Bimodal Oxidation Electrochemiluminescence Mechanism of Coreactant-Embedded Covalent Organic Frameworks via Postsynthetic Modification.

Electrochemiluminescence (ECL) efficiency is determined by charge transfer between coreactants and emitters in coreactant systems, which are usually limited by their slow intermolecular charge transfer. In this study, a covalent organic framework (COF) with aldehyde residue was synthesized, and then coreactants were covalently integrated into the skeleton through the postsynthetic modification strategy, resulting in a crystalline coreactant-embedded COF nanoemitter (C-COF). Compared to the pristine COF with an equivalent external coreactant, C-COF exhibited an extraordinary 1008-fold enhancement of ECL intensity due to the rapid intrareticular charge transfer. Significantly, with the pH increase, C-COF shows protonation-induced ECL enhancement for the first ECL peaked at +1.1 V and an opposite trend for the second ECL at +1.4 V, which were attributed to the antedating oxidation of coreactant in framework and COF self-oxidation, respectively. The resulting bimodal oxidation ECL mechanism was rationalized by spectral characterization and density functional theory calculations. The postsynthetic coreactant-embedded nanoemitters present innovative and universal avenues for advancing ECL systems.

Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ expression.

Metformin can prevent hyperglycaemia-induced osteoporosis and decrease the bone fracture rate, but the mechanism has not been fully elucidated. To reveal the mechanism by which metformin affects hyperglycaemia-induced osteoporosis, we treat a mouse osteoporosis cell model with metformin and find that osteoblast mineralization increases and PPARγ expression decreases. Single-cell mRNA sequencing analysis show that PPARγ is highly expressed in the bone tissue of osteoporosis patients, which highlights the role of PPARγ in osteoporosis. Furthermore, we find that PPARγ is the effector through which metformin prevents osteoporosis. We further examine the mechanism of PPARγ regulation and reveal that metformin regulates PPARγ expression through the AMPK pathway and that PPARγ affects osteoblasts through the endoplasmic reticulum stress (ERS) pathway. Moreover, we verify the association between the effect of metformin on bone metabolism and the expression of PPARγ in high-fat diet-induced diabetic rats. Thus, we identify and functionally validate that metformin prevents hyperglycaemia-induced osteoporosis by regulating the AMPK-PPARγ-ERS axis.

An imbalanced ratio between PC(16:0/16:0) and LPC(16:0) revealed by lipidomics supports the role of the Lands cycle in ischemic brain injury.

Promoting brain recovery after stroke is challenging as a plethora of inhibitory molecules are produced in the brain preventing it from full healing. Moreover, the full scope of inhibitory molecules produced is not well understood. Here, using a high-sensitivity UPLC-MS-based shotgun lipidomics strategy, we semiquantitively measured the differential lipid contents in the mouse cerebral cortex recovering from a transient middle cerebral artery occlusion (MCAO). The lipidomic data were interrogated using the soft independent modeling of class analogy (SIMCA) method involving principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Statistics of the 578 confirmed lipids revealed 84 species were differentially changed during MCAO/reperfusion. The most dynamic changes in lipids occurred between 1 and 7 days post-MCAO, whereas concentrations had subsided to the Sham group level at 14 and 28 days post-MCAO. Quantitative analyses revealed a strong monotonic relationship between the reduction in phosphatidylcholine (PC)(16:0/16:0) and the increase in lysophosphatidylcholine (LPC)(16:0) levels (Spearman's Rs = -0.86) during the 1 to 7 days reperfusion period. Inhibition of cPLA2 prevented changes in the ratio between PC(16:0/16:0) and LPC(16:0), indicating altered Land's cycle of PC. A series of in vitro studies showed that LPC(16:0), but not PC(16:0/16:0), was detrimental to the integrity of neuronal growth cones and neuronal viability through evoking intracellular calcium influx. In contrast, PC(16:0/16:0) significantly suppressed microglial secretion of IL-1ß and TNF-α, limiting neuroinflammation pathways. Together, these data support the role of the imbalanced ratio between PC(16:0/16:0) and LPC(16:0), maintained by Lands' cycle, in neuronal damage and microglia-mediated inflammatory response during ischemic recovery.

