Signaling pathways and targeted therapy for rosacea.

Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF-κB), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF-α), IL-6, IL-1ß, C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies.

Differences in the Clinical Characteristics of Male Patients With Different Ages of Rosacea: A Retrospective Study of 215 Male Outpatients.

BACKGROUND: Rosacea is more common in women and Caucasians, leading to little research on rosacea in Asian men. Additionally, there is limited research on the patients across different age groups. AIMS: The aim of this study is to analyze and compare the characteristics of male patients of rosacea among different age groups. METHODS: A retrospective analysis was conducted on 215 male patients with rosacea, investigating their characteristics, clinical symptoms, exacerbating factors, complications, psychological status, and treatment, as well as exploring factors influencing the early onset of male rosacea. RESULTS: The patients were divided into three age groups (≤ 30 years, 31-44 years, and ≥ 45 years), with the study revealing an average age of 38.59 ± 13.13 years among the patients. The most common subtype of rosacea in men was erythematotelangiectatic rosacea (ETR), followed by phymatous rosacea (PhR). The main reported features included persistent erythema (87.4%) and telangiectasia (71.2%), predominantly affecting the nose (58.6%) and cheeks (56.3%). Twenty-six percent of patients reported concurrent skin diseases, with 14.0% reporting systemic diseases. Significant differences were observed among different age groups regarding family history, clinical features, lesion distribution, symptom severity, aggravating factors, presence of systemic diseases, and treatment preferences. Subjective skin typing, Fitzpatrick phototype, and positive family history were identified as factors influencing the age of onset of rosacea in men. CONCLUSION: Male patients with rosacea exhibit distinct clinical characteristics, with a greater prevalence of nasal involvement and nasal lesions among male patients. Clinical features vary among different age groups, with patients aged ≥ 45 experiencing more complex and severe symptoms. Patients aged ≤ 30 may be more influenced by genetic factors and have higher treatment expectations.

[Chemical Spatiotemporal Characteristics and Environmental Driving Factors of Groundwater in Hetao Irrigation Area].

To explore the chemical characteristics and environmental factors of groundwater in the Hetao Irrigation Area of Inner Mongolia, five irrigation fields, including UulanBuh, Jiefangzha, Yongji, Yichang, and Wulat, were selected as the research area. From 72 groundwater observation wells, a total of 216 groundwater samples were collected throughout three typical periods： the end of freeze-thaw （March）, the middle of irrigation （July）, and the end of autumn watering （November）. Comprehensive methods were utilized, such as statistical analysis, Piper three-line diagram, Gibbs diagram, ion ratio, and principal component analysis, to explore the changes in the groundwater chemical environment and the environmental driving factors of groundwater component formation. The groundwater drinking suitability was evaluated using the water quality index （WQI）, and the irrigation suitability was analyzed using the USSL and Wilcox plots. The results indicated that the groundwater in the research areas was generally saline, and the total anion and cation concentrations in each period in ascending order were as follows： late freeze-thaw stage, late autumn irrigation stage, and mid-irrigation stage, with Na+ and Cl- being the major contributing ions. The chemical type of groundwater was dominated by Cl-Na, followed by Cl·SO4-Ca·Mg and a coexistence with SO4-Ca·Mg, HCO3·Cl-Na, HCO3-Na, and HCO3-Ca·Mg. Based on WQI values, the shallow groundwater in Hetao Irrigation District was mainly classified as Class IV and Class V, and the quality was poor in general. According to the USSL diagram and Wilcox diagram, the comprehensive evaluation results showed that the salinity and sodium concentration of shallow groundwater in the irrigation area were generally high. A total of 80.6% of the water samples during the late freeze-thaw period, 76.1% during the mid-irrigation period, and 77.6% during the late autumn irrigation period lacked irrigation suitability. Two major controlling factors of groundwater chemical characteristics were present in the study area, namely, evaporation and rock weathering, and Na+ and Cl- mainly came from the dissolution and cation exchange of salt rocks. Agricultural irrigation and drought were the chief driving factors of groundwater chemical evolution in the Hetao Irrigation Area. The study provides technical support for optimizing agricultural management measures and a theoretical reference for rational utilization of groundwater resources in the Yellow River irrigation area of Inner Mongolia.

