Selenium participates in the formation of kidney stones by alleviating endoplasmic reticulum stress and apoptosis of renal tubular epithelial cells.

Objectives: To investigate the role of selenium and selenium-containing proteins in the etiology and pathogenesis of kidney stones.Methods: The HK-2 cell line was subjected to supersaturation oxalate treatment to establish an in vitro model of calcium oxalate kidney stones, while SD rats were administered with ethylene glycol to establish an in vivo model of calcium oxalate kidney stones. qPCR analysis was employed to investigate the alterations in selenoproteins within the models, and subsequently, genes exhibiting significant changes were identified. Subsequently, based on the functions of these genes, their regulatory effects on endoplasmic reticulum stress (ERS) and apoptosis during the disease progression were examined both in HK-2 cells and rat kidneys. Finally, Selenomethionine (SeMet) supplementation was introduced to explore its therapeutic potential for kidney stone management.Results: The involvement of Selenoprotein K in the pathogenesis of calcium oxalate kidney stone disease has been confirmed, exhibiting significant alterations. Manipulation of its expression levels through overexpression and knockdown techniques resulted in a corresponding reduction or increase in oxidative stress, ERS, and apoptosis within renal tubular epithelial cells. SelK regulates ERS and apoptosis by controlling the IRE1-ASK1-JNK pathway. In addition, SeMet treatment, which contains selenium, effectively reduced the levels of oxidative stress, ERS, and apoptosis in vivo and in vitro models, thereby alleviating tubular epithelial cell damage and reducing the formation of kidney stones in experimental rats.Discussion: Selenium is involved in the occurrence and development of kidney stones by regulating oxidative damage to renal tubular epithelial cells. The results suggest that dietary selenium supplementation in daily life may be of great significance for the prevention and treatment of kidney stones.

The effect of diet quality and body mass index on depression in older adults: a growth curve analysis.

BACKGROUND: Nutrition not only plays an important role in one's physical health, but also mental health. The causal association between nutrition and mental health remains unclear. While a healthy dietary pattern may protect one against mental illness, it is also possible that poor mental health could lead to unhealthy eating habits or choices. Furthermore, emerging studies suggest that a higher body mass index (BMI) is associated with a lower risk of depressive symptoms in older adults, contrasting the effect observed in other populations. With an ageing population, this study aimed to investigate the long-term impact of a healthy dietary pattern, BMI, and other covariates on depressive symptoms in older adults. METHODS: We conducted a cohort study between 2014 and 2017, with each follow-up assessment being one year apart. A total of 2081 participants above 65 years old (M = 79.65, SD = 7.94) completed the baseline assessment in 2014, which included basic demographics, self-reported eating habits, depressive symptoms, and the measurement of height and weight. Distance to supermarkets and fast food was calculated based on participants' residential addresses. Two growth models were performed to assess the trajectory of change in depressive symptoms over time. RESULTS: Older adults experienced a significant decrease in depressive symptoms over time (intercept = 2.68, p < .001; slope = -0.25, p < .001). At baseline, a higher diet quality (B = -0.95, p < .001), higher BMI (B = -0.09, p < .001), younger age (B = 0.40, p = .001), being a male (B = 0.76, p < .001), and having fewer chronic diseases (B = 0.39, p < .001) were associated with lower levels of depressive symptoms. Over time, a higher diet quality (B = 0.14, p = .05), higher BMI (B = 0.02, p = .04), and fewer chronic diseases (B = -0.08, p < .001) predicted lower levels of depressive symptoms over time. CONCLUSIONS: A higher diet quality and higher BMI may serve as protective factors for depressive symptoms in older adults. Potential implications are being discussed.

Association between gray matter regional structural-functional connectivity couplings and visual memory in major depressive disorder.