Sex differences in factors associated with neck pain among undergraduate healthcare students: a cross-sectional survey.

BACKGROUND: Neck pain is widespread among students in healthcare-related fields. Although neck pain is more prevalent in females, since most research involves mixed-sex samples we know very little about sex differences in contributors to neck pain. Thus, this study sought to explore sex differences in the risk factors for neck pain in this high-risk population. METHODS: This cross-sectional study was conducted in China in 2021 and included a sample of 1921 undergraduate healthcare students (693 males, 1228 females) from 7 health professional schools at Fujian Medical University. We collected data on neck pain symptoms, demographics, behavioral and psychological factors. Multiple regression analysis was conducted to examine sex differences in the risk factors of neck pain. RESULTS: The overall prevalence of neck pain was 41.6% with female students having a higher prevalence than male students (44.4% vs. 36.7%, respectively). The adjusted analyses showed that self-study time ≥ 6 h/day (OR = 1.44, 95% CI:1.13-1.83), flexed neck posture >20 degrees (OR = 2.19, 95% CI: 1.28-3.74), static duration posture >2 h (OR = 1.42, 95% CI: 1.02-1.97), and psychological distress (high: OR = 2.04, 95% CI:1.42-2.94; very high: OR = 2.50, 95% CI:1.57-3.74; respectively) were independent factors for neck pain in females. Among males, self-study time ≥ 6 h/day (OR = 1.43, 95% CI: 1.02-2.01) and psychological distress (moderate: OR = 2.04, 95% CI:1.28-3.25; high: OR = 2.37, 95% CI:1.49-3.79; very high: OR = 2.97, 95% CI:1.75-5.02; respectively) were significant risk factors for neck pain. CONCLUSIONS: These findings suggest that the risk profiles of neck pain differ between females and males. The modifiable risk factors for neck pain, such as prolonged self-study time and elevated psychological distress, as well as poor posture among females, could be targeted through health promotion interventions in university settings.

Fluorescent Talarolactones from Talaromyces sp.

(+)-Talarolactone C (1), Talarolactone A (2), Talarolactone B (3, sulfoxide derivative), and Talarolactone D (4, sulfone derivative) were isolated from Talaromyces sp. which was cultured in rice medium with sodium butyrate. The structures of talarolactone analogs above were characterized by a combination of spectroscopic, X-ray crystallographic, and computational methods. These talarolactones and Talarolactone A sodium (5) with the same carbon skeleton showed different fluorescence characteristics.

Review of the quality of printed patient education materials on asthma available in primary care in Singapore.

Objective: Patient education materials (PEMs) are commonly used for patient education. This study assessed readability, format quality, accuracy, understandability and actionability of printed asthma PEMs available in primary care in Singapore.Methods: Primary care in Singapore is provided by island-wide polyclinics and private general practices. We invited the three polyclinic healthcare groups and private general practices via the Primary Care Research Network to submit asthma-related PEMs. Readability was assessed using Simple Measure of Gobbledegook (SMOG) and Flesch-Kincaid (FK) score. Format quality was assessed using "Clear-print and large-print golden rules" from UK Association for Accessible Formats (UKAAF). Understandability and actionability were evaluated using Patient Education Materials Assessment Tool - Printed. Three pulmonologists assessed content accuracy.Results: Thirty leaflets were assessed. SMOG and FK estimated 93% (mean 9.3, range 5-14, SD 1.8) and 47% (mean 6.8, range 2.4-9.9, SD 2.0) exceeded the recommended sixth-grade reading level, respectively. About a third (37%) were fully concordant with UKAAF guidelines, with poor format quality contributed by small font size, poor text emphasis methods, and not using left-aligned text. Leaflets generally scored well in both understandability (mean 84%) and actionability (mean 72%). Thirteen leaflets were inaccurate, 92% of which contained at least one inaccuracy judged to have potentially harmful consequences to patients, including wrong emergency advice.Conclusion: While understandability and actionability are adequate, current asthma PEMs are limited by inappropriately high reading levels, poor format quality and inaccuracies. Healthcare professionals need to assess patients' reading abilities and ensure PEMs are accurate and suitable for their patients.

