Dissection of potential anti-osteoporosis mechanism of isopsoralen - a quality control marker in Psoraleae Fructus - by metabolite profiling and network pharmacology.

RATIONALE: Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. METHODS: The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. RESULTS: A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.

Decision fatigue experience of front-line nurses in the context of public health emergency: an interpretative phenomenological analysis.

BACKGROUND: Decision fatigue is a new concept in the field of psychology and refers to a state of fatigue alongside impaired cognitive processing and emotional regulation ability. Previous studies have confirmed that nurses are prone to decision fatigue, and nurses who experience decision fatigue may implement nursing measures that are inconsistent with clinical evidence, thus affecting patients' benefits. COVID-19, as a large-scale global public health emergency, increased the workload and burden of nurses and aggravated decision fatigue. However, the factors leading to decision fatigue among nurses have not yet been identified. METHODS: This study is guided by interpretative phenomenology. During the epidemic period of COVID-19: From November 2022 to February 2023, a one-to-one, semi-structured in-depth interview was conducted among nurses with decision fatigue experience who were participating in front-line work in Jilin Province using homogenous sampling. The interview recordings and related data were transcribed into text within 24 h, and data analysis was assisted by NVivo 12.0 software. RESULTS: After a total of 14 front-line nurses were analyzed in this study, The thematic level reaches saturation, the findings present a persuasive and coherent narrative, and the study is terminated, and finally extracted and formed three core themes: "Cognition, influence and attitude of decision fatigue", "Approaching factors of decision fatigue" and "Avoidant factors of decision fatigue". CONCLUSION: This study confirmed that decision fatigue was widespread in the work of front-line nurses, affecting the physical and psychological health of nurses, the quality of nursing work, the degree of benefit of patients and the clinical outcome. However, nursing staff do not know enough about decision fatigue, so the popularization and research of decision fatigue should be strengthened. Improve the attention of medical institutions, nursing managers and nursing staff.Some suggestions are put forward for the intervention of decision fatigue through personnel, task, tool and technology, organization and environment.

Functional analysis of the novel mitochondrial tRNATrp and tRNASer(AGY) variants associated with type 2 diabetes mellitus.

BACKGROUND: Mutations in mitochondrial tRNA (mt-tRNA) genes that result in mitochondrial dysfunction play important roles in type 2 diabetes mellitus (T2DM). We pre-viously reported a large Chinese pedigree with maternally inherited T2DM that harbors novel mt-tRNA Trp A5514G and tRNA Ser(AGY) C12237T variants, however, the effects of these mt-tRNA variants on T2DM progression are largely unknown. AIM: To assess the potential pathogenicity of T2DM-associated m.A5514G and m.C12237T variants at genetic, molecular, and biochemical levels. METHODS: Cytoplasmic hybrid (cybrid) cells carrying both m.A5514G and m.C12237T variants, and healthy control cells without these mitochondrial DNA (mtDNA) variants were generated using trans-mitochondrial technology. Mitochondrial features, including mt-tRNA steady-state level, levels of adenosine triphosphate (ATP), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mtDNA copy number, nicotinamide adenine dinucleotide (NAD+)/NADH ratio, enzymatic activities of respiratory chain complexes (RCCs), 8-hydroxy-deo-xyguanine (8-OhdG), malondialdehyde (MDA), and superoxide dismutase (SOD) were examined in cell lines with and without these mt-tRNA variants. RESULTS: Compared with control cells, the m.A5514G variant caused an approximately 35% reduction in the steady-state level of mt-tRNA Trp (P < 0.0001); however, the m.C12237T variant did not affect the mt-tRNA Ser(AGY) steady-state level (P = 0.5849). Biochemical analysis revealed that cells with both m.A5514G and m.C12237T variants exhibited more severe mitochondrial dysfunctions and elevated oxidative stress than control cells: ATP, MMP, NAD+/NADH ratio, enzyme activities of RCCs and SOD levels were markedly decreased in mutant cells (P < 0.05 for all measures). By contrast, the levels of ROS, 8-OhdG and MDA were significantly increased (P < 0.05 for all measures), but mtDNA copy number was not affected by m.A5514G and m.C12237T variants (P = 0.5942). CONCLUSION: The m.A5514G variant impaired mt-tRNA Trp metabolism, which subsequently caused mitochondrial dysfunction. The m.C12237T variant did not alter the steady-state level of mt-tRNA Ser(AGY), indicating that it may be a modifier of the m.A5514G variant. The m.A5514G variant may exacerbate the pathogenesis and progression of T2DM in this Chinese pedigree.

