High-performance flexible resistive random-access memory based on SnS2 quantum dots with a charge trapping/de-trapping effect.

The application of resistive random-access memory (RRAM) in storage and neuromorphic computing has attracted widespread attention. Benefitting from the quantum effect, transition metal dichalcogenides (TMD) quantum dots (QDs) exhibit distinctive optical and electronic properties, which make them promising candidates for emerging RRAM. Here, we show a high-performance forming-free flexible RRAM based on high-quality tin disulfide (SnS2) QDs prepared by a facile liquid phase method. The RRAM device demonstrates high flexibility with a large on/off ratio of ∼106 and a long retention time of over 3 × 104 s. The excellent switching behavior of the memristor is elucidated by a charge trapping/de-trapping mechanism where the SnS2 QDs act as charge trapping centers. This study is of significance for the understanding and development of TMD QD-based flexible memristors.

Natural Prenylflavonoids from Sophora flavescens Root Bark against Multidrug-Resistant Methicillin-Sensitive Staphylococcus aureus Targeting the Membrane Permeability.

The overuse of antibiotics in animal farming and aquaculture has led to multidrug-resistant methicillin-sensitive Staphylococcus aureus (MR-MSSA) becoming a common pathogen in foodborne diseases. Sophora flavescens Ait. serves as a traditional plant antibacterial agent and functional food ingredient. A total of 30 compounds (1-30) were isolated from the root bark of S. flavescens, consisting of 20 new compounds (1-20). In the biological activity assay, compound 1 demonstrated a remarkable inhibitory effect on MR-MSSA, with an MIC of 2 µg/mL. Furthermore, 1 was found to rapidly eliminate bacteria, inhibit biofilm growth, and exhibit exceptionally low cytotoxicity. Mechanistic studies have revealed that 1 possesses an enhanced membrane-targeting ability, binding to the bacterial cell membrane components phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and cardiolipin (CL). This disruption of bacterial cell membrane integrity increases intracellular reactive oxygen species, protein and DNA leakage, reduced bacterial metabolism, and ultimately bacterial death. In summary, these findings suggest that compound 1 holds promise as a lead compound against MR-MSSA.

Two undescribed constituents from Salvia castanea Diels and evaluation of their cytotoxic activity.

One previously undescribed abietane diterpene alkaloid containing an oxazole ring (1), one unreported abietane diterpene (2), and nine known abietane diterpenes (3-11) were isolated from the roots and rhizomes of Salvia castanea Diels. Their structures and absolute configurations were elucidated by a combination of HRESIMS, 1D and 2D NMR, and ECD. All compounds were evaluated for their cytotoxic activity against several human cancer cell lines (HepG2, A549, H460, MCF7, PC3, and Hela). The results showed that 1 exhibited a moderate cytotoxic effect on HepG2 cells (IC50: 14.22 ± 1.05 µM) and was able to inhibit the cell growth of MCF7 and Hela cells by 35.08% and 47.26% respectively, at a concentration of 20 µM, while other compounds showed low cytotoxic activity.

Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

Salvirrane A-F, six undescribed nordrimane sesquiterpene derivatives from Salvia castanea Diels f. tomentosa Stib and their cytotoxic activities.

Six undescribed nordrimane sesquiterpene derivatives, salvirrane A-F (1-6), were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Comprehensive spectral analysis and a quantum chemical calculation strategy were employed to determine their structures. These compounds represent four previously unreported nordrimane carbon skeletal types in Salvia genus, including 15-nor-drimane, 11,15-di-nor-drimane, 14,15-di-nor-drimane, and 11,14,15-tri-nor-drimane sesquiterpenes. All compounds were evaluated for their cytotoxic activities against several human cancer cell lines (A549, H460, Hep3B, MCF7, PC3, and HeLa). The results showed that 3 exhibited low activity against MCF7 cells (IC50,72.72 ± 6.95 µM) and moderate activity against HeLa cells (IC50, 9.80 ± 0.64 µM). Moreover, the EdU (5-ethynyl-2'-deoxyuridine) assay demonstrates that 3 displays dose-dependent efficacy in suppressing the proliferation of HeLa cells. Network pharmacology and molecular docking technology implied that 3 may potentially bind to Src (proto-oncogene tyrosine-protein kinase) to exert anti-proliferative activity.

(±)-Salvicatone A: A Pair of C27-Meroterpenoid Enantiomers with Skeletons from the Roots and Rhizomes of Salvia castanea Diels f. tomentosa Stib.