Causal relationship between immune cells and pulmonary arterial hypertension: Mendelian randomization analysis.

Immunity and inflammation in pulmonary arterial hypertension (PAH) has gained more attention. This research aimed to investigate the potential causal connections between 731 immunophenotypes and the likelihood of developing PAH. We obtained immunocyte data and PAH from openly accessible database and used Mendelian randomization (MR) analysis to evaluate the causal association between each immunophenotype and PAH. Various statistical methods were employed: the MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode. In the study of 731 different types of immune cells, it was found that 9 showed a potential positive connection (IVW P < .05) with increased risk of PAH, while 19 had a possible negative link to decreased risk. Following false discovery rate (FDR) adjustment, the analysis using the IVW method demonstrated that 5 immune phenotypes were significantly associated with PAH (FDR < 0.05, OR > 1). Conversely, there was a negative correlation between PAH and 4 immune cell types (FDR < 0.05, OR < 1). Sensitivity analyses suggested the robustness of all MR findings. This research, for the first time, has revealed indicative evidence of a causal link between circulating immune cell phenotypes and PAH through genetic mechanisms. These results underscore the importance of immune cells in the pathogenesis of PAH.

Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

Assessing the risk of tumor lysis syndrome associated with the use of antineoplastic agents: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database.

Background: The use of antineoplastic agents is one of the important triggers of tumor lysis syndrome (TLS), but there is still a lack of comprehensive understanding of antineoplastic agents that may trigger TLS and the TLS risk differences between different antineoplastic agents. Objectives: This study aims to investigate the TLS risk of different antineoplastic agents and provide reference information for clinical practice. Design: Real-world adverse events data in the FDA Adverse Event Reporting System (FAERS) database were used as the basis for the disproportionality analysis. Methods: We reviewed the TLS reports in the FAERS database from 2004 to 2022 to summarize an antineoplastic agent list that was reported to trigger TLS, based on which we conducted disproportionality analysis to assess the TLS risk of each antineoplastic agent. Results: In all, 164 antineoplastic agents were reported to trigger TLS. On the whole, rituximab was the most reported antineoplastic agent in TLS reports, followed by cyclophosphamide, venetoclax, doxorubicin, and etoposide, while tagraxofusp was the antineoplastic agent with the highest adverse drug reaction (ADR) signal strength in signal detection, followed by floxuridine, pentostatin, tebentafusp, and venetoclax. Integrating ADR signal detection results, 129 of 164 antineoplastic agents showed at least one positive ADR signal, and six antineoplastic agents (bevacizumab, carboplatin, cisplatin, fluorouracil, lenvatinib, and paclitaxel) have the highest total number of positive signals. Further classifying the 164 antineoplastic agents into 46 chemical subgroups to conduct ADR signal detection, nitrogen mustard analogs were the most reported antineoplastic agent subclasses, followed by clusters of differentiation 20 inhibitors, and pyrimidine analogs, while clusters of differentiation 22 inhibitors were the antineoplastic agent subclass with the highest ADR signal strength, followed by podophyllotoxin derivatives and actinomycines. Conclusion: Our study showed the TLS risk characteristics of 164 antineoplastic agents by detecting and integrating ADR signals, which may help to optimize clinical practice.

METHODS: Using data from the FDA Adverse Event Reporting System (FAERS) between the years 2004 and 2022, we reviewed TLS reports associated with antineoplastic agent exposure, summarized an antineoplastic agent list that was reported as the potential culprit-drug of TLS, and explored the TLS risk of different antineoplastic agents by disproportionality analysis. RESULTS: Our results showed that 164 antineoplastic agents, involving 64 antineoplastic agent subclasses, were reported as the potential culprit-drug of TLS in the FAERS database, in which 129 antineoplastic agents and 39 antineoplastic agent subclasses were associated with increased TLS risk to varying degrees. CONCLUSIONS: Our research expounded the differences in TLS risks of different antineoplastic agents, which helps us pay attention to the occurrence of TLS and give timely treatment when prescribing high-TLS-risk antineoplastic agents to patients.