Characterization of metabolic features and potential anti-osteoporosis mechanism of pinoresinol diglucoside using metabolite profiling and network pharmacology.

RATIONALE: Eucommia cortex is the core herb in traditional Chinese medicine preparations for the treatment of osteoporosis. Pinoresinol diglucoside (PDG), the quality control marker and the key pharmacodynamic component in Eucommia cortex, has attracted global attention because of its definite effects on osteoporosis. However, the in vivo metabolic characteristics of PDG and its anti-osteoporotic mechanism are still unclear, restricting its development and application. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to analyze the metabolic characteristics of PDG in rats, and its anti-osteoporosis targets and mechanism were predicted using network pharmacology. RESULTS: A total of 51 metabolites were identified or tentatively characterized in rats after oral administration of PDG (10 mg/kg/day), including 9 in plasma, 28 in urine, 13 in feces, 10 in liver, 4 in heart, 3 in spleen, 11 in kidneys, and 5 in lungs. Furan-ring opening, dimethoxylation, glucuronidation, and sulfation were the main metabolic characteristics of PDG in vivo. The potential mechanism of PDG against osteoporosis was predicted using network pharmacology. PDG and its metabolites could regulate BCL2, MARK3, ALB, and IL6, involving PI3K-Akt signaling pathway, estrogen signaling pathway, and so on. CONCLUSIONS: This study was the first to demonstrate the metabolic characteristics of PDG in vivo and its potential anti-osteoporosis mechanism, providing the data for further pharmacological validation of PDG in the treatment of osteoporosis.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Osthole Activates the Cholinergic Anti-Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses.

Osthole (also known as Osthol) is the main anti-inflammatory coumarin found in Cnidium monnieri and severs as the exclusive quality-controlled component according the Chinese Pharmacopoeia. However, its underlying anti-inflammatory mechanism remains unknown. In this study, we demonstrated that Osthole treatment significantly inhibited the generation of TNF-α, but not IL-6 in the classical LPS-stimulated RAW264.7 macrophage model. In addition, LPS induced the activation of both MAPK and NF-κB signalling pathways, of which the former was dose-dependently restrained by Osthole via suppressing the phosphorylation of JNK and P38 proteins, while the phosphorylation of IκB and P65 proteins remained unaffected. Interestingly, Osthole dose-dependently up-regulated the expression of the key cholinergic anti-inflammatory pathway regulator α7nAChR, and the TNF-α inhibition effect of Osthole was also significantly alleviated by the treatment of α7nAChR antagonist methylbetaine. These results demonstrate that Osthole may regulate TNF-α by promoting the expression of α7nAChR, thereby activate the vagus nerve-dependent cholinergic anti-inflammatory pathway.

Cucurbit[8]uril-Based Supramolecular Probe for the Detection of 3-Nitrotyrosine in Human Serum and Plasma.

The biomarker 3-nitrotyrosine (3-NT) is widely recognized as an indicator of renal oxidative stress injury, making its detection crucial for the early identification of renal insufficiency. This study presents the design and synthesis of a tetraphenylstyrene imidazole derivative (TIPE-MI), which is utilized to create a supramolecular probe in conjunction with cucurbit[8]uril (Q[8]) through host-guest interactions. The resulting supramolecular self-assembly exhibits excellent optical properties and has been employed for the specific detection of 3-NT through fluorescence quenching. The introduction of 3-NT resulted in a decreased fluorescence intensity of the yellow fluorescent probe, which gradually transitioned from bright yellow to light yellow and then became colorless as the 3-NT concentration was increased. A portable detection platform was devised to augment the efficiency of detection. In order to facilitate biological applications, we have substantiated the probe's exceptional precision in detecting 3-NT in biological samples, encompassing human serum and plasma. The probe also exhibited negligible cytotoxicity. The accumulation of the probe in renal cells elicited a fluorescence signal, thereby indicating the prospective viability of this system for visual detection with renal cytocompatibility.

Exosome-mediated repair of spinal cord injury: a promising therapeutic strategy.