Gallic acid disruption of Aß1-42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse.

Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aß aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aß1-42 aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of 4-month-old APP/PS1 mice, but also significantly reduced the more severe deficits developed in the 9-month-old APP/PS1 mice in terms of spatial learning, reference memory, short-term recognition and spatial working memory. The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated 9-month-old APP/PS1 mice with increased expression of synaptic marker proteins. Evidence from atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA significantly reduces Aß1-42 aggregation both in vitro and in vivo. Further, pre-incubating GA with oligomeric Aß1-42 reduced Aß1-42-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of Aß1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and ε-amino group of Lys16 is also critical for the disruption of Aß1-42 S-shaped triple-ß-motif and toxicity. Together, these studies demonstrated that GA can be further developed as a drug to treat AD through disrupting the formation of Aß1-42 aggregation.

Influence of White Sound on Sleep Quality, Anxiety, and Depression in Patients with Schizophrenia.

BACKGROUND: Patients with schizophrenia frequently experience issues such as poor sleep quality, anxiety, and depression. White sound has been identified as a potential therapeutic strategy to enhance sleep quality and alleviate negative emotions. This study aimed to investigate the effectiveness of white sound in improving sleep quality, anxiety, and depression among patients with schizophrenia. MATERIALS AND METHODS: This retrospective analysis included clinical data from 212 patients with schizophrenia divided into two groups based on their treatment approach. Group C (control, without white sound, n = 106) received standard pharmacological treatments, while group W (white sound, n = 106) was exposed to white sound (40-50 dB) for 2 hours nightly at 9:00 pm. All patients were assessed using the Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) before and after 12 weeks of intervention. RESULTS: After 12 weeks, group W showed significant improvements in sleep latency, sleep efficiency, and overall PSQI scores compared to group C (P < 0.05). Furthermore, the HAMD and HAMA scores were significantly lower in group W (P < 0.05), indicating reduced levels of anxiety and depression. The negative symptoms score was significantly lower in group W (P < 0.05) after treatment. CONCLUSION: White sound shows promise in improving sleep quality, and alleviating anxiety and depression in patients with schizophrenia.

High expression of ACKR1 predicts a good prognosis and suppresses sarcoma cell progression via regulating the tumor immune microenvironment.

Sarcoma is a malignant tumor originating from mesenchymal tissue with a poor prognosis. Atypical chemokine receptor 1 (ACKR1) is found closely related to cancer progression. However, the effects of ACKR1 in soft tissue sarcoma have not been well investigated. Therefore, our present study is devoted to analyze the functions of ACKR1 in sarcoma progression and its potential mechanism. We detected the expression of ACKR1 in the Cancer Genome Atlas (TCGA)-pan-cancer database, TCGA-Sarcoma from TCGA databases, and GSE21122 from Gene Expression Omnibus (GEO) database. The relationships between ACKR1 expression, clinicopathological data, and survival status were evaluated in the TCGA-Sarcoma database. Moreover, overexpression negative control (OE-NC) and overexpression ACKR1 (OE-ACKR1) were used to further verify the effects of ACKR1 overexpression in the progression of sarcoma cells by using Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR), cell counting kit-8 (CCK-8), 5-Ethyny-2'-Deoxyuridine (EdU), wound healing, transwell assay, and flow cytometry assays. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were carried out to explore the potential enriched biological process of ACKR1 expression in sarcoma. Furthermore, tumor-immune system interactions databases (TISIDB) were applied to further confirm the relations between ACKR1 and tumor immune microenvironment in sarcoma. Our study found that ACKR1 is downregulated in multiple cancers (including sarcoma), and low expression of ACKR1 is related to poor survival status in sarcoma. The biological experiments found that promoting expression of ACKR1 can suppress sarcoma cell proliferation, migration, invasion, promote cell apoptosis, and arrest cell cycle. The GO-KEGG, GSEA, and TISIDB analysis showed that ACKR1 is related to the tumor immune microenvironment. In conclusion, low expression of ACKR1 presented as an independent prognostic biomarker in sarcoma. Overexpression of ACKR1 can significantly suppress cell progression ability in sarcoma by regulating the immune microenvironment.

