chinese patent medicines based on clinical practices, and introduced the method in terms of research thought, methodology and implementation procedure.

Ca(ClO)2 pretreatment enhancing suspended solids removal through flocculation from digested dairy wastewater and its mechanisms.

Intensive animal farming produces large volume of digested liquid, and overdose application often causes the pollution of surface water and groundwater. Therefore, post-treatment is very necessary for the discharging of surplus digested liquid, but the removal of high concentrations of suspended solids (SS) in the digested liquid is a challenge. In this study, the effect of Ca(ClO)2 pretreatment on SS flocculation removal of digested dairy wastewater was investigated. The results showed that, without Ca(ClO)2 pretreatment, the flocculation by polyacrylamide (PAM), polyferric sulfate (PFS) or polymeric aluminum chloride (PAC) only removed 42.6 %-50.4 % SS from anaerobic digested liquid. With the combination of Ca(ClO)2 pretreatment and PAC flocculation together, the SS removal efficiency can reach 80 %. The total chemical oxygen demand (TCOD) removal had a similar trend with SS removal, but soluble chemical oxygen demand (SCOD) removal was less affected by the pretreatment and flocculation. More than 75 % of orthophosphate (SRP) and total soluble phosphorus (TSP) was removed after Ca(ClO)2 pretreatment and flocculation with PFS or PAC. Ca(ClO)2 pretreatment also effectively inactivated fecal bacteria. The mechanisms of Ca(ClO)2 pretreatment enhancing SS flocculation removal were further elucidated. The SS removal was the action of ClO- and Ca2+ together. The function of ClO- was to break down suspended particles, change the surface, and decrease the absolute Zeta potential, while the function of Ca2+ was to form precipitation. This result indicates that Ca(ClO)2 pretreatment can effectively enhance the SS flocculation removal of anaerobic digested liquid.

Sponge-like nano-system suppresses tumor recurrence and metastasis by restraining myeloid-derived suppressor cells-mediated immunosuppression and formation of pre-metastatic niche.

Tumor recurrence and metastasis still greatly limit the therapeutic efficiency on the majority of postoperative clinical cases. With the aim to realize more powerful treatment outcomes on postoperative malignant tumors, a sponge-like neutrophil membrane-coated nano-system (NM/PPcDG/D) was fabricated to inhibit tumor recurrence and metastasis by inhibiting the recruitment and functions of myeloid-derived suppressor cell (MDSCs), which reinforced anti-tumor immunity and also suppressed pulmonary metastasis by inhibiting the formation of pre-metastatic niche (PMN). Firstly, PPcDG/D nanoparticles (NPs) were formulated by the self-assembling and crosslinking of synthesized redox-responsive polymer (PPDG) with doxorubicin (DOX) loading in the nanocore (PPcDG/D), followed by coating with activated neutrophils membrane to fabricate biomimetic NM/PPcDG/D. The sponge-like NM/PPcDG/D not only showed obvious natural tropism to postoperative inflammatory site, but also inhibited the recruitment and functions of MDSCs, thus relieved MDSCs-mediated immunosuppression. Additionally, NM/PPcDG/D also suppressed the formation of PMN to inhibit pulmonary metastasis by reducing the recruitment of MDSCs, decreasing the permeability of pulmonary vessels and inhibiting the implantation of circulating tumor cell (CTCs). Eventually, this fabricated NM/PPcDG/D NPs significantly inhibited tumor recurrence and metastasis on postoperative triple negative breast cancer (TNBC) model, presenting a promising therapeutic strategy on postoperative malignant tumors. STATEMENT OF SIGNIFICANCE: Myeloid-derived suppressor cells (MDSCs) play important roles in accelerating tumor recurrence and metastasis by promoting the establishment of immunosuppression in postoperative inflammatory regions and facilitating the formation of pulmonary pre-metastasis niche (PMN). In order to achieve enhanced suppression of recurrence and metastasis, a sponge-like NM/PPcDG/D nano-system was designed and fabricated. This nano-system is also the first attempt to integrate the regulation effects of a nano-sponge and anti-inflammatory agent to achieve enhanced multi-mode manipulation of MDSCs. Ultimately, NM/PPcDG/D powerfully restrained the recurrence and spontaneous metastasis on TNBC model. This article also revealed the particular roles of MDSCs involved in the regulation networks of postoperative recurrence and metastasis, immunosuppression and inflammation.

