Spatial position changes in the semicircular canals may be the anatomical basis of Meniere's disease: a preliminary study based on ultra-high-resolution computed tomography (CT) and intelligent segmentation.

Background: Meniere's disease (MD) is an ear-related vestibular disorder accompanied by vertigo, hearing loss, and tinnitus. The anatomical structure and spatial position of the semicircular canals are important for understanding vestibular function and disease; however, research on MD and the effect of anatomical changes in the semicircular canals is limited. This study explored the relationship between the spatial location of the semicircular canals and MD using ultra-high-resolution computed tomography (U-HRCT) and intelligent segmentation. Methods: Isotropic U-HRCT images obtained from patients with MD and healthy controls (HCs) were retrospectively analyzed. We extracted the semicircular canal structures and extracted their skeleton. The plane of the skeleton of each semicircular canal was fitted separately. The mutual angles between the semicircular canals, and the angles between each semicircular canal and each plane of the coordinate system were measured. Results: Among 45 MD-affected ears (MDAEs), 33 MD-healthy ears (MDHEs), and 45 HC ears, the angle between the superior and lateral semicircular canals (LSCs) and the angle between the superior and posterior semicircular canals (PSCs) were larger in the MDAE and MDHE groups than the HC group (P<0.01), while the angle between the posterior and LSCs was smaller in the MDAE group than the HC group (P<0.001). The angles between the superior and PSCs and coronal plane (CP) of the coordinate system were significantly smaller in the MDAE and MDHE groups than the HC group (P<0.01); however, the angles between the LSC and axial plane and CP were significantly larger in the MDAE and MDHE groups than the HC group (P<0.001). Conclusions: Spatial position changes in the semicircular canals may be the anatomical basis of MD.

Impact of historical disease conditions on mortality and life expectancy in patients with advanced schistosomiasis in Hunan Province, China.

BACKGROUND: Although the prognosis of advanced schistosomiasis patients has significantly improved, the impact of historical disease conditions on life expectancy remains unclear. METHODS: Utilizing data from an advanced schistosomiasis cohort (n=10 362) from 2008 to 2019 in Hunan, China, we examined five historical disease conditions: times of praziquantel treatment, the history of ascites, splenectomy, upper gastrointestinal bleeding (UGIB) and hepatic coma. Using latent class analysis, participants were categorized into three groups: Group 1 (characterized by no risk conditions), Group 2 (had ≤3 times of praziquantel treatment without UGIB history) and Group 3 (had UGIB history). Life expectancies were calculated using the life table method. RESULTS: At the age of 45 y, patients with ≤3 times of praziquantel treatment, a history of ascites, UGIB, hepatic coma and those without splenectomy exhibited lower life expectancies. Groups 1, 2 and 3 had estimated life expectancies of 32.32, 26.76 and 25.38 y, respectively. Compared with Group 1, women in Group 3 experienced greater life expectancy loss than those in Group 2, with the difference narrowing with age. CONCLUSIONS: Based on the consideration of overall physical conditions, tailored treatment and healthcare, along with public health interventions targeting diverse populations, could mitigate the prevalence of poor disease conditions and premature deaths.

The effect of optical-acoustic phonon coupling on the thermal conductivity of 2D MgI2.

2D MgI2 has a large phonon band gap and strong coupling of optical and acoustic phonons, and it is difficult to accurately predict thermal conductivity by considering only three-phonon scattering. Thus, in this study, the effect of four-phonon scattering on the thermal conductivity of a 2D MgI2 lattice was investigated using first-principles calculations combined with Boltzmann transport theory. The results show that with increasing temperature, four-phonon scattering induces an increase in the scattering of phonons at the optical and acoustic phonon coupling (2 THz), as well as in the vicinity of the optical phonon branch (4.5 THz), which leads to the enhancement of the anharmonicity of phonon transport and results in a decrease in the thermal conductivity of the 2D material. At 700 K, the thermal conductivity of MgI2 decreases by over half, from 0.47 W m-1 K-1 to 0.23 W m-1 K-1, when considering both three- and four-phonon scattering, compared to considering only three-phonon scattering. This study confirms the need to consider the role of four-phonon scattering to enhance optical and acoustic phonon coupling to accurately predict the thermal conductivity of 2D materials with larger phonon band gaps.

Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

BACKGROUND AND PURPOSES: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. METHODS: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. RESULTS: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. CONCLUSIONS: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

Giant strong coupling in a Q-BICs' tetramer metasurface.

Due to their ultrahigh Q-factor and small mode volume, bound states in the continuum (BICs) are intriguing for the fundamental study of the strong coupling regime. However, the strong coupling generated by BICs in one metasurface is not always strong enough, which highly limits its efficiency in applications. In this work, we realize a giant strong coupling of at most 60 meV in a quasi-BICs' (Q-BICs) tetramer metasurface composed of four Si cylinders with two different sets of diagonal lengths. The Q-BICs are induced from two types of electric quadrupole (EQ), for which detuning can be flexibly controlled by manipulating the C4v symmetry breaking Δd. The giant Rabi splitting in our proposed metasurface performs more than 15 times of the previous works, which provides more possibilities for important nonlinear and quantum applications, such as nanolaser and quantum optics.

Global Path Planning for Articulated Steering Tractor Based on Multi-Objective Hybrid Algorithm.

With the development of smart agriculture, autopilot technology is being used more and more widely in agriculture. Because most of the current global path planning only considers the shortest path, it is difficult to meet the articulated steering tractor operation needs in the orchard environment and address other issues, so this paper proposes a hybrid algorithm of an improved bidirectional search A* algorithm and improved differential evolution genetic algorithm(AGADE). First, the integrated priority function and search method of the traditional A* algorithm are improved by adding weight influence to the integrated priority, and the search method is changed to a bidirectional search. Second, the genetic algorithm fitness function and search strategy are improved; the fitness function is set as the path tree row center offset factor; the smoothing factor and safety coefficient are set; and the search strategy adopts differential evolution for cross mutation. Finally, the shortest path obtained by the improved bidirectional search A* algorithm is used as the initial population of an improved differential evolution genetic algorithm, optimized iteratively, and the optimal path is obtained by adding kinematic constraints through a cubic B-spline curve smoothing path. The convergence of the AGADE hybrid algorithm and GA algorithm on four different maps, path length, and trajectory curve are compared and analyzed through simulation tests. The convergence speed of the AGADE hybrid algorithm on four different complexity maps is improved by 92.8%, 64.5%, 50.0%, and 71.2% respectively. The path length is slightly increased compared with the GA algorithm, but the path trajectory curve is located in the center of the tree row, with fewer turns, and it meets the articulated steering tractor operation needs in the orchard environment, proving that the improved hybrid algorithm is effective.

Interactive and lag effects of environmental factors on the density of schistosome-transmitting Oncomelania hupensis: A twelve-year monthly repeated survey.

Schistosomiasis is a significant public health threat, and Oncomelania hupensis is the only intermediate host for schistosoma japonicum. We conducted 12-year monthly repeated surveys to explore the interactive and lag effects of environmental factors on snail density and to monitor their long-term and seasonal trends in a bottomland around the Dongting Lake region in China. Relevant environmental data were obtained from multiple sources. A Bayesian kernel machine regression model and a Bayesian temporal model combined with a distributed lag model were constructed to analyze interactive and lag effects of environmental factors on snail density. The results indicated the average annual snail density in the study site exhibited an increasing and then decreasing trend, peaking in 2013. Snail densities were the highest in October and the lowest in January in a year. Normalized Difference Vegetation Index (NDVI) and water level were the most effective predictors of snail density, with potential interactions among temperature, precipitation, and NDVI. The mean minimum temperature in January, water level, precipitation and NDVI were positively correlated with snail density at lags ranging from 1 to 4 months. These findings could serve as references for relevant authorities to monitor the changing trend of snail density and implement control measures, thereby reducing the occurrence of schistosomiasis.

Discrete Illumination-Based Compressed Ultrafast Photography for High-Fidelity Dynamic Imaging.