Spinal cord injury (SCI) is a catastrophic injury to the central nervous system (CNS) that can lead to sensory and motor dysfunction, which seriously affects patients' quality of life and imposes a major economic burden on society. The pathological process of SCI is divided into primary and secondary injury, and secondary injury is a cascade of amplified responses triggered by the primary injury. Due to the complexity of the pathological mechanisms of SCI, there is no clear and effective treatment strategy in clinical practice. Exosomes, which are extracellular vesicles of endoplasmic origin with a diameter of 30-150 nm, play a critical role in intercellular communication and have become an ideal vehicle for drug delivery. A growing body of evidence suggests that exosomes have great potential for repairing SCI. In this review, we introduce exosome preparation, functions, and administration routes. In addition, we summarize the effect and mechanism by which various exosomes repair SCI and review the efficacy of exosomes in combination with other strategies to repair SCI. Finally, the challenges and prospects of the use of exosomes to repair SCI are described.

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development.

Nanoformulation of active payloads or pharmaceutical ingredients (APIs) has always been an area of interest to achieve targeted, sustained, and efficacious delivery. Various delivery platforms have been explored, but loading and delivery of APIs have been challenging because of the chemical and structural properties of these molecules. Polymersomes made from amphiphilic block copolymers (ABCPs) have shown enormous promise as a tunable API delivery platform and confer multifold advantages over lipid-based systems. For example, a COVID booster vaccine comprising polymersomes encapsulating spike protein (ACM-001) has recently completed a Phase I clinical trial and provides a case for developing safe drug products based on ABCP delivery platforms. However, several limitations need to be resolved before they can reach their full potential. In this Perspective, we would like to highlight such aspects requiring further development for translating an ABCP-based delivery platform from a proof of concept to a viable commercial product.

Microplastics affect mosquito from aquatic to terrestrial lifestyles and are transferred to mammals through mosquito bites.

Microplastics (MPs) transfer from the environment to living organisms is a nonignorable global problem. As a complete metamorphosis insect, the larvae and adult Culex quinquefasciatus mosquito live in aquatic and terrestrial environments, respectively, where they easily access MPs. However, little is known about mosquitoes' potential role in MPs accumulation throughout ecosystems. Therefore, we conducted a study with different MPs particle sizes (0.1/1/10 µm) and concentrations (0.5/5/50 µg/mL) on Cx. quinquefasciatus to address this issue. Once exposed at the young larval stage, MPs could accompany the mosquitoes their entire life. The fluorescence signals of MPs in the larvae were mainly located in the intestines. Its intensity increased (from 3.72 × 106 AU to 5.45 × 107 AU) as the concentrations of MPs increases. The fluorescence signals of MPs were also detected in the blood and skin tissues of mice bitten by adult mosquitoes with MPs containing in their bodies. Mosquitos exposed to MPs showed longer larval pupation and eclosion time as well as lower adult body weight. In addition, MPs significantly reduced the lethal effect of pyrethroid insecticides (97.77 % vs. 48.88 %, p < 0.05) with 15.1 % removal of the deltamethrin concentration. After MPs exposure, the relative abundance of the Cx. quinquefasciatus gut microbiome, such as Wolbachia spp., Elizabethkingia spp., and Asaia spp., changed as the MPs size and concentration changes. Mosquitoes provide a new pathway for MPs accumulation and transfer to higher-level living organisms. Moreover, MPs significantly reduce the control effect of deltamethrin, providing new guidelines for mosquito insecticide application in MPs contamination circumstances.

Improving the beam quality of single-grating spectrally combined fiber lasers with adaptive optics.

Spectral combination is promising for diffraction-limited beam quality and single aperture beams. Unfortunately, beamlet deviations, linewidth broadening, and thermal aberrations inevitably degrade the beam quality. Many high-power laser systems integrate adaptive optics systems to maintain beam qualities. However, owing to the nature of incoherent combination, there is no well-defined wavefront in the spectrally combined beam, and whether phase compensations can enhance beam quality has not been discussed yet. We present the feasibility of improving the beam quality of spectral combined fiber lasers by adaptive optics. Simulations indicate that common path aberrations can be effectively corrected by adaptive optics, while beam quality degraded by displacement deviations and linewidth broadening cannot be improved. Additionally, the combined beam could be directly used as the beacon light in the propagation tunnel. To our knowledge, this study is the first to demonstrate that adaptive optics can improve the beam quality of spectrally combined fiber lasers and enable a further step toward diffraction-limited beam quality.