Alterations in structural-functional (SC-FC) coupling have been linked to major depressive disorder (MDD). A newly developed algorithm for regional-specific SC-FC coupling analysis shows potential in advancing psychiatric research. In this study, we calculated the gray matter regional-specific SC-FC coupling of 114 MDD patients and 131 healthy controls (HCs). The delayed matching to sample (DMS) and Pattern Recognition Memory (PRM) subtests of the computerized Cambridge Neurocognitive Test Automated Battery (CANTAB) were used to evaluate visual memory. We found that the Xgboost model exhibited robust discriminative performance (Area under the ROC curve [95% CI]: 0.75 [0.65 to 0.85], Accuracy [95% CI]: 0.73 [0.63 to 0.84], Sensitivity [95% CI]: 0.65 [0.53 to 0.76], Specificity [95% CI]: 0.82 [0.77 to 0.87]). MDD patients showed lower SC-FC coupling in the left inferior frontal orbital gyrus (IFGorb_L) and the right inferior occipital gyrus (IOG_R) and higher SC-FC coupling in the left superior temporal pole (TPOsup_L) and the right middle temporal pole (TPOmid_R) than HCs. SC-FC coupling of IFGorb_L negatively correlated with current duration of illness (r = -0.26, P = 0.007), IOG_R negatively correlated with HAMD-17 cognitive factor score (r = -0.24, P = 0.011), while TPOsup_L positively correlated with percent correct in PRM delayed task among MDD patients (r = 0.31, P = 0.003). In conclusion, the study suggested that altered regional SC-FC coupling may be involved in MDD pathophysiology and associated with visual memory impairment.

Immune-inflammatory process in nephrolithiasis: A bibliometric analysis (2000-2023).

The research on the mechanism of nephrolithiasis formation is of great importance due to the fact that the high incidence and recurrence rate of nephrolithiasis bring considerable economic burdens to patients and society. As an important component in the nephrolithiasis formation process, the immune-inflammatory process has been gradually valued by researchers in recent years. In this study, articles related to the immune-inflammatory process of nephrolithiasis published since 2000 were retrieved based on the Web of Science (WoS) database. Eventually, a total of 370 articles were selected for subsequent analyses. Besides, VOSviewer, CiteSpace, and Bibliometrix were employed to quantitatively analyze and visualize the data. The number of articles related to the immune-inflammatory process of nephrolithiasis has increased rapidly in the last five years. From the country level, most articles were contributed by China (n = 140) and the United States (n = 99) contributed the most documents. From the institution level, University of Florida (n = 36) and Nagoya City University (n = 21) had the most articles. From the journal level, Journal of Urology and Urolithiasis published the most articles in this field. Keywords mainly included inflammation, oxidative stress, calcium oxalate, osteopontin, and hyperoxaluria, which represented the research directions in this field. The most productive author was Khan SR (n = 33), whose articles obtained the highest number of citations (2086 times). These efforts may help researchers understand the current progress and status of research on the immune-inflammatory process of nephrolithiasis and identify future research hotspots and directions.

Dynamic changes in the metabolome and microbiome during Citrus depressa Hayata liquid fermentation.

Citri Reticulatae Pericarpium (CRP) is a common traditional Chinese herbal medicine, valued for its multi-bioactivity. However, its processing time, environment, and microorganisms all affect its quality and bioactivity. To address this, the study replaced solid-state fermentation with liquid fermentation using microorganisms and isolated Bacillus amyloliquefaciens, respectively. This aimed to discover a more stable processing method and examine metabolite-micobiota correlations. Non-targeted metabolomics identified 70 differential metabolites, focusing on amino acids, polymethoxyflavones (PMFs), and carbohydrates. Long-read sequencing showed a shift in dominant bacterial genera from Lactobacillus to Pediococcus, then to Clostridium. Spearman analysis revealed a positive correlation between specific Clostridium species and PMFs production. B. amyloliquefaciens fermentation notably increased PMFs content without reducing hesperidin levels, suggesting its potential as an alternative processing method. This study offers valuable insights into metabolome-microbiome interactions for future biotransformation research.