Co-precipitation of heavy metals with struvite from digested swine wastewater: Role of suspended solids.

Struvite production can recover ammonia and phosphorous from digested wastewater as fertilizer. During struvite generation, most of the heavy metals was co-precipitated with ammonia and phosphorous into struvite. Understanding the precipitation behavior of heavy metals with suspended solids (SS) might provide the possible strategy for the control of co-precipitation. In this study, the distribution of heavy metals in SS and their role on the co-precipitation during struvite recovery from digested swine wastewater were investigated. The results showed that the concentration of heavy metal (including Mn, Zn, Cu, Ni, Cr, Pb and As) ranged from 0.05 to 17.05 mg/L in the digested swine wastewater. The distribution analysis showed that SS with particles > 50 µm harbored most of individual heavy metal (41.3-55.6%), followed by particles 0.45-50 µm (20.9-43.3%), and SS-removed filtrate (5.2-32.9%). During struvite generation, 56.9-80.3% of individual heavy metal was co-precipitated into struvite. The contributions of SS with particles > 50 µm, 0.45-50 µm, and SS-removed filtrate on the individual heavy metal co-precipitation were 40.9-64.3%, 25.3-48.3% and 1.9-22.9%, respectively. These finding provides potential way for controlling the co-precipitation of heavy metals in struvite.

Role of suspended solids on the co-precipitation of pathogenic indicators and antibiotic resistance genes with struvite from digested swine wastewater.

Struvite recovered from wastewater contains high concentration of fecal indicator bacteria (FIB), porcine adenoviruses (PAdV) and antibiotic resistance genes (ARGs), becoming potential resources of these microbial hazards. Understanding the precipitation behavior of pathogenic indicators and ARGs with suspended solids (SS) will provide the possible strategy for the control of co-precipitation. In this study, SS was divided into high-density SS (separated by centrifugation) and low-density SS (further separated by filtration), and the role of SS on the co-precipitation of FIB, PAdV and ARGs was investigated. The distribution analysis showed that 35.5-73.0% FIB, 79.6% PAdV and 64.5-94.8% ARGs existed in high-density SS, while the corresponding values were 26.9-64.4%, 11.7% and 3.5-24.3% in low-density SS. During struvite generation, 82.7-96.9% FIB, 75.5% PAdV and 56.3-86.5% ARGs were co-precipitated into struvite. High-density SS contributed 20.7-68.5% FIB, 63.9% PAdV and 38.7-87.2% ARGs co-precipitation, and the corresponding contribution of low-density SS was 31.4-79.2%, 3.9% and 6.2-54.7%. Moreover, the precipitated SS in struvite obviously decreased inactivation efficiency of FIB and ARGs in drying process. These results provide a potential way to control the co-precipitation and inactivation of FIB, PAdV and ARGs in struvite through removing high-density SS prior to struvite recovery.

Autophagy-Interfering Nanoboat Drifting along CD44-Golgi-ER Flow as RNAi Therapeutics for Hepatic Fibrosis.