[Evaluation of lower limb function and gait characteristics after fibulectomy in adults].

Objective: To explore the effects of fibulectomy on lower limb function and gait of adult patients through gait analysis, in order to provide guidance for clinical treatment. Methods: A clinical data of 24 patients who underwent fibulectomy and met the selection criteria between January 2017 and December 2022 was retrospectively analyzed. There were 12 males and 12 females with an average age of 25 years (range, 18-68 years). The length of fibulectomy was 10-19 cm, with an average of 15 cm. The patients underwent routine rehabilitation training after operation. The occurrence of postoperative complications was recorded, the pain degree of surgical incision was evaluated by visual analogue scale (VAS) score, and the residual fibular bone was reviewed by imaging. A gait test system was used before operation and at 6 months after operation to collect gait data of healthy and affected sides under slow, medium, and fast velocity conditions, including gait parameters (foot rotation angle, step length, support phase, swing phase, gait line length, single support line, maximum force 1, maximum force 2) and the tripod area parameters (maximum pressure, time maximum force, and contact time of forefoot, midfoot, and hindfoot). Results: All incisions healed by first intention after operation. All patients were followed up 1-5 years, with an average of 3 years. The great dorso-extension muscle strength decreased in 3 cases, and the sensory defects in the operative area and distal part occurred in 5 cases. The VAS scores of incisions were 0-6 (mean, 4) at 6 months after operation and 0-5 (mean, 2) at last follow-up. During follow-up, imaging review showed that 5 cases had osteoporotic changes of distal residual bone of the fibula, and the residual segment was shorter and more significant; 3 cases had new bone formation. The results of gait test showed that the gait parameters and the tripod area parameters under the three gait speeds were consistent. There was no significant difference in the gait parameters and the tripod area parameters between the healthy side and the affected side before operation ( P>0.05). Compared with the healthy side, the foot rotation angle, the single support line, the maximum force 1, the maximum force 2, and the maximum pressures of the forefoot and midfoot of the affected side significantly decreased after operation ( P<0.05), and the step length, the time maximum force of midfoot and hindfoot, and the contact time of the forefoot and midfoot significantly increased ( P<0.05). Compared with preoperative conditions on the same side, the foot rotation angle, the gait line length of both sides significantly decreased ( P<0.05), and the maximum pressures of the forefoot, midfoot, and hindfoot and the time maximum force of the midfoot significantly increased ( P<0.05); the step length on healthy side significantly decreased, while the affected side significantly increased ( P<0.05); the maximum force 1 and the maximum force 2 on the healthy side significantly increased, while the affected side significantly decreased ( P<0.05); the single support line on the affected side significantly decreased ( P<0.05). Conclusion: Different degrees of clinical symptoms occurred, gait pattern changes, compensatory gait appears, gait stability decreases, and the risk of tumble increases in adult patients after partial fibulectomy. Therefore, it is recommended to walk slowly after fibulectomy.