Compressed ultrafast photography (CUP) can capture irreversible or difficult-to-repeat dynamic scenes at the imaging speed of more than one billion frames per second, which is obtained by compressive sensing-based image reconstruction from a compressed 2D image through the discretization of detector pixels. However, an excessively high data compression ratio in CUP severely degrades the image reconstruction quality, thereby restricting its ability to observe ultrafast dynamic scenes with complex spatial structures. To address this issue, a discrete illumination-based CUP (DI-CUP) with high fidelity is reported. In DI-CUP, the dynamic scenes are loaded into an ultrashort laser pulse train with controllable sub-pulse number and time interval, thus the data compression ratio, as well as the overlap between adjacent frames, is greatly decreased and flexibly controlled through the discretization of dynamic scenes based on laser pulse train illumination, and high-fidelity image reconstruction can be realized within the same observation time window. Furthermore, the superior performance of DI-CUP is verified by observing femtosecond laser-induced ablation dynamics and plasma channel evolution, which are hardly resolved in the spatial structures using conventional CUP. It is anticipated that DI-CUP will be widely and dependably used in the real-time observations of various ultrafast dynamics.

Machine learning-based autophagy-related prognostic signature for personalized risk stratification and therapeutic approaches in bladder cancer.

OBJECTIVE: Bladder cancer (BCa) is a highly lethal urological malignancy characterized by its notable histological heterogeneity. Autophagy has swiftly emerged as a diagnostic and prognostic biomarker in diverse cancer types. Nonetheless, the currently accessible autophagy-related signature specific to BCa remains limited. METHODS: A refined autophagy-related signature was developed through a 10-fold cross-validation framework, incorporating 101 combinations of machine learning algorithms. The performance of this signature in predicting prognosis and response to immunotherapy was thoroughly evaluated, along with an exploration of potential drug targets and compounds. In vitro and in vivo experiments were conducted to verify the regulatory mechanism of hub gene. RESULTS: The autophagy-related prognostic signature (ARPS) has exhibited superior performance in predicting the prognosis of BCa compared to the majority of clinical features and other developed markers. Higher ARPS is associated with poorer prognosis and reduced sensitivity to immunotherapy. Four potential targets and five therapeutic agents were screened for patients in the high-ARPS group. In vitro and vivo experiments have confirmed that FKBP9 promotes the proliferation, invasion, and metastasis of BCa. CONCLUSIONS: Overall, our study developed a valuable tool to optimize risk stratification and decision-making for BCa patients.

Environmental explanation of prostate cancer progression based on the comprehensive analysis of polychlorinated biphenyls.

OBJECTIVE: Polychlorinated biphenyls (PCBs) have caused great environmental concerns. The study aims to investigate underlying molecular mechanisms between PCBs exposure and prostate cancer (PCa). METHODS: To investigate the association between PCBs exposure and prostate cancer by using CTD, TCGA, and GEO datasets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to explore pathways associated with PCBs-related genes (PRGs). Using Lasso regression analysis, a novel PCBs-related prognostic model was developed. Both internal and external validations were conducted to assess the model's validity. Molecular docking was utilized to assess the binding capacity of PCBs to crucial genes. At last, preliminary experimental validations were conducted to confirm the biological roles of Aroclor 1254 in PCa cells. RESULTS: The GO enrichment analysis of PRGs revealed that the biological processes were most enriched in the regulation of transcription from the RNA polymerase II promoter and signal transduction. The KEGG enrichment analysis showed that of the pathways in cancer is the most significantly enriched. Next, a PCBs-related model was constructed. In the training, test, GSE70770, and GSE116918 cohorts, the biochemical recurrences free survival of the patients with high-risk scores was considerably lower. The AUCs at 5 years were 0.691, 0.718, 0.714, and 0.672 in the four cohorts, demonstrating the modest predictive ability. A nomogram that incorporated clinical characteristics was constructed. The results of the anti-cancer drug sensitivity analysis show chemotherapy might be more beneficial for patients at low risk. The molecular docking analysis demonstrated PCBs' ability to bind to crucial genes. PCa cells exposed to Aroclor 1254 at a concentration of 1 µM showed increased proliferation and invasion capabilities. CONCLUSIONS: This study provides new insights into the function of PCBs in PCa and accentuates the need for deeper exploration into the mechanistic links between PCBs exposure and PCa progression.