Smartphone-assisted ratiometric fluorescent sensor to quantitatively detect curcumin in traditional Chinese medicine based on Förster resonance energy transfer.

A ratiometric fluorescence sensor (Fe-MIL-88-NH2/curcumin) based on luminescent metal-organic frameworks (LMOFs) for the determination of curcumin was constructed. Upon the addition of curcumin, the 535-nm emission of curcumin was enhanced, while the fluorescence emission at 438 nm was quenched, under 367-nm excitation. This sensor demonstrated a broad linear range from 1.5 to 40 µM, a low detection limit of 35 nM, and a fast response time of at most 30 s. We verified the Förster resonance energy transfer (FRET) mechanism between donor (Fe-MIL-88-NH2) and acceptor (curcumin), which further proved the selectivity of the approach. The sensing system enabled the detection of curcumin in the traditional Chinese medicine (TCM) Turmeric. A smartphone-assisted sensing platform was prepared to visually detect curcumin in a portable manner. This study represents the first attempt to fabricate LMOFs for ratiometric fluorescence detection of curcumin, which has promising potential for application in TCM.

Research landscape and pharmacological mechanisms of traditional Chinese medicines in treating and preventing urolithiasis: Unearthing an anti-urolithic treasure trove.

ETHNOPHARMACOLOGICAL RELEVANCE: Urolithiasis represents a predominant concern within urology due to its high recurrence rate and consequential surgical complications. Traditional Chinese Medicine (TCM), with a history spanning over 2000 years in treating kidney diseases, not only offers a less invasive and cost-effective option for treating and preventing urolithiasis, but also serves as a pharmacological treasure trove for the development of anti-urolithic drugs. AIM OF THE STUDY: With the continuous deepening of research on the anti-urolithic effects of Chinese medicines, the pharmacological mechanisms of TCMs against urolithiasis are continuously evolving. Therefore, it is essential to summarize the current research status, clinical effectiveness, and mechanisms of TCM in treating and preventing urolithiasis, to ascertain its potential in anti-urolithic treatments, and to provide a reference for future anti-urolithiasis drug research. METHODS: The electronic databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) have been utilized to retrieve relevant literature spanning from 2000 to September 2023, using keywords "Traditional Chinese Medicine" and "Urolithiasis". Then we conducted a visual analysis of the current status of related research, as well as a systematic organization of the therapeutic effects and underlying mechanisms of anti-urolithic TCMs. RESULTS: Through the organization of research models, therapeutic effects, and active ingredients of 31 potential anti-urolithic TCMs, we have systematically summarized the underlying mechanisms of TCMs in management of urolithiasis. Mechanistically, Chinese herbs facilitate stone expulsion by enhancing diuresis, instigating anti-spasmodic effects, and promoting ureteral peristalsis when addressing calculi. They also harbor the potential to dissolve pre-existing stones. In terms of stone recurrence prevention, TCM compounds obstruct stone formation through targeting the sequence of crystal adhesion, nucleation, growth, and aggregation to inhibit stone formation. Additionally, TCM's significant roles include stifling oxidative stress, augmenting urinary stone inhibitors, and harmonizing oxalate metabolism, all of which are critical actions in stone prevention. CONCLUSION: The anti-urolithic mechanism of TCM is multifaceted. Investigating the anti-urolithiasis mechanisms of TCM not only illuminates the potential of Chinese medicine in treating and preventing urolithiasis, but also uncovers active molecules and targets for drug treatment against calculus formation.

Comparison of networks of loneliness, depressive symptoms, and anxiety symptoms in at-risk community-dwelling older adults before and during COVID-19.

