Viral shedding pattern of severe fever with thrombocytopenia syndrome virus in severely ill patients: A prospective, Multicenter cohort study.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is spreading rapidly in Asia. The pathway of SFTS virus shedding from patient and specific use of personal protective equipments (PPEs) against viral transmission have rarely been reported. The study was to determine SFTS virus (SFTSV) shedding pattern from the respiratory, digestive and urinary tract to outside in patients. Methods: Patients were divided into mild and severe groups in three sentinel hospitals for SFTS in Anhui province from April 2020 to October 2022. SFTSV level from blood, throat swabs, fecal/anal swabs, urine and bedside environment swabs of SFTS patients were detected by qRT-PCR. Specific PPEs were applied in healthcare workers contacting with the patients who had oropharyngeal virus shedding and hemorrhagic signs. Results: A total of 189 SFTSV-confirmed patients were included in the study, 54 patients died (case fatality rate, 28.57 %). Positive SFTSV in throat swabs (T-SFTSV), fecal/anal swabs (F-SFTSV) and urine (U-SFTSV) were detected in 121 (64.02 %), 91 (48.15 %) and 65 (34.4 %) severely ill patients, respectively. The levels of T-SFTSV, F-SFTSV and U-SFTSV were positively correlated with the load of SFTSV in blood. We firstly revealed that SFTSV positive rate of throat swabs were correlated with occurrence of pneumonia and case fatality rate of patients (P < 0.0001). Specific precaution measures were applied by healthcare workers in participating cardiopulmonary resuscitation and orotracheal intubation for severely ill patients with positive T-SFTSV, no event of SFTSV human-to-human transmission occurred after application of effective PPEs. Conclusions: Our research demonstrated SFTSV could shed out from blood, oropharynx, feces and urine in severely ill patients. The excretion of SFTSV from these parts was positively correlated with viral load in the blood. Effective prevention measures against SFTSV human-to-human transmission are needed.

Ectopic eruption of maxillary first permanent molars: Risk factors and association with alveolar and maxillary characteristics on children.

Background/purpose: The etiology of the ectopic eruption (EE) of the maxillary first permanent molars (FPM) remains unclear and controversial. This study was designed to explore the dental and skeletal factors for EE of the FPM in children. Materials and methods: Children aged 6-10 years were recruited to this study. Subjects were assigned to the ectopic eruption group (EEG) and the normal eruption group (NEG). Lateral cephalometric radiographs and panoramic radiographs were measured by angular and linear indices. Results: The prevalence of EE of maxillary FPM was higher in males and at younger ages. Subjects with skeletal class III malocclusion were more likely to be diagnosed with EE of maxillary FPM. The SNA, ANB, FMIA, Wits, Ptm-A, ANS-PNS, overbite, and overjet were significantly different between the EEG and the NEG. The length of the posterior region of the maxillary alveolar bone, U6-OP, and eruptive angulation of the maxillary FPM were statistically different between the two groups. Conclusion: Male sex, skeletal class III malocclusion, mesial inclination of the maxillary FPM, hypoplasia of the maxilla, and insufficient length of the posterior region of the maxillary alveolar bone were related to EE of the maxillary FPM.

Direct Synthesis of α-Ketothioamide Derivatives through a One-Pot Reaction of Sulfur Ylides, Nitrosobenzenes, and Thioacetic Acid.

A one-pot approach has been developed for the synthesis of α-ketothioamide derivatives from sulfur ylides, nitrosobenzenes, and thioacetic acid. This protocol is carried out under mild reaction conditions in generally moderate to excellent yields without any precious catalysts, affording the derivatives with structural diversity. Additionally, a possible mechanism for this chemical transformation is proposed.

Full life cycle changes of low impacted mandibular third molar associated cystic lesions and adjacent tooth root resorption: a retrospective study.