Magnetic resonance imaging-based radiomics nomogram for the evaluation of therapeutic responses to neoadjuvant chemohormonal therapy in high-risk non-metastatic prostate cancer.

PURPOSE: The aim of this study was to assess the potential application of a radiomics features-based nomogram for predicting therapeutic responses to neoadjuvant chemohormonal therapy (NCHT) in patients with high-risk non-metastatic prostate cancer (PCa). METHODS: Clinicopathologic information was retrospectively collected from 162 patients with high-risk non-metastatic PCa receiving NCHT and radical prostatectomy at our center. The postoperative pathological findings were used as the gold standard for evaluating the efficacy of NCHT. The least absolute shrinkage and selection operator (LASSO) was conducted to develop radiomics signature. Multivariate logistic regression analyses were conducted to identify the predictors of a positive pathological response to NCHT, and a nomogram was constructed based on these predictors. RESULTS: Sixty-three patients (38.89%) experienced positive pathological response to NCHT. Receiver operating characteristic analyses showed that the area under the curve (AUC) of periprostatic fat (PPF) radiomics signature was 0.835 (95% CI, 0.754-0.898), while the AUC of intratumoral radiomics signature was 0.822 (95% CI, 0.739-0.888). Multivariate logistic regression analysis revealed that PSA level, PPF radiomics signature and intratumoral radiomics signature were independent predictors of positive pathological response. A nomogram based on these three predictors was constructed. The AUC was 0.908 (95% CI, 0.839-0.954). The Hosmer-Lemeshow goodness-of-fit test showed that the nomogram was well calibrated. Decision curve analysis revealed the favorable clinical practicability of the nomogram. The nomogram was successfully validated in the validation cohort. Kaplan-Meier analyses showed that nomogram and positive pathological response were significantly related with survival of PCa. CONCLUSION: The radiomics-clinical nomogram based on mpMRI radiomics features exhibited superior predictive ability for positive pathological response to NCHT in high-risk non-metastatic PCa.

Plancitoxin-1 mediates extracellular trap evasion by the parasitic helminth Trichinella spiralis.

BACKGROUND: Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths. RESULTS: In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host. CONCLUSIONS: In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate.

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

DNMT1-Mediated the Downregulation of FOXF1 Promotes High Glucose-induced Podocyte Damage by Regulating the miR-342-3p/E2F1 Axis.

Podocyte damage plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Accumulating evidence suggests that dysregulation of transcription factors plays a crucial role in podocyte damage in DN. However, the biological functions and underlying mechanisms of most transcription factors in hyperglycemia-induced podocytes damage remain largely unknown. Through integrated analysis of data mining, bioinformatics, and RT-qPCR validation, we identified a critical transcription factor forkhead box F1 (FOXF1) implicated in DN progression. Moreover, we discovered that FOXF1 was extensively down-regulated in renal tissue and serum from DN patients as well as in high glucose (HG)-induced podocyte damage. Meanwhile, our findings showed that FOXF1 might be a viable diagnostic marker for DN patients. Functional experiments demonstrated that overexpression of FOXF1 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and fibrosis in HG-induced podocytes damage. Mechanistically, we found that the downregulation of FOXF1 in HG-induced podocyte damage was caused by DNMT1 directly binding to FOXF1 promoter and mediating DNA hypermethylation to block FOXF1 transcriptional activity. Furthermore, we found that FOXF1 inhibited the transcriptional expression of miR-342-3p by binding to the promoter of miR-342, resulting in reduced sponge adsorption of miR-342-3p to E2F1, promoting the expression of E2F1, and thereby inhibiting HG-induced podocytes damage. In conclusion, our findings showed that blocking the FOXF1/miR-342-3p/E2F1 axis greatly alleviated HG-induced podocyte damage, which provided a fresh perspective on the pathogenesis and therapeutic strategies for DN patients.