Network analysis provides an innovative approach to examining symptom-to-symptom interactions in mental health, and adverse external conditions may change the network structures. This study compared the networks of common risk factors and mental health problems (loneliness, depressive symptoms, and anxiety symptoms) in community-dwelling older people before and during COVID-19. Older adults (aged ≥ 60) at risk for depression were recruited through non-governmental organizations. Loneliness, depressive symptoms and anxiety symptoms were measured using the three-item Loneliness Scale (UCLA-3), nine-item Patient Health Questionnaire (PHQ-9), and seven-item Generalized Anxiety Disorder Scale (GAD-7), respectively. Data from 2549 (before) and 3506 (during COVID-19) respondents were included using propensity score matching. Being restless (GAD-7-item5) was most central, indicated by Expected Influence, in both pre and during COVID-19 networks despite low severity (mean score). The network during COVID-19 had higher global strength and edge variability than the pre-pandemic network, suggesting easier symptom spread and potentially more complex symptom presentation. In addition, feeling isolated from others (UCLA-3-item3) had stronger connections with feeling worthless/guilty (PHQ-9-item6) and anticipatory anxiety (GAD-7-item7) during COVID-19 than before. These findings may enhance our knowledge of the symptom structure of common mental health problems and the impacts of the pandemic. Targeting central symptoms may offer novel preventive strategies for older people.

Exploring unmet healthcare needs and associated inequalities among middle-aged and older adults in Eastern China during the progression toward universal health coverage.

BACKGROUND: Given the rapid population aging in China, achieving universal health coverage (UHC) presents a primary challenge in addressing unmet healthcare needs and associated inequalities among middle-aged and older adults. Several studies have focused on healthcare utilization and its inequalities, but little attention has been paid to the inequality in unmet healthcare needs. This study aimed to analyze the inequalities in unmet the healthcare needs of middle-aged and older adults in eastern China during the progression toward UHC. METHODS: Data were obtained from the fourth, fifth, and sixth National Health Service Survey (NHSS) of Jiangsu Province, located in eastern China, during the years 2008, 2013, and 2018, respectively. Logistic regression models were used to assess the associated factors of unmet healthcare needs. The inequality was measured according to the concentration index (CI) and its decomposition. RESULTS: In this study, we found that 12.86%, 2.22%, and 48.89% of middle-aged and older adults reported unmet needs for outpatient and inpatient services and physical examinations, respectively. The prevalence of unmet outpatient needs increased from 2008 to 2018, while the prevalence of unmet inpatient services was lower but maintained. The prevalence of unmet needs for physical examinations among middle-aged and older adults markedly decreased since 2008. Rural areas had a higher prevalence of unmet needs for inpatient services and physical examinations than urban areas. Unmet healthcare needs were more prevalent among the poor. The pro-poor inequalities of unmet healthcare needs have been mitigated during the progression toward UHC; however, they remain predominant among rural middle-aged and older adults for outpatient and inpatient services. Socioeconomic factors significantly influenced unmet healthcare needs and contributed to their inequalities. CONCLUSIONS: The findings characterize the prevalence and inequality of unmet healthcare need among middle-aged and older adults in eastern China during the progression toward UHC. Policy interventions should be actively advocated to effectively mitigate the unmet healthcare needs and address the associated inequalities.

Perceptions of social class through Chinese speech cues.

Speech is a complex auditory signal that contains multiple layers of linguistic and non-linguistic structure, it contains both linguistic and social class information. Perceivers are exquisitely sensitive to this layered structure and extract not only linguistic properties, but also indexical characteristics that provide information about individual talkers and groups of talkers. Social class information involves inferring the speaker's social class or forming an impression of their social status based on their speech. Previous research on social class perception in speech has primarily focused on English, with relatively little research on Chinese. This study examines social class perception in Chinese speech. Study 1 employed class judgment and evaluation tasks with a subjective social class scale as the main measure to examine whether listeners could infer class information from Chinese speech and how their own class background influenced their perception. The results of Study 1 showed that subjects could accurately discriminate between speakers' social classes, but there may be a response bias that overestimates lower-class speakers as upper-class speakers. Study 2 focused on whether the speech of different classes of speakers actually differed on a number of indicators. It was found that the speech of higher class speakers was perceived to be more standardised, more pleasant to listen to and less accent-intensive. Overall, listeners can perceive class information from Chinese speech; different classes of Chinese speech do contain different levels of indexical information. In Chinese language societies, individuals can also judge their class information through the speech, which is consistent with the relevant research results in English.

Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.

A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines.

Significant advances in chemotherapy drugs have reduced mortality in patients with malignant tumors. However, chemotherapy-related cardiotoxicity increases the morbidity and mortality of patients, and has become the second leading cause of death after tumor recurrence, which has received more and more attention in recent years. Arrhythmia is one of the common types of chemotherapy-induced cardiotoxicity, and has become a new risk related to chemotherapy treatment, which seriously affects the therapeutic outcome in patients. Traditional Chinese medicine has experienced thousands of years of clinical practice in China, and has accumulated a wealth of medical theories and treatment formulas, which has unique advantages in the prevention and treatment of malignant diseases. Traditional Chinese medicine may reduce the arrhythmic toxicity caused by chemotherapy without affecting the anti-cancer effect. This paper mainly discussed the types and pathogenesis of secondary chemotherapeutic drug-induced arrhythmia (CDIA), and summarized the studies on Chinese medicine compounds, Chinese medicine Combination Formula and Chinese medicine injection that may be beneficial in intervention with secondary CDIA including atrial fibrillation, ventricular arrhythmia and sinus bradycardia, in order to provide reference for clinical prevention and treatment of chemotherapy-induced arrhythmias.

Xanthine oxidase inhibition study of isolated secondary metabolites from Dolichandrone spathacea (Bignoniaceae): In vitro and in silico approach.

Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during purine metabolism in the liver. One of the standard treatment approaches involves reducing uric acid levels by inhibiting XO activity. In this study, the leaf extract of Dolichandrone spathacea, traditionally used in folk medicine, was found to inhibit XO activity in the ethyl acetate and butanol fractions at a concentration of 100 µg/mL, their values were 78.57 ± 3.85 % (IC50 = 55.93 ± 5.73 µg/ml) and 69.43 ± 8.68 % (IC50 = 70.17 ± 7.98 µg/ml), respectively. The potential XO inhibitory components were isolated by bioactivity assays and the HR-ESI-MS and NMR spectra system. The main constituents of leaf extracts of Dolichandrone spathacea, six compounds, namely trans-4-methoxycinnamic acid (3), trans-3,4-dimethoxycinnamic acid (4), p-coumaric acid (5), martynoside (6), 6-O-(p-methoxy-E-cinnamoyl)-ajugol (7), and scolymoside (17), were identified as potent XO inhibitors with IC50 values ranging from 19.34 ± 1.63 µM to 64.50 ± 0.94 µM. The enzyme kinetics indicated that compounds 3-5, 7, and 17 displayed competitive inhibition like allopurinol, while compound 6 displayed a mixed-type inhibition. Computational studies corroborated these experimental results, highlighting the interactions between potential metabolites and XO enzyme. The hydrogen bonds played crucial roles in the binding interaction, especially, scolymoside (17) forms a hydrogen bond with Mos3004, exhibited the lowest binding energy (-18.3286 kcal/mol) corresponding to the lowest IC50 (19.34 ± 1.63 µM). Furthermore, nine compounds were isolated for the first time from this plant. In conclusion, Dolichandrone spathacea and its constituents possess the potential to modulate the xanthine oxidase enzyme involved in metabolism.

Third-order exceptional line in a nitrogen-vacancy spin system.