OBJECTIVE: Low impacted third molars are usually asymptomatic and are often found by X-ray examination. The removal of asymptomatic low impacted third molars is one of the most controversial clinical issues in oral and maxillofacial surgery. METHODS: In this study, 806 patients with low impacted mandibular third molars (LIMTMs) (full bony impaction) were analyzed to determine the prevalence and risk factors for cystic lesions and adjacent tooth root resorption throughout the patients' entire life cycle. RESULTS: The results showed that the prevalence of adjacent tooth root resorption and cystic lesions was age-related, exhibiting a trend of first increasing and then decreasing; prevalence peaked at the age of 41 to 45 years old, the prevalence rates were 12.50% and 11.11% respectively. And the lowest prevalence rate was 2.86% and 2.44% in ≥ 61 group and 56- to 60-year age group respectively. Age was an independent risk factor for adjacent tooth root resorption of LIMTMs, whereas age and impaction type (especially inverted impaction) were independent risk factors for cystic lesions. CONCLUSIONS: The full life cycle management strategy for LIMTMs may need to be individualized. Surgical removal is recommended for LIMTMs in patients younger than 41 to 45 years, especially for inverted, mesioangular, and horizontally impacted LIMTMs. LIMTMs in patients older than 41 to 45 years may be treated conservatively with regular follow-up, but surgical removal of inverted impacted LIMTMs is still recommended to avoid cyst formation.

Role of epigenetic regulatory mechanisms in age-related bone homeostasis imbalance.

Alterations to the human organism that are brought about by aging are comprehensive and detrimental. Of these, an imbalance in bone homeostasis is a major outward manifestation of aging. In older adults, the decreased osteogenic activity of bone marrow mesenchymal stem cells and the inhibition of bone marrow mesenchymal stem cell differentiation lead to decreased bone mass, increased risk of fracture, and impaired bone injury healing. In the past decades, numerous studies have reported the epigenetic alterations that occur during aging, such as decreased core histones, altered DNA methylation patterns, and abnormalities in noncoding RNAs, which ultimately lead to genomic abnormalities and affect the expression of downstream signaling osteoporosis treatment and promoter of fracture healing in older adults. The current review summarizes the impact of epigenetic regulation mechanisms on age-related bone homeostasis imbalance.

Prediction of severe hypertriglyceridemia-associated acute pancreatitis using a nomogram based on CT findings and blood biomarkers.

Hypertriglyceridemia is a common cause of acute pancreatitis (AP). Fatty liver, a manifestation of metabolic syndrome, is related to the severity of AP. The present study aimed to construct an accurate predictive model for severe AP (SAP) by combining the fatty liver infiltration on a computerized tomography (CT) scan with a series of blood biomarkers in patients with hypertriglyceridemia-associated AP (HTG-AP). A total of 213 patients diagnosed with HTG-AP were included in the present retrospective study. Clinical information and imageological findings were retrospectively analyzed. The model was constructed from independent risk factors using univariate analysis, the least absolute shrinkage and selection operator method. Subsequently, the data from the training group of 111 patients with HTG-AP was analyzed using logistic regression analysis. The efficacy of the model was verified using an external validation group of 102 patients through the receiver operating characteristic curve (ROC). Independent predictors, including serum calcium, C-reactive protein, lactate dehydrogenase and liver-to-spleen CT attenuation ratio (L/S ratio), were incorporated into the nomogram model for SAP in HTG-AP. The model achieved a sensitivity of 91.3% and a specificity of 88.6% in the training group. Compared with the Ranson model, the established nomogram model exhibited a better discriminative ability in the training group [area under the curve (AUC): 0.957] and external validation group (AUC: 0.930), as well as better calibration and clinical benefits. The present study demonstrates that the constructed nomogram based on CT findings and blood biomarkers is useful for the accurate prediction of SAP in HTG-AP.

Targeting HOXA11-AS to mitigate prostate cancer via the glycolytic metabolism: In vitro and in vivo.