Association of whole blood copper, zinc, calcium, magnesium, and iron with non-alcoholic fatty liver disease in overweight and obese children. / å ¨è¡€é“œã€é”Œã€é’™ã€é•ã€é“ä¸Žè¶ é‡è‚¥èƒ–å„¿ç«¥éžé ’ç²¾æ€§è„‚è‚ªè‚ç— çš„å ³è”.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder in overweight and obese children, and its etiology and pathogenesis remain unclear, lacking effective preventive and therapeutic measures. This study aims to explore the association between whole blood copper, zinc, calcium, magnesium and iron levels and NAFLD in overweight and obese children aged 6 to 17 years, providing a scientific basis for the prevention and intervention of early NAFLD in overweight and obese children. METHODS: A cross-sectional study design was used to collect relevant data from overweight and obese children who visited the Hunan Children's Hospital from January 2019 to December 2021 through questionnaire surveys. Fasting blood samples were collected from the subjects, and various indicators such as blood glucose, blood lipid, and mineral elements were detected. All children were divided into an overweight group (n=400) and a NAFLD group (n=202). The NAFLD group was divided into 2 subgroups according to the ALT level: A non-alcoholic fatty liver (NAFL) group and a non-alcoholic steatohepatitis (NASH) group. Logistic regression analysis was used to analyze the association between minerals (copper, zinc, calcium, magnesium, and iron) and NAFLD, NAFL and NASH. RESULTS: A total of 602 subjects were included, of whom 73.6% were male, with a median age of 10 (9, 11) years, and a body mass index (BMI) of 24.9 (22.7, 27.4) kg/m2. The intergroup comparison results showed that compared with the overweight group, the NAFLD group had higher levels of age, BMI, diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG), low density lipoprotein (LDL), alanine transaminase (ALT) and aspartate aminotransferase (AST), and lower level of high density lipoprotein (HDL). The NAFL group had higher levels of age, BMI, DBP, SBP, ALT, and AST, and lower levels of HDL compared with the overweight group. The levels of age, BMI, DBP, SBP, TG, LDL, ALT, and AST of NASH were higher than those in the overweight group, while the level of HDL was lower than that in overweight group (all P<0.017). After adjusting for a variety of confounders, the OR of NAFLD for the highest quantile of iron was 1.79 (95% CI 1.07 to 3.00) compared to the lowest quantile, and no significant association was observed between copper, zinc, calcium, and magnesium, and NAFLD. The subgroup analysis of NAFLD showed that the OR for the highest quantile of iron in children with NAFL was 2.21 (95% CI 1.26 to 3.88), while no significant association was observed between iron level and NASH. In addition, no significant associations were observed between copper, zinc, calcium, and magnesium levels and NAFL or NASH. CONCLUSIONS: High iron level increases the risk of NAFLD (more likely NAFL) in overweight and obese children, while copper, zinc, calcium, magnesium, and other elements are not associated with the risk of NAFLD in overweight and obese children.

A modified withdrawal time estimation and risk assessment of enrofloxacin in grass carp (Ctenopharyngodon idella) after ad libitum medicated feed based on statistical approaches in natural cultured environments.

Enrofloxacin (EF) is a broad-spectrum and highly efficient antibiotic commonly used for treating diseases in aquatic animals. However, its abuse in aquaculture applications often leads to excess residue in tissues of grass carp (Ctenopharyngodon idella). Hence, this study aimed to estimate the withdrawal time (WT) of EF and its metabolite of ciprofloxacin (CF) administered medicated feed in natural culture environments and conduct a risk assessment. Plasma and tissue samples were gathered at appropriate time points and detected by high-performance liquid chromatography. The data homogeneity was evaluated by Bartlett's test and Cochran's test. The linearity of the regressed line was evaluated by visual inspection and F test. Outliers were estimated on a normal probability scale by plotting the standardized residual versus their cumulative frequency distribution. Finally, the WT was calculated to be 51 days in muscle + skin based on the maximum residue limit of 100 µg/kg. After 51 days, the concentration of EF and CF fell below 10 µg/kg. The estimated daily intake was calculated to be 0.009 µg/kg/d. Hazard quotient was computed to be 0.002, which was far below one. These results suggested that calculated WT of EF could ensure the safety of products from grass carp for humans.

Local Anesthetic Bupivacaine Inhibits Melanoma Proliferation and Metastasis by Targeting PAPSS2.