Antineoplastic agent and the risk of tumor lysis syndrome Background: Antineoplastic agents are medicines that help treat cancer. It is one of the most outstanding achievements of human beings in medicine, which plays an increasingly important role in improving human health and prolonging the life span of cancer patients. However, adverse reactions (ADRs) associated with the use of antineoplastic agents may also cause unexpected harm to patients. Therefore, it is essential to have a comprehensive understanding of antineoplastic-related ADRs to ensure the lives of cancer patients. Tumor lysis syndrome (TLS) is a potentially life-threatening ADR that may occur during antineoplastic agent treatment. However, there is still a lack of comprehensive understanding of antineoplastic agents that may trigger TLS and their risk differences. This study aimed to comprehensively investigate the TLS risk of antineoplastic agents from the pharmacovigilance perspective, providing reference information for patients, health professionals, regulators, and others concerned with antineoplastic agent safety.

Redox interference-free bimodal paraoxon sensing enabled by an aggregation-induced emission nanozyme catalytically hydrolyzing phosphoesters specifically.

In view of the current serious situation of organophosphorus pesticides (OPs) residue contamination, developing rapid and accurate OPs sensors is a matter of urgency. Redox-nanozyme based colorimetric sensors have been widely researched and utilized in OPs residue determination, but overcoming the interference of external redox substances and the effect of single-signal modes on detection performance is still a challenge. Here we fabricated a Zr-based metal-organic framework (MOF) featuring specific phosphatase-like activity and strong aggregation-induced emission (AIE) fluorescence for redox interference-free bimodal pesticide sensing. In the MOF, the activity-tunable Zr4+ node offered high hydrolytic activity and affinity toward P-O containing substrates, and the rigid framework structure effectively enhanced the fluorescence emission of the ligand 1,1,2,2-tetra(4-carboxylphenyl)ethylene. The developed AIEzyme could efficiently catalyze the hydrolysis of paraoxon to yellow p-nitrophenol, which further reduced the intrinsic AIE fluorescence of AIEzyme through internal filtration effect. Thereby, a natural enzyme-free dual-mode colorimetric/fluorescence approach was established for paraoxon detection with no interference from redox substances, and a smartphone-assisted portable platform was further developed to enable the facile, rapid, and high-performance sensing of the pesticide in complex practical matrices.

Evidence of a causal relationship between blood pressure and pathological scars: a bidirectional Mendelian randomization study.

Background: Recent advancements in basic medicine and epidemiology suggest a potential influence of blood pressure on scar formation, yet the specifics of this relationship are not fully understood. This study aims to clarify the causal link between blood pressure and the development of pathological scars using Mendelian randomization (MR). Methods: This study employed genetic variants closely linked to blood pressure as instrumental variables to explore the relationship between blood pressure and pathological scars. The inverse variance weighted (IVW) method was used for analysis. Results: Our analysis identified a notable association where higher blood pressure was correlated with a lower risk of pathological scars. Specifically, an increase in diastolic blood pressure (odds ratio [OR] per standard deviation increase: 0.67 [95% Confidence Interval [CI], 0.49-0.99]), systolic blood pressure (OR per standard deviation increase: 0.66 [95% CI, 0.46-0.93]), and hypertension (pooled OR: 0.39 [95% CI, 0.18-0.85]) were significantly associated with a reduced risk of keloids. Similarly, a genetic predisposition to hypertension (pooled OR: 0.31 [95% CI, 0.11-0.89]) was significantly associated with a reduced risk of hypertrophic scars. Neither reverse MR analysis nor Steiger's test indicated a significant reverse causal relationship between hypertension and either keloids or hypertrophic scars. Conclusion: The findings suggest a protective role of higher blood pressure against the development of pathological scars, including keloids and hypertrophic scars. However, the inconsistency observed across different MR methods warrants cautious interpretation and underscores the need for further investigation to confirm these findings.

Nanozyme-Enabled Biomedical Diagnosis: Advances, Trends, and Challenges.