As oncogenes or oncogene suppressors, long-stranded non-coding RNAs are essential for the formation and progression of human tumours. However, the mechanisms behind the regulatory role of RNA HOXA11-AS in prostate cancer (PCa) are unclear. PCa is a common malignant tumour worldwide, and an increasing number of studies have focused on its metabolic profile. Studies have shown that the long non-coding RNA (lncRNA) HOXA11-AS is aberrantly expressed in many tumours. However, the role of HOXA11-AS in PCa is unclear. This work aimed to determine how HOXA11-AS regulated PCa in vitro and in vivo. We first explored the clinical role of HOXA11-AS in PCa using bioinformatics methods, including single sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-logistics systematically. In this study, PCa cell lines were selected to assess the PCa regulatory role of HOXA11-AS overexpression versus silencing in vitro, and tumour xenografts were performed in nude mice to assess tumour suppression by HOXA11-AS silencing in vivo. HOXA11-AS expression was significantly correlated with clinicopathological factors, epithelial-mesenchymal transition (EMT) and glycolysis. Moreover, key genes downstream of HOXA11-AS exhibited good clinical diagnostic properties for PCa. Furthermore, we studied both in vitro and in vivo effects of HOXA11-AS expression on PCa. Overexpression of HOXA11-AS increased PCa cell proliferation, migration and EMT, while silencing HOXA11-AS had the opposite effect on PCa cells. In addition, multiple metabolites were downregulated by silencing HOXA11-AS via the glycolytic pathway. HOXA11-AS silencing significantly inhibited tumour development in vivo. In summary, silencing HOXA11-AS can inhibit PCa by regulating glucose metabolism and may provide a future guidance for the treatment of PCa.

Proteasome activation: A novel strategy for targeting undruggable intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are characterized by their inability to adopt well-defined tertiary structures under physiological conditions. Nonetheless, they often play pivotal roles in the progression of various diseases, including cancer, neurodegenerative disorders, and cardiovascular ailments. Owing to their inherent dynamism, conventional drug design approaches based on structural considerations encounter substantial challenges when applied to IDPs. Consequently, the pursuit of therapeutic interventions directed towards IDPs presents a complex endeavor. While there are indeed existing methodologies for targeting IDPs, they are encumbered by noteworthy constrains. Hence, there exists an imminent imperative to investigate more efficacious and universally applicable strategies for modulating IDPs. Here, we present an overview of the latest advancements in the research pertaining to IDPs, along with the indirect regulation approach involving the modulation of IDP degradation through proteasome. By comprehending these advancements in research, novel insights can be generated to facilitate the development of new drugs targeted at addressing the accumulation of IDPs in diverse pathological conditions.

Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.

Synergistic Interaction between Metal Single-Atoms and Defective WO3- x Nanosheets for Enhanced Sonodynamic Cancer Therapy.

Although metal single-atom (SA)-based nanomaterials are explored as sonosensitizers for sonodynamic therapy (SDT), they normally exhibit poor activities and need to combine with other therapeutic strategies. Herein, the deposition of metal SAs on oxygen vacancy (OV)-rich WO3- x nanosheets to generate a synergistic effect for efficient SDT is reported. Crystalline WO3 and OV-rich WO3- x nanosheets are first prepared by simple calcination of the WO3·H2O nanosheets under an air and N2 atmosphere, respectively. Pt, Cu, Fe, Co, and Ni metal SAs are then deposited on WO3- x nanosheets to obtain metal SA-decorated WO3- x nanocomposites (M-WO3- x). Importantly, the Cu-WO3- x sonosensitizer exhibits a much higher activity for ultrasound (US)-induced production of reactive oxygen species than that of the WO3- x and Cu SA-decorated WO3, which is also higher than other M-WO3- x nanosheets. Both the experimental and theoretical results suggest that the excellent SDT performance of the Cu-WO3- x nanosheets should be attributed to the synergistic effect between Cu SAs and WO3- x OVs. Therefore, after polyethylene glycol modification, the Cu-WO3- x can quickly kill cancer cells in vitro and effectively eradicate tumors in vivo under US irradiation. Transcriptome sequencing analysis and further molecular validation suggest that the Cu-WO3- x-mediated SDT-activated apoptosis and TNF signaling pathways are potential drivers of tumor apoptosis induction.