BACKGROUND: Melanoma is a highly invasive skin cancer with limited treatment strategies. Bupivacaine, a commonly used local anesthetic recognized for its safety, has shown promise in combating tumors. 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2) is a key enzyme in the sulfation process and is associated with the development and metastasis of various tumors. This study aimed to explore the mechanism by which bupivacaine inhibits melanoma proliferation and metastasis by targeting PAPSS2. METHODS: The effects of bupivacaine on the proliferation of A375 and A2058 melanoma cells were evaluated using Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) labeling, and clonogenic assays. Cell migration, invasion, and PAPSS2 expression were evaluated using Transwell experiments and Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) analysis. Additionally, an in vivo melanoma tumor model in nude mice was constructed to evaluate the impact of bupivacaine on melanoma growth and metastasis. Immunohistochemistry was used to assess tumor metastasis and PAPSS2 expression levels in the nude mouse model. RESULTS: Experimental results demonstrated that bupivacaine significantly inhibited melanoma proliferation and invasion compared to the control group. Notably, this inhibitory effect was partially reversed by PAPSS2 overexpression. In vivo experiments demonstrated that bupivacaine-treated nude mice exhibited reduced tumor volumes, weights, and fewer lung metastatic foci. Molecular analysis via qRT-PCR and immunohistochemistry analysis further indicated that bupivacaine significantly reduced PAPSS2 in tumor tissues. CONCLUSION: This study confirms that bupivacaine, a local anesthetic, can inhibit melanoma proliferation and metastasis by targeting the PAPSS2 signaling pathway. These findings suggest its potential as an anti-tumor medication and present new treatment strategies for melanoma.

Naoxintong capsule for treating cardiovascular and cerebrovascular diseases: from bench to bedside.

Naoxintong Capsule (NXT), a renowned traditional Chinese medicine (TCM) formulation, has been broadly applied in China for more than 30 years. Over decades, accumulating evidences have proven satisfactory efficacy and safety of NXT in treating cardiovascular and cerebrovascular diseases (CCVD). Studies have been conducted unceasingly, while this growing latest knowledge of NXT has not yet been interpreted properly and summarized comprehensively. Hence, we systematically review the advancements in NXT research, from its chemical constituents, quality control, pharmacokinetics, to its profound pharmacological activities as well as its clinical applications in CCVD. Moreover, we further propose specific challenges for its future perspectives: 1) to precisely clarify bioactivities of single compound in complicated mixtures; 2) to evaluate the pharmacokinetic behaviors of NXT feature components in clinical studies, especially drug-drug interactions in CCVD patients; 3) to explore and validate its multi-target mechanisms by integrating multi-omics technologies; 4) to re-evaluate the safety and efficacy of NXT by carrying out large-scale, multicenter randomized controlled trials. In brief, this review aims to straighten out a paradigm for TCM modernization, which help to contribute NXT as a piece of Chinese Wisdom into the advanced intervention strategy for CCVD therapy.

Current status and prospect of the DNA double-strand break repair pathway in colorectal cancer development and treatment.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Double-strand break (DSB) is the most severe type of DNA damage. However, few reviews have thoroughly examined the involvement of DSB in CRC. Latest researches demonstrated that DSB repair plays an important role in CRC. For example, DSB-related genes such as BRCA1, Ku-70 and DNA polymerase theta (POLQ) are associated with the occurrence of CRC, and POLQ even showed to affect the prognosis and resistance for radiotherapy in CRC. This review comprehensively summarizes the DSB role in CRC, explores the mechanisms and discusses the association with CRC treatment. Four pathways for DSB have been demonstrated. 1. Nonhomologous end joining (NHEJ) is the major pathway. Its core genes including Ku70 and Ku80 bind to broken ends and recruit repair factors to form a complex that mediates the connection of DNA breaks. 2. Homologous recombination (HR) is another important pathway. Its key genes including BRCA1 and BRCA2 are involved in finding, pairing, and joining broken ends, and ensure the restoration of breaks in a normal double-stranded DNA structure. 3. Single-strand annealing (SSA) pathway, and 4. POLθ-mediated end-joining (alt-EJ) is a backup pathway. This paper elucidates roles of the DSB repair pathways in CRC, which could contribute to the development of potential new treatment approaches and provide new opportunities for CRC treatment and more individualized treatment options based on therapeutic strategies targeting these DNA repair pathways.