Cucurbit[7]uril-based carbon dots for recognizing histamine.

Fluorescent carbon quantum dots (CQDs) were synthesized from cucurbit[7]uril (Q[7]) and 2,2-bis(hydroxymethyl)propionic (DMPA) by a hydrothermal method. The Q[7]-DMPA complex was confirmed by X-ray crystallography. The CQDs showed blue fluorescence, photostability, and ionic strength stability. They were used to detect histamine with a low limit of 2.33 × 10-6 M.

Red Room-Temperature Phosphorescence Supramolecular Assemblies Based on Cucurbit[7]uril: Reversible Temperature Stimulation Response and Cell-Specific Silver Ion Imaging.

Solid-state materials with efficient room-temperature phosphorescence (RTP) emission have been widely used in materials science, and organic RTP-emitting systems with heavy-metal doping in aqueous solutions have attracted much attention in recent years. A novel supramolecular interaction was induced by host-guest assembly using cucurbit[7]uril (Q[7]) as the host and brominated naphthalimide phosphor as the guest. This interaction was further enhanced through synergistic chelation stimulated by analytical silver ion complexation. This approach facilitated the system's structural rigidity, intersystem crossing, and oxygen shielding. We achieved deep red phosphorescence emission in aqueous solution and ambient conditions along with quantitative determination of silver ions. The new complex exhibited good reversible thermoresponsive behavior and was successfully applied for the first time to target phosphorescence imaging of silver ions in the mitochondria of A549 cancer cells. These results are beneficial for constructing novel RTP systems with stimulus-responsive luminescence in aqueous solution, contributing to future research in bioimaging, detection, optical sensors, and thermometry materials.

Catechol oxidase nanozyme based colorimetric sensors array for highly selective distinction among multiple catecholamines.

In order to effectively monitor multiple catecholamine (CA) neurotransmitters with extreme similar structures, a rapid, sensitive and selective detection strategy has become an urgent problem to be solved. In this paper, a novel colorimetric sensors array based on CuNCs protected by various ligands such as tannic acid, ascorbic acid and polymethylacrylic acid (CuNCs@TA, CuNCs@AA and CuNCs@PMAA) was constructed. All of these CuNCs could mimic catechol oxidase to selective catalyze catechol-type analogues (such as CAs) to corresponding quinones along with color changes. Furthermore, experiments and theory calculations demonstrated that Cr6+-modification on the surface of CuNCs facilitated the steady-state kinetics of enzymatic activity. Based on these CuNCs as sensing probes, this sensors array can quickly detect different CAs (such as epinephrine (EP), including dopamine (DA), norepinephrine (NE) and l-dopa) with similar structures. When those analogues were added to the CuNC-based colorimetric array sensors, different absorbance changes were produced at 485 nm. Linear discriminant analysis (LDA) showed that the tri-probe colorimetric array sensors could recognize and distinguish these analogues, and corresponding binary and ternary mixtures could be well categorized. The value of Factor 1 of an array with varied CA concentrations had a good linear correlation, and the detection limit (LOD) was as low as 10-8∼10-9 mol/L. Four CA analogues in real samples were identified by CuNCs-based colorimetric array sensors. This work provides a fast and convenient experimental basis for monitoring the complex structure CAs neurotransmitters.

Responses of the microbial community and the production of extracellular polymeric substances to sulfamethazine shocks in a novel two-stage biological contact oxidation system.

Introduction: The biological contact oxidation reactor is an effective technology for the treatment of antibiotic wastewater, but there has been little research investigating its performance on the sulfamethazine wastewater treatment. Methods: In this study, a novel two-stage biological contact oxidation reactor was used for the first time to explore the impact of sulfamethazine (SMZ) on the performance, microbial community, extracellular polymeric substances (EPS), and antibiotic-resistant genes (ARGs). Results: The chemical oxygen demand (COD) and ammonia nitrogen (NH4+-N) removal efficiencies kept stable at 86.93% and 83.97% with 0.1-1 mg/L SMZ addition and were inhibited at 3 mg/L SMZ. The presence of SMZ could affect the production and chemical composition of EPS in the biofilm, especially for the pronounced increase in TB-PN yield in response against the threat of SMZ. Metagenomics sequencing demonstrated that SMZ could impact on the microbial community, a high abundance of Candidatus_Promineofilum, unclassified_c__Anaerolineae, and unclassified_c__Betaproteobacteria were positively correlated to SMZ, especially for Candidatus_Promineofilum. Discussion: Candidatus_Promineofilum not only had the ability of EPS secretion, but also was significantly associated with the primary SMZ resistance genes of sul1 and sul2, which developed resistance against SMZ pressure through the mechanism of targeted gene changes, further provided a useful and easy-implement technology for sulfamethazine wastewater treatment.