Predictive power of lipid-related indicators for testosterone deficiency: a comparative analysis, NHANES 2011-2016.

BACKGROUND: Studies have shown that lipid-related indicators are associated with testosterone deficiency. However, it is difficult to determine which indicator is the most accurate predictor of testosterone deficiency. We aimed to identify the lipid-related indicators most predictive of testosterone deficiency in adults in the United States. METHODS: This observational research was conducted on a population aged ≥ 20 years. By plotting the receiver operating characteristic curve (ROC) and obtaining the corresponding area under the curve (AUC) value, we assessed the predictive capacity of TyG, WTI, LAP, and VAI for testosterone deficiency. We compared the area under the curve (AUC) values of these measures to determine if there were any statistically significant differences. The relationship between lipid-related indices and testosterone hormones was investigated using regression modeling, eXtreme Gradient Boosting (XGBoost) modeling, and sensitivity analysis. RESULTS: A total of 3,272 eligible participants were included in the study. Testosterone deficiency was found to exist in 20.63% of the participants. Subjects with higher lipid-related markers were more likely to have lower testosterone levels. LAP was the best predictor of testosterone deficiency in ROC analysis over other indicators (AUC = 0.7176, (95% CI: 0.6964-0.7389)). CONCLUSION: LAP is the most straightforward and convenient indicator for identifying testosterone deficiency in clinical practice.

Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.

Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.

With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging. It is widely acknowledged that the proteostasis network encompasses molecular chaperones, autophagy, and the ubiquitin proteasome system (UPS). Consequently, the proteostasis network emerges as an appealing target for therapeutic interventions in cardiovascular diseases. Numerous small molecules, acting as modulators of the proteostasis machinery, have exhibited therapeutic efficacy in managing cardiovascular diseases. This review centers on elucidating the role of the proteostasis network in various cardiovascular diseases and explores the potential of small molecules as therapeutic agents.

Association of TyG index with prostate-specific antigen (PSA) in American men: results from NHANES, 2003-2010.

BACKGROUND: In recent years, triglyceride-glucose index (TyG) was a new indicator of insulin resistance, and it has been widely reported that it may be associated with serum prostate-specific antigen (PSA) concentrations. AIMS: We intended to investigate the possible connection between serum PSA concentration and the TyG index. METHODS: This is a cross-sectional study of adults with complete data on TyG and serum PSA concentrations (ng/ml) from the NHANES, 2003-2010. The TyG index is obtained by the formula below: TyG = Ln [triglycerides (mg/dL) × fasting glucose(mg/dL)/2]. Multivariate regression analysis and subgroup analysis were used to examine the connection between the TyG index and serum PSA levels. RESULTS: Multiple regression analysis of the weighted linear model showed that individuals with a higher TyG index had lower PSA levels. Subgroup analyses and interaction tests showed no apparent dependence on age, race/ethnicity, BMI, household income ratio, education level, and marital status on this negative association (all interactions p > 0.05). CONCLUSIONS: TyG index is related to lower serum PSA concentrations in adult men from the USA. Further comprehensive prospective studies are needed to confirm our findings.

Prognostic Factors and Outcomes in Advanced Stage Lung Cancer Patients with COVID-19 Omicron Variant Infection.