Identification and validation of a prognostic signature based on six immune-related genes for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with high mortality and morbidity rates. Although the significant efficacy of immunotherapy is well established, it is only beneficial for a limited number of individuals with CRC. METHODS: Differentially expressed immune-related genes (DE-IRGs) were retrieved from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ImmPort databases. A prognostic signature comprising DE-IRGs was developed using univariate, LASSO, and multivariate Cox regression analyses. A nomogram integrating the independent prognostic factors was also developed. CIBERSORT was used to assess immune cell infiltration (ICI). Furthermore, wound-healing, colony formation, migration, and invasion assays were performed to study the involvement of ACTG1 in CRC. RESULTS: A signature including six DE-IRGs was developed. The overall survival (OS) rate was accurately estimated for TCGA and GSE38832 cohorts. The risk score (RS) of the signature was an independent factor for OS. Moreover, a nomogram encompassing age, RS, and pathological T stage accurately predicted the long-term OS probability of individuals with CRC. The high-risk group had an elevated proportion of patients treated with ICIs, including native B cells, relative to the low-risk group. Additionally, ACTG1 expression was upregulated, which supported the proliferation, migration, and invasion abilities of CRC cells. CONCLUSIONS: An immune-related prognostic signature was developed for predicting OS and for determining the immune status of individuals with CRC. The present study provides new insights into accurate immunotherapy for individuals with CRC. Moreover, ACTG1 may serve as a new immune biomarker.

Lanthanide-Sensitized Upconversion Iridium Complex via Triplet Energy Transfer.

Cyclometalated iridium (Ir) complexes demonstrate impressive capabilities across a range of fields, including biology and photocatalysis, due to their tunable optical characteristics and structure flexibility. However, generating upconversion luminescence of Ir complexes under near-infrared light excitation is challenging. Herein, by employing lanthanide-doped upconversion nanoparticles (UCNPs) as the sensitizer, a new strategy is demonstrated to gain upconversion luminescence of Ir complexes via triplet energy transfer. This design relies on a rationally designed hybrid of core-shell structured NaYbF4:Tb@NaTbF4 UCNPs and new Ir phosphonate complexes, in which UCNPs can migrate upconverted energy to the surface of nanoparticles through Tb3+-mediated energy migration and then sensitize the upconversion luminescence of Ir complexes upon 980 nm excitation. Both experimental and theoretical investigations highlight the significance of triplet energy transfer from excited Tb3+ ions to the triplet state of Ir complexes in the sensitization of upconversion luminescence of Ir complexes. These findings may open exciting avenues for fabricating hybrid Ir materials with new functions and driving the development of UCNP-based nanomaterials.

Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation.

Osteoporosis is a chronic disease that endangers the health of the elderly. Inhibiting osteoclast hyperactivity is a key aspect of osteoporosis prevention and treatment. Several studies have shown that interferon regulatory factor 9 (IRF9) not only regulates innate and adaptive immune responses but also plays an important role in inflammation, antiviral response, and cell development. However, the exact role of IRF9 in osteoclasts has not been reported. To elucidate the role of IRF9 in osteoclast differentiation, we established the ovariectomized mouse model of postmenopausal osteoporosis and found that IRF9 expression was reduced in ovariectomized mice with overactive osteoclasts. Furthermore, knockdown of IRF9 expression enhanced osteoclast differentiation in vitro. Using RNA sequencing, we identified that the differentially expressed genes enriched by IRF9 knockdown were related to ferroptosis. We observed that IRF9 knockdown promoted osteoclast differentiation via decreased ferroptosis in vitro and further verified that IRF9 knockdown reduced ferroptosis by activating signal transducer and activator of transcription 3 (STAT3) to promote osteoclastogenesis. In conclusion, we identified an essential role of IRF9 in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism.