The upregulated autophagy fuels the activation of hepatic stellate cells (HSCs) to promote hepatic fibrosis. However, the lack of specific inhibitors targeting autophagy and high requirements for cell targeting impede the application of antifibrotic therapy that targets autophagy. RNA interference (RNAi)-based short interfering RNA (siRNA) provides an approach to specifically inhibit autophagy. The therapeutic potential of siRNA, however, is far from being exploited due to the lack of safe and effective delivery vehicles. The cytoplasmic delivery of siRNA is essential for RNAi, and the intracellular trafficking pathway of vehicles determines the fate of siRNA. Unfortunately, the lysosomal degradation pathway, the intracellular fate of most gene vehicles, impedes RNAi efficiency. Inspired by the trafficking pathway of some viruses infecting cells, KDEL-grafted chondroitin sulfate (CK) was designed to alter the intracellular delivery fate of siRNA. The well-designed CD44-Golgi-ER trafficking pathway of CK was realized by triple cascade targeting including (1) CD44 targeting mediated by chondroitin sulfate, (2) Golgi apparatus targeting mediated by the caveolin-mediated endocytic pathway, and (3) endoplasmic reticulum (ER) targeting mediated by coat protein I (COP I) vesicles. CK was adsorbed on the complex of cationic liposomes (Lip) encapsulating siRNA targeting autophagy-related gene 7 (siATG7) to afford Lip/siATG7/CK. Lip/siATG7/CK functions as a drifting boat that follows the CD44-Golgi-ER flow and travels downstream to its destination (ER), bypassing the lysosomal degradation pathway and endowing HSCs with excellent RNAi efficiency. The efficient downregulation of ATG7 leads to an excellent antifibrotic effect both in vitro and in vivo.

Electrocatalytic Lignin Valorization into Aromatic Products via Oxidative Cleavage of Cα-Cß Bonds.

Lignin is the most promising candidate for producing aromatic compounds from biomass. However, the challenge lies in the cleavage of C-C bonds between lignin monomers under mild conditions, as these bonds have high dissociation energy. Electrochemical oxidation, which allows for mild cleavage of C-C bonds, is considered an attractive solution. To achieve low-energy consumption in the valorization of lignin, the use of highly efficient electrocatalysts is essential. In this study, a meticulously designed catalyst consisting of cobalt-doped nickel (oxy)hydroxide on molybdenum disulfide heterojunction was developed. The presence of molybdenum in a high valence state promoted the adsorption of tert-butyl hydroperoxide, leading to the formation of critical radical intermediates. In addition, the incorporation of cobalt doping regulated the electronic structure of nickel, resulting in a lower energy barrier. As a result, the heterojunction catalyst demonstrated a selectivity of 85.36% for cleaving the Cα-Cß bond in lignin model compound, achieving a substrate conversion of 93.69% under ambient conditions. In addition, the electrocatalyst depolymerized 49.82 wt% of soluble fractions from organosolv lignin (OL), resulting in a yield of up to 13 wt% of aromatic monomers. Significantly, the effectiveness of the prepared electrocatalyst was also demonstrated using industrial Kraft lignin (KL). Therefore, this research offers a practical approach for implementing electrocatalytic oxidation in lignin refining.

A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer.

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3ß signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects.

Background: Sotagliflozin (LX4211) is a dual inhibitor of sodium-glucose cotransporter (SGLT)1 and SGLT2 being investigated to improve glycemic control in adults with diabetes. This study was firstly conducted to assess the pharmacokinetic (PK), pharmacodynamic (PD) profiles, safety and tolerability in Chinese healthy subjects after administration of sotagliflozin. Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotagliflozin or placebo once daily for 8 days, respectively. PK parameters of sotagliflozin and LX4211-GLU (main metabolite), as measured by blood samples collected pre/postdose on Day 1/predose on Day 2-Day 8/postdose on Day 8, and PD parameters of absolute urinary glucose excretion (UGE) were determined. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Overall, 24 subjects were enrolled and randomized to sotagliflozin 200 mg (N = 9), sotagliflozin 400 mg (N = 9), or placebo (N = 6) group, and all subjects completed the study. Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree (less than 2-fold) of accumulation. Sotagliflozin plasma concentrations peaked at 1.0 h post dose. On Day 8, the estimated increases for Cmax and AUCtau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotagliflozin was 1.57 for Cmax and 1.84 for AUCtau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotagliflozin groups relative to the placebo group. All TEAEs were mild and resolved without sequelae. There were no serious AEs or other significant TEAEs. Conclusion: Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree of accumulation. Both 200 mg and 400 mg sotagliflozin per day were well tolerated in Chinese healthy subjects.