Background: We study the characteristics and outcomes in lung cancer patients with COVID-19 Omicron variant infection. Methods: Hospitalized lung cancer patients with advanced-stage disease and laboratory-confirmed COVID-19 Omicron infection were included. Pneumonitis involving at least 25% of lung parenchyma on CT scans, accompanied by symptoms and oxygen saturation below 93%, were criteria for enrollment. Pneumonitis severity was graded using CTCAE v5.0. Treatment included Paxlovid, prednisolone, anticoagulation, and ventilation. Initial data, radiographic findings, and outcomes were compared. Logistic regression was employed to determine risk factors for in-hospital mortality. Results: Fifteen patients (median age: 65 years; 80.0% males) were included. 73.3% improved and were discharged, 20.0% died, and 6.7% remained intubated. Initial symptoms included cough (100.0%), fever (73.3%), and shortness of breath (53.3%). Symptoms resolved in discharged patients. Median fever duration was 3.5 days, and respiratory symptom recovery took 26 days. Three patients died due to respiratory failure from Omicron pneumonia. Lower oxygen saturation, reduced lymphocyte/neutrophil ratio on day 7, and diffuse bilateral lung lesions were poor prognostic factors. Conclusion: This study underscores the importance of prompt intervention and early diagnosis for lung cancer patients infected with the COVID-19 Omicron variant. Lower oxygen saturation, decreased lymphocyte/neutrophil ratio on day 7, and diffuse lung lesions on CT scans were associated with worse outcomes. Clinicians should prioritize timely and comprehensive management to improve survival rates in this population.

Cemento-Osseous Dysplasia: A Detailed Comparison of the 2005 and 2017 WHO Classifications and Case Analysis.

The WHO substantially redefined cemento-osseous dysplasia (COD) in 2017. The descriptions of COD in the 2005 and 2017 WHO classifications are quite different. In this study, we compared the difference in COD description between the 2005 and 2017 editions of the WHO classifications in detail. There are remarkable differences in the terminology, definition, synonyms, epidemiology, classifications, clinical features, radiation/pathology, prognosis, and predictive factors of COD between the two versions. At present, the surgical treatment of COD is less defined, and there is no clear guidance for the treatment of sclerotic bone. In this study, we extracted the affected teeth without removing the sclerotic bone when the bone absorption line can be only found between the root and the lesion, and we extracted the teeth as well as the lesion and curetted the granulation tissue when a bone absorption line could be seen between the lesion and the alveolar bone. According to our observation, the position of the bone absorption line can be used as a reference for the selection of sclerotic bone treatment. Sclerotic bone preservation did not increase its volume and density after tooth extraction. Sclerotic bone was composed of highly mineralized tissue with less blood vessels and cells. The position of the bone resorption line can be used as a basis for treatment selection. The high mineralization of the lesion may weaken its anti-infection ability.

Design of Multi-User Noncoherent Massive SIMO Systems for Scalable URLLC.

This paper develops and optimizes a non-orthogonal and noncoherent multi-user massive single-input multiple-output (SIMO) framework, with the objective of enabling scalable ultra-reliable low-latency communications (sURLLC) in Beyond-5G (B5G)/6G wireless communication systems. In this framework, the huge diversity gain associated with the large-scale antenna array in the massive SIMO system is leveraged to ensure ultra-high reliability. To reduce the overhead and latency induced by the channel estimation process, we advocate for the noncoherent communication technique, which does not need the knowledge of instantaneous channel state information (CSI) but only relies on large-scale fading coefficients for message decoding. To boost the scalability of noncoherent massive SIMO systems, we enable the non-orthogonal channel access of multiple users by devising a new differential modulation scheme to ensure that each transmitted signal matrix can be uniquely determined in the noise-free case and be reliably estimated in noisy cases when the antenna array size is scaled up. The key idea is to make the transmitted signals from multiple geographically separated users be superimposed properly over the air, such that when the sum signal is correctly detected, the signal sent by each individual user can be uniquely determined. To further enhance the average error performance when the array antenna number is large, we propose a max-min Kullback-Leibler (KL) divergence-based design by jointly optimizing the transmitted powers of all users and the sub-constellation assignments among them. The simulation results show that the proposed design significantly outperforms the existing max-min Euclidean distance-based counterpart in terms of error performance. Moreover, our proposed approach also has a better error performance compared to the conventional coherent zero-forcing (ZF) receiver with orthogonal channel training, particularly for cell-edge users.

Catalyzing Generation and Stabilization of Oxygen Vacancies on CeO2-x Nanorods by Pt Nanoclusters as Nanozymes for Catalytic Therapy.