Human-derived fecal microbiota transplantation alleviates social deficits of the BTBR mouse model of autism through a potential mechanism involving vitamin B6 metabolism.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficiencies and stereotypic behaviors influenced by hereditary and/or environmental risk factors. There are currently no approved medications for treating the core symptoms of ASD. Human fecal microbiota transplantation (FMT) has emerged as a potential intervention to improve autistic symptoms, but the underlying mechanisms are not fully understood. In this study, we evaluated the effects of human-derived FMT on behavioral and multi-omics profiles of the BTBR mice, an established model for ASD. FMT effectively alleviated the social deficits in the BTBR mice and normalized their distinct plasma metabolic profile, notably reducing the elevated long-chain acylcarnitines. Integrative analysis linked these phenotypic changes to specific Bacteroides species and vitamin B6 metabolism. Indeed, vitamin B6 supplementation improved the social behaviors in BTBR mice. Collectively, these findings shed new light on the interplay between FMT and vitamin B6 metabolism and revealed a potential mechanism underlying the therapeutic role of FMT in ASD.IMPORTANCEAccumulating evidence supports the beneficial effects of human fecal microbiota transplantation (FMT) on symptoms associated with autism spectrum disorder (ASD). However, the precise mechanism by which FMT induces a shift in the microbiota and leads to symptom improvement remains incompletely understood. This study integrated data from colon-content metagenomics, colon-content metabolomics, and plasma metabolomics to investigate the effects of FMT treatment on the BTBR mouse model for ASD. The analysis linked the amelioration of social deficits following FMT treatment to the restoration of mitochondrial function and the modulation of vitamin B6 metabolism. Bacterial species and compounds with beneficial roles in vitamin B6 metabolism and mitochondrial function may further contribute to improving FMT products and designing novel therapies for ASD treatment.

Assessing Morinidazole for Surgical Site Infection in Class â ¢ Wounds Prevention: A Multicenter, Randomized, Single-Blind, Parallel-Controlled Study.

INTRODUCTION: Surgical site infections are significant postoperative risks, antibiotic prophylaxis is crucial due to the presence of anaerobic bacteria. This study investigated the efficacy and safety of a novel nitroimidazole, morinidazole, in SSI reduction in class Ⅲ wounds, as there is currently a lack of evidence in the existing literature. METHODS: A multicenter randomized clinical trial was conducted from December 2020 to October 2022 in the general surgery departments of 12 tertiary hospitals in China. 459 patients in two treatment groups using morinidazole plus ceftriaxone or ceftriaxone alone. Efficacy and safety were evaluated including SSI incidence, adverse events, and compliance. Statistical analysis employed SAS 9.4 software. Data analysis was performed from February to May 2023. RESULTS: A total of 440 participants (median [IQR] age, 63.0 [54.0, 70.0] years; 282 males [64.09%]; 437 patients were of Han race [99.32%]) were randomized. The experimental group exhibited a significantly lower SSI rate compared with the control group (31 [14.49%] vs 52 [23.01%]; risk difference, 1.76%, 95%CI, 1.08% to 2.88%; P=0.0224). The superficial incisional site infections revealed a marked reduction in the experimental group (12 [5.61%] vs 31 [13.37%]; risk difference,2.68%; 95%CI,1.34%to5.36%; P=0.0042). Non-surgical site infections, severe postoperative complications, and total adverse events showed no statistically significant differences between the groups (P>0.05). CONCLUSION: The significant decrease in SSI rates and superficial incisional infections demonstrates morinidazole as a valuable prophylactic antibiotic. Our findings provided valuable insights for clinical practice, where this new-generation nitroimidazole can play a crucial role in SSI prevention.

Gelsenicine disrupted the intestinal barrier of Caenorhabditis elegans.