Exceptional points (EPs) are singularities in non-Hermitian systems, where k (k ≥ 2) eigenvalues and eigenstates coalesce. High-order EPs exhibit richer topological characteristics and better sensing performance than second-order EPs. Theory predicts even richer non-Hermitian topological phases for high-order EP geometries, such as lines or rings formed entirely by high-order EPs. However, experimental exploration of high-order EP geometries has hitherto proved difficult due to the demand for more degrees of freedom in the Hamiltonian's parameter space or a higher level of symmetries. Here we observe a third-order exceptional line in an atomic-scale system. To this end, we use a nitrogen-vacancy spin in diamond and introduce multiple symmetries in the non-Hermitian Hamiltonian realized with the system. Furthermore, we show that the symmetries play an essential role in the occurrence of high-order EP geometries. Our approach can in future be further applied to explore high-order EP-related topological physics at the atomic scale and, potentially, for applications of high-order EPs in quantum technologies.

Predicting Prognosis and Immunotherapy Response in Multiple Cancers Based on the Association of PANoptosis-Related Genes with Tumor Heterogeneity.

PANoptosis is a newly recognized inflammatory pathway for programmed cell death (PCD). It participates in regulating the internal environment, homeostasis, and disease process in various complex ways and plays a crucial role in tumor development, but its mechanism of action is still unclear. In this study, we comprehensively analyzed the expression of 14 PANoptosis-related genes (PANRGs) in 28 types of tumors. Most PANRGs are upregulated in tumors, including Z-DNA binding protein 1 (ZBP1), nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3), caspase (CASP) 1, CASP6, CASP8, PYCARD, FADD, MAP3K7, RNF31, and RBCK1. PANRGs are highly expressed in GBM, LGG, and PAAD, while their levels in ACC are much lower than those in normal tissues. We found that both the CNV and SNV gene sets in BLCA are closely related to survival performance. Subsequently, we conducted clustering and LASSO analysis on each tumor and found that the inhibitory and the stimulating immune checkpoints positively correlate with ZBP1, NLRP3, CASP1, CASP8, and TNFAIP3. The immune infiltration results indicated that KIRC is associated with most infiltrating immune cells. According to the six tumor dryness indicators, PANRGs in LGG show the strongest tumor dryness but have a negative correlation with RNAss. In KIRC, LIHC, and TGCT, most PANRGs play an important role in tumor heterogeneity. Additionally, we analyzed the linear relationship between PANRGs and miRNA and found that MAP3K7 correlates to many miRNAs in most cancers. Finally, we predicted the possible drugs for targeted therapy of the cancers. These data greatly enhance our understanding of the components of cancer and may lead to the discovery of new biomarkers for predicting immunotherapy response and improving the prognosis of cancer patients.

Femtosecond laser lithotripsy: a novel alternative for kidney stone treatment? Evaluating the safety and effectiveness in an ex vivo study.

The Holmium (Ho:YAG) laser is presently the most extensively employed in laser lithotripsy for the management of kidney stones. Despite its adoption as the gold standard for laser lithotripsy, Ho:YAG laser lithotripsy poses three significant challenges, namely thermal effect, insufficient stone fragmentation, and stone displacement, which have garnered increased attention from urologic surgeons. Nowadays, the femtosecond laser is regarded as a potential alternative to the Ho:YAG laser due to its capacity to ablate diverse materials with minimal thermal effect. In our ex vivo investigation, we assessed the dimensions of ablation pits, the efficacy of ablation, the degree of stone fragmentation, the alterations in water temperature surrounding stones, and the degree of tissue damage associated with Femtosecond laser lithotripsy utilizing adjustable power settings (1-50 W). Our findings indicate that the ablation pits generated by the Femtosecond laser exhibited uniform geometries, and the effectiveness of ablation and fragmentation for Femtosecond laser lithotripsy were significantly and positively correlated with laser power. When the laser power remained constant, the Femtosecond laser with higher pulse energy demonstrated superior efficiency in stone ablation, but inferior performance in stone fragmentation. Conversely, the Femtosecond laser with higher pulse frequency exhibited the opposite behavior. Furthermore, the thermal effect increased proportionally with laser power, leading to a tentative recommendation of 10W laser power for future investigations. Our in vitro findings suggest that the Femtosecond laser holds promise as a safe and effective alternative to holmium lasers.