As nanoscale materials with the function of catalyzing substrates through enzymatic kinetics, nanozymes are regarded as potential alternatives to natural enzymes. Compared to protein-based enzymes, nanozymes exhibit attractive characteristics of low preparation cost, robust activity, flexible performance adjustment, and versatile functionalization. These advantages endow them with wide use from biochemical sensing and environmental remediation to medical theranostics. Especially in biomedical diagnosis, the feature of catalytic signal amplification provided by nanozymes makes them function as emerging labels for the detection of biomarkers and diseases, with rapid developments observed in recent years. To provide a comprehensive overview of recent progress made in this dynamic field, here an overview of biomedical diagnosis enabled by nanozymes is provided. This review first summarizes the synthesis of nanozyme materials and then discusses the main strategies applied to enhance their catalytic activity and specificity. Subsequently, representative utilization of nanozymes combined with biological elements in disease diagnosis is reviewed, including the detection of biomarkers related to metabolic, cardiovascular, nervous, and digestive diseases as well as cancers. Finally, some development trends in nanozyme-enabled biomedical diagnosis are highlighted, and corresponding challenges are also pointed out, aiming to inspire future efforts to further advance this promising field.

Evaluating the therapeutic effect of LIPUS in the early stage of traumatic brain injury using FA and T2* in rats.

To evaluate the protective effect of LIPUS at the early stage of brain trauma in rats, 45 rats were randomly divided into 3 groups: sham (n = 15), TBI (n = 15) and LIPUS treatment groups (n = 15). Ipsilateral and contralateral cortical and thalamic parameters obtained by diffusion tensor imaging (DTI) and fast low-angle shot magnetic resonance imaging (FLASH-MRI) were measured at different times after trauma. For fractional anisotropy (FA) and T2* values, two-way repeated measures ANOVA with Tukey's post hoc was used for intergroup comparisons. With observation time prolonged, the FA values of the ipsilateral cortex in the TBI group gradually increased and were significantly higher than those in the LIPUS treatment group on Day 7 (adjusted P = 0.0067). FA values in the contralateral cortex decreased at this time and were significantly lower than those in the LIPUS treatment group (adjusted P = 0.0192). Meanwhile, compared with LIPUS group, FA values were significantly higher in the injured thalamus (adjusted P = 0.0025). Combined with correlation analysis, FA values were positively correlated with neuronal damage (P = 0.0148, r2 = 0.895). At 7 days after trauma, T2* values in the ipsilateral cortex of the TBI group were significantly lower. After analysis of ferritin content and correlation, we found that T2* values were negatively correlated with ferritin (P = 0.0259, r2 = -0.849). By measuring post-traumatic changes in FA and T2* values, it is possible to demonstrate a neuronal protective effect of LIPUS in the early phase of TBI rats and promote brain rehabilitation.

Claude 3 Opus and ChatGPT With GPT-4 in Dermoscopic Image Analysis for Melanoma Diagnosis: Comparative Performance Analysis.

BACKGROUND: Recent advancements in artificial intelligence (AI) and large language models (LLMs) have shown potential in medical fields, including dermatology. With the introduction of image analysis capabilities in LLMs, their application in dermatological diagnostics has garnered significant interest. These capabilities are enabled by the integration of computer vision techniques into the underlying architecture of LLMs. OBJECTIVE: This study aimed to compare the diagnostic performance of Claude 3 Opus and ChatGPT with GPT-4 in analyzing dermoscopic images for melanoma detection, providing insights into their strengths and limitations. METHODS: We randomly selected 100 histopathology-confirmed dermoscopic images (50 malignant, 50 benign) from the International Skin Imaging Collaboration (ISIC) archive using a computer-generated randomization process. The ISIC archive was chosen due to its comprehensive and well-annotated collection of dermoscopic images, ensuring a diverse and representative sample. Images were included if they were dermoscopic images of melanocytic lesions with histopathologically confirmed diagnoses. Each model was given the same prompt, instructing it to provide the top 3 differential diagnoses for each image, ranked by likelihood. Primary diagnosis accuracy, accuracy of the top 3 differential diagnoses, and malignancy discrimination ability were assessed. The McNemar test was chosen to compare the diagnostic performance of the 2 models, as it is suitable for analyzing paired nominal data. RESULTS: In the primary diagnosis, Claude 3 Opus achieved 54.9% sensitivity (95% CI 44.08%-65.37%), 57.14% specificity (95% CI 46.31%-67.46%), and 56% accuracy (95% CI 46.22%-65.42%), while ChatGPT demonstrated 56.86% sensitivity (95% CI 45.99%-67.21%), 38.78% specificity (95% CI 28.77%-49.59%), and 48% accuracy (95% CI 38.37%-57.75%). The McNemar test showed no significant difference between the 2 models (P=.17). For the top 3 differential diagnoses, Claude 3 Opus and ChatGPT included the correct diagnosis in 76% (95% CI 66.33%-83.77%) and 78% (95% CI 68.46%-85.45%) of cases, respectively. The McNemar test showed no significant difference (P=.56). In malignancy discrimination, Claude 3 Opus outperformed ChatGPT with 47.06% sensitivity, 81.63% specificity, and 64% accuracy, compared to 45.1%, 42.86%, and 44%, respectively. The McNemar test showed a significant difference (P<.001). Claude 3 Opus had an odds ratio of 3.951 (95% CI 1.685-9.263) in discriminating malignancy, while ChatGPT-4 had an odds ratio of 0.616 (95% CI 0.297-1.278). CONCLUSIONS: Our study highlights the potential of LLMs in assisting dermatologists but also reveals their limitations. Both models made errors in diagnosing melanoma and benign lesions. These findings underscore the need for developing robust, transparent, and clinically validated AI models through collaborative efforts between AI researchers, dermatologists, and other health care professionals. While AI can provide valuable insights, it cannot yet replace the expertise of trained clinicians.