(±)-Salvicatone A (1), a C27-meroterpenoid featuring a unique 6/6/6/6/6-pentacyclic carbon skeleton with a 7,8,8a,9,10,10a-hexahydropyren-1 (6H)-one motif, was isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Its structure was characterized by comprehensive spectroscopic analyses along with computer-assisted structure elucidation, including ACD/structure elucidator and quantum chemical calculations with 1H/13C NMR and electronic circular dichroism. Biogenetically, compound 1 was constructed from decarboxylation following [4 + 2] Diels-Alder cycloaddition reaction between caffeic acid and miltirone analogue. Bioassays showed that (-)-1 and (+)-1 inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophage cells with an IC50 value of 6.48 ± 1.25 and 15.76 ± 5.55 µM, respectively. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking and molecular dynamics simulations study, implied that (-)-1 and (+)-1 may potentially bind to retinoic acid receptor-related orphan receptor C to exert anti-inflammatory activities.

Two new sesquiterpenoids with glycosides from the leaves and stems of Schisandra chinensis (Turcz.) Baill.

Two previously undescribed glycosidic bisnorsesquiterpenoids A - B (1 - 2), together with two known compounds (3 - 4), were isolated from the leaves and stems of Schisandra chinensis. Their structures were elucidated by extensive spectroscopic data (1D, 2D NMR, and HRESIMS). The anti-inflammatory activity, ABTS+ radical scavenging activity, and DPPH radical scavenging activity of compounds 1 - 4 were tested. However, all of these compounds showed only weak anti-inflammatory or antioxidant effects.

Head-to-head comparison of azvudine and nirmatrelvir/ritonavir for the hospitalized patients with COVID-19: a real-world retrospective cohort study with propensity score matching.

Background: Nirmatrelvir/ritonavir and azvudine have been approved for the early treatment of COVID-19 in China, however, limited real-world data exists regarding their effectiveness and safety. Methods: We conducted a retrospective cohort study involving the hospitalized COVID-19 patients in China between December 2022 and January 2023. Demographic, clinical, and safety variables were recorded. Results: Among the 6,616 hospitalized COVID-19 patients, we included a total of 725 patients including azvudine recipients (N = 461) and nirmatrelvir/ritonavir (N = 264) recipients after exclusions and propensity score matching (1:2). There was no significant difference in the composite disease progression events between azvudine (98, 21.26%) and nirmatrelvir/ritonavir (72, 27.27%) groups (p = 0.066). Azvudine was associated with a significant reduction in secondary outcomes, including the percentage of intensive care unit admission (p = 0.038) and the need for invasive mechanical ventilation (p = 0.035), while the in-hospital death event did not significantly differ (p = 0.991). As for safety outcomes, 33 out of 461 patients (7.16%) in azvudine group and 22 out of 264 patients (8.33%) in nirmatrelvir/ritonavir group experienced drug-related adverse events between the day of admission (p = 0.565). Conclusion: In our real-world setting, azvudine treatment demonstrated similar safety compared to nirmatrelvir/ritonavir in hospitalized COVID-19 patients. Additionally, it showed slightly better clinical benefits in this population. However, further confirmation through additional clinical trials is necessary.

Genome-wide identification of DUF506 gene family in Oryzasativa and expression profiling under abiotic stresses.

The domain of unknown function 560 (DUF560), also known as the PDDEXK_6 family, is a ubiquitous plant protein that has been confirmed to play critical roles in Arabidopsis root development as well as ABA and abiotic responses. However, genome-wide identification and expression pattern analysis in rice (Oryza sativa) still need to be improved. Based on the phylogenetic relationship, 10 OsDUF506 genes were identified and classified into four subfamilies. Segmental duplication was essential to the expansion of OsDUF506s, which were subjected to purifying selective pressure. Except for OsDUF50609 and OsDUF50610, the OsDUF506s shared colinear gene pairs with five monocot species, showing that they were conserved in evolution. Furthermore, the conserved domains, gene structures, SNPs distribution, and targeting miRNAs were systematically investigated. Massive cis-regulatory elements were discovered in promoter regions, implying that OsDUF506s may be important in hormone regulation and abiotic stress response. Therefore, we analyzed plant hormone-induced transcriptome data and performed qRT-PCR on eight OsDUF506s under drought, cold, and phosphorus-deficient stresses. The results revealed that most OsDUF506s respond to ABA and JA treatment, as well as drought and cold conditions. In conclusion, our findings provided insights into the evolution and function of OsDUF506s, which could benefit crop breeding in the future.

Effects of early aquatic exercise intervention on trunk strength and functional recovery of patients with lumbar fusion: a randomized controlled trial.