Methyl Canthin-6-one-2-carboxylate Restrains the Migration/Invasion Properties of Fibroblast-like Synoviocytes by Suppressing the Hippo/YAP Signaling Pathway.

Rheumatoid arthritis (RA) is an inflammatory condition that causes severe cartilage degradation and synovial damage in the joints with multiple systemic implications. Previous studies have revealed that fibroblast-like synoviocytes (FLSs) play a pivotal role in the pathogenesis of RA. The appropriate regulation of FLS function is an efficient approach for the treatment of this disease. In the present study, we explored the effects of methyl canthin-6-one-2-carboxylate (Cant), a novel canthin-6-one alkaloid, on the function of FLSs. Our data showed that exposure to Cant significantly suppressed RA-FLS migration and invasion properties in a dose-dependent manner. Meanwhile, pre-treatment with Cant also had an inhibitory effect on the release of several pro-inflammatory cytokines, including IL-6 and IL-1ß, as well as the production of MMP1 and MMP3, which are important mediators of FLS invasion. In further mechanistic studies, we found that Cant had an inhibitory effect on the Hippo/YAP signaling pathway. Treatment with Cant suppressed YAP expression and phosphorylation on serine 127 and serine 397 while enhancing LATS1 and MST1 levels, both being important upstream regulators of YAP. Moreover, YAP-specific siRNA or YAP inhibition significantly inhibited wound healing as well as the migration and invasion rate of FLS cells, an impact similar to Cant treatment. Meanwhile, the over-expression of YAP significantly reversed the Cant-induced decline in RA-FLS cell migration and invasion, indicating that YAP was required in the inhibitory effect of Cant on the migration and invasion of RA-FLS cells. Additionally, supplementation of MMP1, but not MMP3, in culture supernatants significantly reversed the inhibitory effect of Cant on RA-FLS cell invasion. Our data collectively demonstrated that Cant may suppress RA-FLS migration and invasion by inhibiting the production of MMP1 via inhibiting the YAP signaling pathway, suggesting a potential of Cant for the further development of anti-RA drugs.

Development and validation of a nomogram based on biparametric MRI PI-RADS v2.1 and clinical parameters to avoid unnecessary prostate biopsies.

BACKGROUND: Biparametric MRI (bpMRI) is a faster, contrast-free, and less expensive MRI protocol that facilitates the detection of prostate cancer. The aim of this study is to determine whether a biparametric MRI PI-RADS v2.1 score-based model could reduce unnecessary biopsies in patients with suspected prostate cancer (PCa). METHODS: The patients who underwent MRI-guided biopsies and systematic biopsies between January 2020 and January 2022 were retrospectively analyzed. The development cohort used to derive the prediction model consisted of 275 patients. Two validation cohorts included 201 patients and 181 patients from 2 independent institutions. Predictive models based on the bpMRI PI-RADS v2.1 score (bpMRI score) and clinical parameters were used to detect clinically significant prostate cancer (csPCa) and compared by analyzing the area under the curve (AUC) and decision curves. Spearman correlation analysis was utilized to determine the relationship between International Society of Urological Pathology (ISUP) grade and clinical parameters/bpMRI score. RESULTS: Logistic regression models were constructed using data from the development cohort to generate nomograms. By applying the models to the all cohorts, the AUC for csPCa was significantly higher for the bpMRI PI-RADS v2.1 score-based model than for the clinical model in both cohorts (p < 0.001). Considering the test trade-offs, urologists would agree to perform 10 fewer bpMRIs to avoid one unnecessary biopsy, with a risk threshold of 10-20% in practice. Correlation analysis showed a strong correlation between the bpMRI score and ISUP grade. CONCLUSION: A predictive model based on the bpMRI score and clinical parameters significantly improved csPCa risk stratification, and the bpMRI score can be used to determine the aggressiveness of PCa prior to biopsy.