Transcriptome- and genome-wide systematic identification of expansin gene family and their expression in tuberous root development and stress responses in sweetpotato (Ipomoea batatas).

Introduction: Expansins (EXPs) are essential components of the plant cell wall that function as relaxation factors to directly promote turgor-driven expansion of the cell wall, thereby controlling plant growth and development and diverse environmental stress responses. EXPs genes have been identified and characterized in numerous plant species, but not in sweetpotato. Results and methods: In the present study, a total of 59 EXP genes unevenly distributed across 14 of 15 chromosomes were identified in the sweetpotato genome, and segmental and tandem duplications were found to make a dominant contribution to the diversity of functions of the IbEXP family. Phylogenetic analysis showed that IbEXP members could be clustered into four subfamilies based on the EXPs from Arabidopsis and rice, and the regularity of protein motif, domain, and gene structures was consistent with this subfamily classification. Collinearity analysis between IbEXP genes and related homologous sequences in nine plants provided further phylogenetic insights into the EXP gene family. Cis-element analysis further revealed the potential roles of IbEXP genes in sweetpotato development and stress responses. RNA-seq and qRT-PCR analysis of eight selected IbEXPs genes provided evidence of their specificity in different tissues and showed that their transcripts were variously induced or suppressed under different hormone treatments (abscisic acid, salicylic acid, jasmonic acid, and 1-aminocyclopropane-1-carboxylic acid) and abiotic stresses (low and high temperature). Discussion: These results provide a foundation for further comprehensive investigation of the functions of IbEXP genes and indicate that several members of this family have potential applications as regulators to control plant development and enhance stress resistance in plants.

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

Study of the multitarget mechanism of Astragalus (HUANGQI) in the treatment of Alzheimer's disease based on network pharmacology and molecular docking technology.

CONTEXT: In China, HUANGQI is widely used for the treatment of Alzheimer's disease (AD). However, a comprehensive understanding of its mechanism of anti-AD effects is lacking. OBJECTIVE: To explore the active ingredients of HUANGQI and its potential targets and mechanisms of action in AD. MATERIALS AND METHODS: The active ingredients and targets of HUANGQI were screened from databases (TCSMP, ETCM, and BATMan), and AD-related genes were obtained from DrugBank and GeneCards. The same target genes were screened, and a drug-target disease network was constructed. The PPI network was constructed and GO and KEGG pathway enrichment analyses of the targets. The Cell Counting Kit-8 (CCK-8) assay was used to determine suitable HUANGQI treatment concentrations for HT-22 cells between 0-480 µg/mL. CCK-8, FITC-phalloidin and propidium iodide (PI) assays were used to examine the protective effect of (0, 60, 120, 240 µg/mL) of HUANGQI on 20 µM Aß1-42-induced HT-22 cell cytotoxicity. RESULTS: Twelve active ingredients of HUANGQI were selected, with 679 common targets associated with AD. GO and KEGG analysis revealed that the therapeutic mechanisms of HUANGQI involve TNF, AGE, the NF-κB pathway, and nuclear receptor activity-related processes. The CCK-8 assay indicated that HUANGQI was not cytotoxic to HT-22 cells at concentrations less than 240 µg/mL and was able to attenuate Aß1-42-induced cellular damage (EC50 = 83.46 µg/mL). FITC-phalloidin and PI assays suggested that HUANGQI could alleviate 20 µM Aß1-42-induced neuronal cell cytotoxicity in a dose-dependent manner. CONCLUSION: HUANGQI has a protective effect on Aß1-42-induced nerve cell injury; further mechanism research was needed.