This study investigated the effectiveness of an early aquatic exercise program on trunk muscle function and functional recovery of patients with lumbar fusion. Twenty-eight subjects were divided into two equal groups. Patients in the aquatic group performed two 60-min aquatic exercise sessions and three 60-min home exercise sessions per week for 6 weeks, whereas those in the control group performed five sessions of 60-min home exercises per week for 6 weeks. The primary outcomes were the Numerical Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI), and the secondary outcomes were Timed Up and Go Test (TUGT), trunk flexor and extensor muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness measured pre- and post-intervention. Compared with participants in the control group, those in the experimental group showed significant improvement in NPRS, ODI, trunk extensor strength, lumbopelvic control, lumbar multifidus muscle thickness, and relative change in multifidus muscle thickness (significant time by group interactions, P < 0.05). Participants in both groups showed significant time effects (P < 0.001) for TUGT and trunk flexor strength outcome. Aquatic exercise combined with home exercise was superior to home exercise alone in reducing pain, disability and improving muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness.

An integrated network pharmacology approach reveals that Darutigenol reduces inflammation and cartilage degradation in a mouse collagen-induced arthritis model by inhibiting the JAK-STAT3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Darutigenol (DL) is a natural active product derived from the Chinese herbal medicine Sigesbeckia glabrescens (Makino) Makino. It is administered as a traditional Chinese medicine (TCM) to dispel rheumatism, benefit the joints, and detoxify. However, its potential mechanism in the treatment of rheumatoid arthritis (RA) remains unknown. AIMS OF THE STUDY: The objectives of this research were to determine the effects and elucidate the modes of action of DL on RA-related joint inflammation. MATERIALS AND METHODS: Network pharmacology and molecular docking were used to screen and validate candidate DL targets for RA treatment, respectively. A DBA/1 mouse rheumatoid arthritis model was induced with bovine type II collagen. Intragastric DL administration was followed by the calculation of the clinical arthritis index. A section of the ankle joint was excised and stained and the pathological changes in it were observed. Enzyme-linked immunosorbent assays (ELISA) and western blotting (WB) were used to clarify the mechanisms of DL in RA treatment. RESULTS: DL effectively attenuated the inflammation, mitigated the articular cartilage degradation, and bone erosion, and alleviated the inflammatory joints associated with RA. Network pharmacology screened six key targets of DL while molecular docking revealed that it docked well with its protein targets. The DL treatment group presented with significantly less ankle joint redness and swelling, a lower arthritis index scores and serum and bone marrow supernatant IL-6 levels, more complete ankle joint surfaces, and less synovial inflammation, cartilage degradation, and bone erosion than the collagen-induced arthritis (CIA) group. The DL treatment also substantially downregulated the Janus kinase (JAK)1, JAK3, matrix metalloproteinase (MMP)2, MMP9, and phospho-signal transducer and activator of transcription (p-STAT)3 proteins in the joints. CONCLUSIONS: To the best of our knowledge, the present work was the first to demonstrate that DL has significant anti-inflammatory efficacy and reduces cartilage degradation and bone erosion. It also demonstrated that the anti-RA effect of DL may be explained by its ability to inhibit joint inflammation and reduce articular cartilage degradation through the interleukin (IL)-6/JAK1,3/STAT3 axis and downregulate MMP2 and MMP9. Hence, DL might play a therapeutic role in a mouse RA model.

Clinical, economic and humanistic outcomes of medication therapy management services: A systematic review and meta-analysis.

Background: Medication therapy management (MTM) services is a method that can effectively improve patients' conditions, but the efficacy of economic and humanistic outcomes remain unclear. This systematic review and meta-analysis aim to use economic, clinical and humanistic outcomes to evaluate the multi-benefits of MTM services. Method: A systematic review and meta-analysis was conducted by retrieving PubMed, EMBASE, the Cochrane Library and ClinicalTrial.gov from the inception to April 2022. There were two reviewers screening the records, extracting the data, and assessing the quality of studies independently. Results: A total of 81 studies with 60,753 participants were included. MTM services were more effective in clinical outcomes with decreasing the rate of readmission (OR: 0.78; 95% CI: 0.73 to 0.83; I2 = 56%), emergency department visit (OR: 0.88; 95% CI: 0.81 to 0.96; I2 = 32%), adverse drug events (All-cause: OR: 0.68; 95% CI: 0.56 to 0.84; I2 = 61%; SAE: OR: 0.51; 95% CI: 0.33 to 0.79; I2 = 35%) and drug-related problems (MD: -1.37; 95% CI: -2.24 to -0.5; I2 = 95%), reducing the length of stay in hospital (MD: -0.74; 95% CI: -1.37 to -0.13; I2 = 70%), while the economic and humanistic outcomes were less effective. Conclusion: Our systematic review and meta-analysis demonstrated that MTM services had great ability to improve patients' clinical conditions while the efficacy of economic and humanistic outcomes, with some of the outcomes showing high degree of heterogeneity and possible publication bias, required more future studies to provide stronger evidence. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349050], identifier [CRD42022349050].