Gelsemium elegans Benth. (G. elegans) is a traditional medicinal herb that has anti-inflammatory, analgesic, sedative, and detumescence effects. However, it can also cause intestinal side effects such as abdominal pain and diarrhea. The toxicological mechanisms of gelsenicine are still unclear. The objective of this study was to assess enterotoxicity induced by gelsenicine in the nematodes Caenorhabditis elegans (C. elegans). The nematodes were treated with gelsenicine, and subsequently their growth, development, and locomotion behavior were evaluated. The targets of gelsenicine were predicted using PharmMapper. mRNA-seq was performed to verify the predicted targets. Intestinal permeability, ROS generation, and lipofuscin accumulation were measured. Additionally, the fluorescence intensities of GFP-labeled proteins involved in oxidative stress and unfolded protein response in endoplasmic reticulum (UPRER) were quantified. As a result, the treatment of gelsenicine resulted in the inhibition of nematode lifespan, as well as reductions in body length, width, and locomotion behavior. A total of 221 targets were predicted by PharmMapper, and 731 differentially expressed genes were screened out by mRNA-seq. GO and KEGG enrichment analysis revealed involvement in redox process and transmembrane transport. The permeability assay showed leakage of blue dye from the intestinal lumen into the body cavity. Abnormal mRNAs expression of gem-4, hmp-1, fil-2, and pho-1, which regulated intestinal development, absorption and catabolism, transmembrane transport, and apical junctions, was observed. Intestinal lipofuscin and ROS were increased, while sod-2 and isp-1 expressions were decreased. Multiple proteins in SKN-1/DAF-16 pathway were found to bind stably with gelsenicine in a predictive model. There was an up-regulation in the expression of SKN-1:GFP, while the nuclear translocation of DAF-16:GFP exhibited abnormality. The UPRER biomarker HSP-4:GFP was down-regulated. In conclusion, the treatment of gelsenicine resulted in the increase of nematode intestinal permeability. The toxicological mechanisms underlying this effect involved the disruption of intestinal barrier integrity, an imbalance between oxidative and antioxidant processes mediated by the SKN-1/DAF-16 pathway, and abnormal unfolded protein reaction.

Reducing the inhibitory effect of cigarette smoke on the activity of oral peroxidase by the addition of berberine in cigarette filter.

This study was carried out to evaluate the effect of cigarette smoke (CS) on the activity of oral peroxidase (OPO) after berberine was added to the cigarette filter. Activated carbon fiber (ACF) was chosen to load berberine as a part of the cellulose acetate (CA) filter to obtain the modified B-ACF cigarette filter. Then the effects of CS from the testing cigarettes on the activity of OPO were investigated in vitro by the 2-nitrobenzoic acid assay, and the smoke chemistry was also analyzed, especially the content of hydrogen cyanide (HCN) in the CS. The results indicated that the loss of activity of OPO in B-ACF filter cigarette group decreased by 20% and 25%, compared with those of ACF and CA filter cigarette groups, respectively. The relative residual activity of OPO in B-ACF filter group was increased with the increase of berberine in the filter compared with the CA filter group. It could be observed that the reduction in HCN might be related to the berberine in the cigarette filter, reducing the inhibition of CS on the activity of OPO.

Planar Chirality for Acid/Base Responsive Macrocyclic Pillararenes Induced by Amino Acid Derivatives: Molecular Dynamics Simulations and Machine Learning.

Chirality is ubiquitous in nature, ranging from a DNA helix to a biological macromolecule, snail's shell, and even a galaxy. However, the precise control of chirality at the nanoscale is a challenge due to the structure complexity of supramolecular assemblies, the small energy differences between different enantiomers, and the difficulty in obtaining polymorphic crystals. The planar chirality of water-soluble pillar[5]arenes (called WP5-Na with Na ions in the side chain) host triggered by the addition of chiral L-amino acid hydrochloride (L-AA-OEt) guests and acid/base is rationalized by the relative stability of different chiral isomers, being estimated by molecular dynamics (MD) simulations and quantum chemical calculations. As an increase in the pH value, the change from a positive to a negative value of the free energy difference (ΔG) between two conformations, pR-WP5-Na⊃L-AA-OEt and pS-WP5-Na⊃L-AA-OEt, suggests an inversed preference of the pS-WP5-Na conformer induced by the deprotonated L-arginine ethyl ester (L-Arg-OEt) at pH = 14, which is supported by the circular dichroism (CD) experiments. On the basis of 2256 WP5-Na⊃L-Ala-OEt and 3299 WP5-Na⊃L-Arg-OEt conformers sampled from MD, the gradient boosting regression (GBR) model exhibits a satisfactory performance (R2 = 0.91) in predicting the chirality of WP5-Na complexations using host-guest binding descriptors, including the geometry matching and binding sites and modes (electrostatics and hydrogen bonding). The machine learning model also performs well on external tests of different hosts (using different side chains and cavity sizes) with the addition of 22 other different guests, with the average chirality prediction accuracy of ML versus experimental CD determinations of 92.8%. The easily accessible host-guest features, binding position coordination and size matching between the cavity and guest, exhibit a close correlation to the chirality of different macrocyclic molecules, water-soluble pillar[6]arenes (WP6) versus WP5, in complexation with different amino acid guests. The exploration of efficient host-guest features in ML displays the great potential of building a large space of various assembled systems and accelerating the on-demand design of chiral supramolecular systems at the nanoscale.