The Roles of Segments and Tone in Mandarin Lexical Processing: An ERP Study.

BACKGROUNDS: Segments and tone are important sub-syllabic units that play large roles in lexical processing in tonal languages. However, their roles in lexical processing remain unclear, and the event-related potential (ERP) technique will benefit the exploration of the cognitive mechanism in lexical processing. METHODS: The high temporal resolution of ERP enables the technique to interpret rapidly changing spoken language performances. The present ERP study examined the different roles of segments and tone in Mandarin Chinese lexical processing. An auditory priming experiment was designed that included five types of priming stimuli: consonant mismatch, vowel mismatch, tone mismatch, unrelated mismatch, and identity. Participants were asked to judge whether the target of the prime-target pair was a real Mandarin disyllabic word or not. RESULTS: Behavioral results including reaction time and response accuracy and ERP results were collected. Results were different from those of previous studies that showed the dominant role of consonants in lexical access in mainly non-tonal languages like English. Our results showed that consonants and vowels play comparable roles, whereas tone plays a less important role than do consonants and vowels in lexical processing in Mandarin. CONCLUSIONS: These results have implications for understanding the brain mechanisms in lexical processing of tonal languages.

METTL1-mediated tRNA m7G methylation and translational dysfunction restricts breast cancer tumorigenesis by fueling cell cycle blockade.

BACKGROUND: RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7G tRNA modifications in breast cancer (BC) remain largely obscure. METHODS: The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of m7G tRNA modification and mRNA translation efficiency in BC, m7G-methylated tRNA immunoprecipitation sequencing (m7G tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms. RESULTS: The tRNA m7G methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased m7G levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with m7G. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. CONCLUSION: Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA m7G modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.

How does the ion concentration affect the functions of kinesin BimC.

BimC family proteins are bipolar motor proteins belonging to the kinesin superfamily which promote mitosis by crosslinking and sliding apart antiparallel microtubules. Understanding the binding mechanism between the kinesin and the microtubule is crucial for researchers to make advances in the treatment of cancer and other malignancies. Experimental research has shown that the ion concentration affects the function of BimC significantly. But the insights of the ion-dependent function of BimC remain unclear. By combining molecular dynamics (MD) simulations with a series of computational approaches, we studied the electrostatic interactions at the binding interfaces of BimC and the microtubule under different KCl concentrations. We found the electrostatic interaction between BimC and microtubule is stronger at 0 mM KCl compared to 150 mM KCl, which is consistent with experimental conclusions. Furthermore, important salt bridges and residues at the binding interfaces of the complex were identified, which illustrates the details of the BimC-microtubule interactions. Molecular dynamics analyses of salt bridges identified that the important residues on the binding interface of BimC are positively charged, while those residues on the binding interface of the tubulin heterodimer are negatively charged. The finding in this work reveals some important mechanisms of kinesin-microtubule binding, which helps the future drug design for cancer therapy.

The Potential Mechanism of Eriodictyol in Treating Alzheimer's Disease: A Study on Computer-assisted Investigational Strategies.