Modulating Catalytic Activity and Stability of Atomically Precise Gold Nanoclusters as Peroxidase Mimics via Ligand Engineering.

Metal nanoclusters (NCs), composed of a metal core and protecting ligands, show promising potentials as enzyme mimics for producing fuels, pharmaceuticals, and valuable chemicals, etc. Herein, we explore the critical role of ligands in modulating the peroxidase mimic activity and stability of Au NCs. A series of Au15(SR)13 NCs with various thiolate ligands [SR = N-acetyl-l-cysteine (NAC), 3-mercaptopropionic acid (MPA), or 3-mercapto-2-methylpropanoic acid (MMPA)] are utilized as model catalysts. It is found that Au15(NAC)13 shows higher structural stability than Au15(MMPA)13 and Au15(MPA)13 against external stimuli (e.g., pH, oxidants, and temperature) because of the intramolecular hydrogen bonds. More importantly, detailed enzymatic kinetics data show that the catalytic activity of Au15(NAC)13 is about 4.3 and 2.7 times higher than the catalytic activity of Au15(MMPA)13 and Au15(MPA)13, respectively. Density functional theory (DFT) calculations reveal that the Au atoms on the motif of Au NCs should be the active centers, whereas the superior peroxidase mimic activity of Au15(NAC)13 should originate from the emptier orbitals of Au atoms because of the electron-withdrawing effect of acetyl amino group in NAC. This work demonstrates the ligand-engineered electronic structure and functionality of atomically precise metal NCs, which afford molecular and atomic level insights for artificial enzyme design.

Lpp of Escherichia coli K1 inhibits host ROS production to counteract neutrophil-mediated elimination.

Escherichia coli (E. coli) is the most common Gram-negative bacterial organism causing neonatal meningitis. The pathogenesis of E. coli meningitis, especially how E. coli escape the host immune defenses, remains to be clarified. Here we show that deletion of bacterial Lpp encoding lipoprotein significantly reduces the pathogenicity of E. coli K1 to induce high-degree of bacteremia necessary for meningitis. The Lpp-deleted E. coli K1 is found to be susceptible to the intracellular bactericidal activity of neutrophils, without affecting the release of neutrophil extracellular traps. The production of reactive oxygen species (ROS), representing the primary antimicrobial mechanism in neutrophils, is significantly increased in response to Lpp-deleted E. coli. We find this enhanced ROS response is associated with the membrane translocation of NADPH oxidase p47phox and p67phox in neutrophils. Then we constructed p47phox knockout mice and we found the incidence of bacteremia and meningitis in neonatal mice induced by Lpp-deleted E. coli is significantly recovered by p47phox knockout. Proteomic profile analysis show that Lpp deficiency induces upregulation of flagellar protein FliC in E. coli. We further demonstrate that FliC is required for the ROS induction in neutrophils by Lpp-deleted E. coli. Taken together, these data uncover the novel role of Lpp in facilitating intracellular survival of E. coli K1 within neutrophils. It can be inferred that Lpp of E. coli K1 is able to suppress FliC expression to restrain the activation of NADPH oxidase in neutrophils resulting in diminished bactericidal activity, thus protecting E. coli K1 from the elimination by neutrophils.

Antiproliferative ent-abietane diterpenoids from Euphorbia fischeriana.

Euphorfinoids M and N (1 and 2), two previously undescribed ent-abietane diterpenoids, together with seven known analogues (3-9), were isolated from the roots of wild Euphorbia fischeriana. Their structures were elucidated by spectroscopic analysis, including extensive NMR, HR-ESIMS, ECD, and comparison with structurally related known analogues. Bioassays against proliferative effects of HeLa cell line showed that compound 1 was the most active with IC50 3.62 ± 0.31 µM.

Euphorfinoids A and B, a pair of ent-atisane diterpenoid epimers from the roots of Euphorbia fischeriana, and their bioactivities.

Euphorfinoids A and B (1 and 2), a pair of ent-atisane diterpenoid epimers with a vicinal 2,3-diol moiety, together with four known analogues (3-6), were isolated from the roots of wild Euphorbia fischeriana. Their structures were elucidated by spectroscopic analysis, including extensive NMR, HR-ESIMS, NMR calculations, X-ray diffraction, and comparison with structurally related known analogues. Our bioassays have established that compound 1 displayed moderate anti-proliferative effects on Hcc1806 cell line with IC50 15.53 ± 0.21 µM, and compound 5 showed remarkable inhibitory effects against AChE with IC50 32.56 ± 2.74 µM by an in vitro screened experiment.