Although CeO2 nanomaterials have been widely explored as nanozymes for catalytic therapy, they still suffer from relatively low activities. Herein, the catalyzing generation and stabilization of oxygen vacancies on CeO2 nanorods by Pt nanoclusters via H2 gas reduction under mild temperature (350 °C) to obtain Pt/CeO2- x , which can serve as a highly efficient nanozyme for catalytic cancer therapy, is reported. The deposited Pt on CeO2 by the atomic layer deposition technique not only can serve as the catalyst to generate oxygen vacancies under mild temperature reduction through the hydrogen spillover effect, but also can stabilize the generated oxygen vacancies. Meanwhile, the oxygen vacancies also provide anchoring sites for Pt forming strong metal-support interactions and thus preventing their agglomerations. Importantly, the Pt/CeO2- x reduced at 350 °C (Pt/CeO2- x -350R) exhibits excellent enzyme-mimicking catalytic activity for generation of reactive oxygen species (e.g., ·OH) as compared to other control samples, including CeO2 , Pt/CeO2 , and Pt/CeO2- x reduced at other temperatures, thus achieving excellent performance for tumor-specific catalytic therapy to efficiently eliminate cancer cells in vitro and ablate tumors in vivo. The excellent enzyme-mimicking catalytic activity of Pt/CeO2- x -350R originates from the good catalytic activities of oxygen vacancy-rich CeO2- x and Pt nanoclusters.

Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents.

Objective: Silibinin, a natural product extracted from the seeds of the Silybum marianum, is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents. Materials and Methods: The cell viability was evaluated by CCK8 assay. Furthermore, cell apoptosis and cell cycle progression were tested by flow cytometry. In addition, the pharmacokinetic assessment of compound 15 and silibinin through intravenous administration (i.v., 2 mg/kg) to ICR mice were performed. Results: The synthesized compounds showed better water solubilities than silibinin. Among them, compound 15 exhibited inhibitory activity against DU145 cells with IC50 value of 1.37 ± 0.140 µM. Moreover, it arrested cell cycle at G2/M phase and induced apoptosis in DU145 cells. Additionally, compound 15 also displayed longer half-life (T1/2 = 128.3 min) in liver microsomes than that of silibinin (T1/2 = 82.5 min) and appropriate pharmacokinetic parameters in mice. Conclusion: Overall, glycosylation of silibinin would be a valid strategy for the development of silibinin derivatives as anti-tumor agents.

Exploring the Mechanisms of Well-Being Occurrence Among Event Tourists: Mixed Empirical Evidence from Positive Psychology.

Introduction: This study explores the well-being dimensional components of event tourists and their identification processes in validating the well-being occurrence mechanism of event tourism and the correlation between the well-being of event tourists and the frequency and length of event tourism. Methods: This study adopted a sequential mixed-methods design that followed a pragmatic paradigm through a photo interview with event tourists and festival travel organizers (N=16). The qualitative research method provided evidence to explore the framework of content and dimensional identification of event tourists' well-being according to Seligman's PERMA model. The quantitative research phase (N=475) focused on identifying and validating the PERMA model in the event tourist well-being dimension through descriptive statistical analysis and validated factor analysis, followed by a one-way analysis of covariance to explore the effects of the frequency and endurance of FSE tourism. Results: The results show quantitative differences in the well-being dimensions and framework presentation of the PERMA model (Positive emotion, Engagement, Relationship, Meaning, and Achievement). R (relationship) and A (achievement) are identified and validated as dimensions of well-being outcomes for event tourists, while single-day or short trips of 2-3 days were most significant for event tourists' perceived well-being. Conclusion: This study provides an empirical argument, thus providing an empirical argument for uncovering the deeper influencing and exhibiting factors of the PERMA theoretical framework and a research paradigm for PERMA theory in more tourism behaviors and psychology. Second, this study provides an in-depth explanation of the five dimensions of well-being in the PERMA model. The findings show the salience of the relationship and achievement in FSE tourism well-being, providing theoretical insight into existing studies integrating positive psychology models for in-depth tourism well-being research.