Effects of varenicline on the serum levels of olanzapine in male patients with Schizophrenia: a randomized controlled trial.

Background: Smoking in patients with Schizophrenia is more common than in the general population. Varenicline, a partial agonist at α4ß2 nicotinic acetylcholine receptors, is an effective smoking cessation pharmacotherapy in patients with Schizophrenia. However, its effects on the serum levels of antipsychotics in Schizophrenia are understudied. This study investigated the impact of smoking cessation with varenicline on the serum concentration of olanzapine in patients with Schizophrenia. Methods: Adult smokers with Schizophrenia were enrolled in a 12-week course of varenicline and placebo for smoking cessation. The serum concentration of olanzapine was measured at baseline and weeks 1, 2, 4, 8, and 12. Data were analyzed with the generalized additive mixed model. Results: During the 12-week study, the results indicated that olanzapine concentrations increased nonlinearly in the varenicline and placebo groups. Threshold effect analysis suggested that the olanzapine concentrations increased over time until the turning point (week 4). However, there was no significant difference between the two treatment groups. Conclusion: Varenicline showed safety and efficacy in smoking cessation in people with Schizophrenia.

Combined with dynamic serum proteomics and clinical follow-up to screen the serum proteins to promote the healing of diabetic foot ulcer.

OBJECTIVE: Non-healing diabetic foot ulcers are a leading cause of disability and death in diabetic patients, which often results in lower limb amputation. This study aimed to investigate the impact of biomarkers on the healing of diabetic foot ulcers by utilizing dynamic serum proteomics and skin proteomic analysis, combined with clinical case follow-up studies. METHODS: To analyze dynamic serum proteomic changes in four groups, age-matched normal subjects, diabetic patients, pretreatment diabetic foot ulcer patients, and healed diabetic foot ulcer patients were selected. The differential proteins were screened in conjunction with normal and diabetic foot ulcer skin proteomics. In this study, a total of 80 patients with diabetic foot ulcers were enrolled and monitored for 3-6 months during treatment. To verify the significance of the differential proteins, age-matched diabetic patients (240 patients) and healthy controls (160 patients) were included as controls. RESULTS: Dynamic serum proteomics trend showed that the level of negative regulatory proteins related to endothelial cell migration, angiogenesis, and vascular development was significantly decreased after treatment of diabetic foot ulcer. GO enrichment analysis suggested that differentially expressed proteins were mainly enriched in protein activation cascade, immunoglobulin production, and complement activation. The researchers identified the core proteins APOA1, LPA, and APOA2 through a convergence of serum and skin proteomics screening. Clinical cases further validated that APOA1 levels are decreased in diabetic foot ulcer patients and are correlated with disease severity. In addition, animal experiments showed that APOA1 could promote wound healing in diabetic mice. CONCLUSIONS: Based on our dynamic proteomics and clinical case studies, our bioinformatic analysis suggests that APOA1 plays a critical role in linking coagulation, inflammation, angiogenesis, and wound repair, making it a key protein that promotes the healing of diabetic foot ulcers.