Diterpenoids from Sigesbeckia glabrescens with anti-inflammatory and AChE inhibitory activities.

Fourteen previously undescribed diterpenoids, including seven ent-pimarane-type diterpenoids and seven phytane-type diterpenes, together with five known ones, were isolated from the aerial parts of Sigesbeckia glabrescens. The structures and absolute configurations of undescribed compounds were elucidated based on extensive spectroscopic techniques, ECD calculations, Mo2(OAC)4-induced ECD, Rh2(OCOCF3)4-induced ECD, calculated 13C NMR, and chemical methods. In the anti-inflammatory bioassay, siegetalis H showed potent inhibitory effect on LPS-induced NO production in RAW264.7 murine macrophages with an IC50 value at 17.29 µM. Furthermore, siegetalis H suppressed the protein expression of iNOS and COX-2 in LPS-stimulated RAW264.7 cells. Mechanistically, siegetalis H suppressed the phosphorylation and degradation of IκBα, as well as the activation of the NF-κB signaling pathway. In addition, the AChE inhibition assay displayed that 3-O-acetyldarutigenol had a remarkable inhibitory effect against AChE with an IC50 value at 7.02 µM. Kinetic study on 3-O-acetyldarutigenol indicated that it acted as a mixed-type inhibitor, and the binding mode was explored by molecular docking.

[Advances in traditional Chinese medicine treatment of non-alcoholic fatty liver disease via farnesoid X receptor].

Non-alcoholic fatty liver disease(NAFLD) is a chronic metabolic condition with rapidly increasing incidence, becoming a public health issue of worldwide concern. Studies have shown that farnesoid X receptor(FXR)-based modulation of downstream targets can improve liver function and metabolic status in the patients with NAFLD and may be a potential drug target for treating this di-sease. Great progress has been achieved in the development of drugs targeting FXR for the treatment of NAFLD. A number of studies have explored the traditional Chinese medicine and their active ingredients for the treatment of NAFLD via FXR considering the high safety and efficacy and mild side effects. This paper systematically describes the mechanism of traditional Chinese medicines in the treatment of NAFLD via FXR and the downstream targets, aiming to provide precise targets for the drug development and clinical treatment of NAFLD.

Advances in traditional Chinese medicine treatment of non-alcoholic fatty liver disease via farnesoid X receptor / 中国中药杂志

Non-alcoholic fatty liver disease(NAFLD) is a chronic metabolic condition with rapidly increasing incidence, becoming a public health issue of worldwide concern. Studies have shown that farnesoid X receptor(FXR)-based modulation of downstream targets can improve liver function and metabolic status in the patients with NAFLD and may be a potential drug target for treating this di-sease. Great progress has been achieved in the development of drugs targeting FXR for the treatment of NAFLD. A number of studies have explored the traditional Chinese medicine and their active ingredients for the treatment of NAFLD via FXR considering the high safety and efficacy and mild side effects. This paper systematically describes the mechanism of traditional Chinese medicines in the treatment of NAFLD via FXR and the downstream targets, aiming to provide precise targets for the drug development and clinical treatment of NAFLD.

[Prevention and treatment of non-alcoholic fatty liver disease by regulation of mitochondrial function with Chinese medicine].

Non-alcoholic fatty liver disease(NAFLD), as a metabolic stress liver injury disease, is one of the most common chronic liver diseases, which seriously threatens people's health. The pathogenesis of NAFLD is very complex. A large number of studies show that the hepatic mitochondrial dysfunction leads to the disorder of hepatic glucose and lipid metabolism, oxidative stress, and inflammation, thus inducing hepatocyte apoptosis, which plays an important role in the progression of NAFLD. In recent years, researchers have begun to focus on developing drugs that slowed the progression of NAFLD by regulating the hepatic mitochondrial function. Chinese medicine has a good curative effect on the treatment of NAFLD, with the advantages of high safety and few side effects. Various studies have shown that Chinese medicine prevented and treated NAFLD by regulating the mitochondrial function. Therefore, this paper summarized the relationship between NAFLD and mitochondria, and the mechanism of Chinese medicine(single Chinese medicine, Chinese medicine monomer, and Chinese medicine compound prescription) in the prevention and treatment of NAFLD by regulating mitochondrial function. This paper is expected to provide references for clinical application of traditional Chinese medicine in the treatment of NAFLD by regulating mitochondrial function.