BACKGROUND: At present, drug development for treating Alzheimer's disease (AD) is still highly challenging. Eriodictyol (ERD) has shown great potential in treating AD, but its molecular mechanism is unknown. OBJECTIVE: We aimed to explore the potential targets and mechanisms of ERD in the treatment of AD through network pharmacology, molecular docking, and molecular dynamics simulations. METHODS: ERD-related targets were predicted based on the CTD, SEA, PharmMapper, Swiss TargetPrediction, and ETCM databases, and AD-related targets were predicted through the TTD, OMIM, DrugBank, GeneCards, Disgenet, and PharmGKB databases. Protein-protein interaction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomics analyses (KEGG) were used to analyse the potential targets and key pathways of the anti-AD effect of ERD. Subsequently, potential DEGs affected by AD were analysed using the AlzData database, and their relationships with ERD were evaluated through molecular docking and molecular dynamics simulations. RESULTS: A total of 198 ERD-related targets, 3716 AD-related targets, and 122 intersecting targets were identified. GO annotation analysis revealed 1497 biological processes, 78 cellular components, and 132 molecular functions of 15 core targets. KEGG enrichment analysis identified 168 signalling pathways. We ultimately identified 9 DEGs associated with AD through analysis of the AlzData data. Molecular docking results showed good affinity between the selected targets and ERD, with PTGS2, HSP90AA1, and BCL2. The interactions were confirmed by molecular dynamics simulations. CONCLUSION: ERD exerts anti-AD effects through multiple targets, pathways, and levels, providing a theoretical foundation and valuable reference for the development of ERD as a natural anti-AD drug.

Potential Mechanism by which Eriodictyol Protects against Doxorubicininduced Cardiotoxicity based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

BACKGROUND: The clinical use of doxorubicin (DOX), an anthracycline antibiotic with broad-spectrum applications against various malignant tumors, is limited by doxorubicininduced cardiotoxicity (DIC). Eriodictyol (ERD) has shown cardioprotective effects, but the mechanism of its protective effect on DIC remains unknown. AIMS: This study aimed to explore the potential mechanisms by which ERD confers protection against DIC. METHODS: ERD and DIC targets were identified from the TCMSP, PharmMaper, SwissTargetPrediction, TargetNet, BATMAN, GeneCards, and PharmGKB databases. Differential gene expression data between DIC and normal tissues were extracted from the GEO database. A protein‒ protein interaction (PPI) network of the intersecting ERD-DIC targets was constructed using the STRING platform and visualized with Cytoscape 3.10.0 software. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for ERD-DIC cross-targets were conducted. Validation included molecular docking with AutoDock Tools software and molecular dynamics simulations with Gromacs 2019.6 software. RESULTS: Network pharmacology analysis revealed 43 intersecting ERD-DIC targets, including 6 key targets. GO functional enrichment analysis indicated that the intersecting targets were enriched in 550 biological processes, 45 cell components, and 41 molecular functions. KEGG pathway enrichment analysis identified 114 enriched signaling pathways. Molecular docking revealed a strong binding affinity between ERD and 6 key targets, as well as multiple targets within the ROS pathway. Molecular dynamics simulations indicated that ERD has favorable binding with 3 crucial targets. CONCLUSION: The systematic network pharmacology analysis suggests that ERD may mitigate DIC through multiple targets and pathways, with the ROS pathway potentially playing a crucial role. These findings provide a reference for foundational research and clinical applications of ERD in treating DIC.

3D-Printed Flexible Microfluidic Health Monitor for In Situ Sweat Analysis and Biomarker Detection.

Wearable sweat biosensors have shown great progress in noninvasive, in situ, and continuous health monitoring to demonstrate individuals' physiological states. Advances in novel nanomaterials and fabrication methods promise to usher in a new era of wearable biosensors. Here, we introduce a three-dimensional (3D)-printed flexible wearable health monitor fabricated through a unique one-step continuous manufacturing process with self-supporting microfluidic channels and novel single-atom catalyst-based bioassays for measuring the sweat rate and concentration of three biomarkers. Direct ink writing is adapted to print the microfluidic device with self-supporting structures to harvest human sweat, which eliminates the need for removing sacrificial supporting materials and addresses the contamination and sweat evaporation issues associated with traditional sampling methods. Additionally, the pick-and-place strategy is employed during the printing process to accurately integrate the bioassays, improving manufacturing efficiency. A single-atom catalyst is developed and utilized in colorimetric bioassays to improve sensitivity and accuracy. A feasibility study on human skin successfully demonstrates the functionality and reliability of our health monitor, generating reliable and quantitative in situ results of sweat rate, glucose, lactate, and uric acid concentrations during physical exercise.