A multifunctional supramolecular assembly based on cucurbit[7]uril: White light material and Fe(CN)63- detection.

White light emitting materials have broad application prospects in fields such as displays, lighting devices, etc., but developing such materials faces considerable challenges. In this study, 1,3,5-tris[4-(pyridine-4-butyl)phenyl]benzene derivative (BTPY) was synthesized and a supramolecular assembly with AIE properties named BTPY@Q[7] was prepared with cucurbit[7]uril (Q[7]). Furthermore, by adding rhodamine 6G (R6G) to it, and controlling its ratio with R6G, a dual-emission white light system (0.33, 0.33) was synthesized and used for white light emitting materials as well as anti-counterfeiting fields. In addition, based on the BTPY@Q[7]-R6G system, a light harvesting system in aqueous phase was constructed, with an energy transfer efficiency (ΦET) of 26.19 % and an antenna effect (AE) of 10.21. Interestingly, the supramolecular self-assembly can also be used as a fluorescent probe, specifically recognize Fe(CN)63- ions in water, with a detection limit of 2.5 × 10-8 M.

Flavobacterium lacisediminis sp. nov., a bacterium isolated from lake sediment.

A taxonomic identification using polyphasic approach was performed on strain TH16-21T, which was isolated from the interfacial sediment of Taihu Lake, PR China. Strain TH16-21T was Gram-stain-negative, aerobic, rod-shaped and catalase-positive. Phylogenetic analysis based on the 16S rRNA gene and genomic sequences indicated that strain TH16-21T was classified within the genus of Flavobacterium. The 16S rRNA gene sequence of strain TH16-21T showed the highest similarity to Flavobacterium cheniae NJ-26T (98.9 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain TH16-21T and F. cheniae NJ-26T were 91.2 and 45.9 %, respectively. The respiratory quinone was menaquinone 6. The major cellular fatty acids (>10 %) comprised iso-C15 : 0, iso-C16 : 0, iso-C15 : 1 G and iso-C16 : 0 3-OH. The genomic DNA G+C content was 32.2 mol%. Phosphatidylethanolamine, six amino lipids and three phospholipids were the main polar lipids. Based on the phenotypic features and phylogenetic position, a novel species with the name Flavobacterium lacisediminis sp. nov. is proposed. The type strain is TH16-21T (=MCCC 1K04592T=KACC 22896T).

A novel portable smart phone sensing platform based on a supramolecular fluorescence probe for quick visual quantitative detection of picric acid.

Picric acid (PA) is a lethal explosive substance that is easily soluble in water and harmful to the environment. Here, a supramolecular polymer material BTPY@Q[8] with aggregation induced emission (AIE) was prepared by supramolecular self-assembly of cucurbit uril (Q[8]) and 1,3,5-tris[4-(pyridin-4-yl) phenyl] benzene derivative (BTPY), which exhibited aggregation-induced fluorescence enhancement. To this supramolecular self-assembly, the addition of a number of nitrophenols was found to have no obvious effect on the fluorescence, however on addition of PA, the fluorescence intensity underwent a dramatic quench. For PA, BTPY@Q[8] had sensitive specificity and effective selectivity. Based on this, a quick and simple on-site visual PA fluorescence quantitative detection platform was developed using smart phones, and the platform was used to monitor temperature. Machine learning (ML) is a popular pattern recognition technology, which can accurately predict the results from data. Therefore, ML has much more potential for analyzing and improving sensing data than the widely used statistical pattern recognition method. In the field of analytical science, the sensing platform offers a reliable method for the quantitative detection of PA that can be applied to other analytes or micropollutant screening.