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1.
Article in English | MEDLINE | ID: mdl-39360599

ABSTRACT

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

2.
Chem Biol Interact ; : 111259, 2024 Oct 03.
Article in English | MEDLINE | ID: mdl-39368770

ABSTRACT

According to the 2022 cancer statistics of the World Health Organization, lung cancer ranks among the top ten causes of death, with lung adenocarcinoma being the most prevalent type. Despite significant advancements in lung cancer therapeutics, many clinical limitations remain, primarily due to the development of drug resistance. The present study investigated the effects of pemetrexed on the drug resistance mechanisms in human lung adenocarcinoma and its association with progesterone receptor membrane component 1 (PGRMC1) expression. Given that KRAS-mutant lung adenocarcinoma cell lines (e.g., A549) exhibit a high folate synthesis activity, pemetrexed, which is structurally similar to folate, was selected as the therapeutic drug. The present study used a lung adenocarcinoma cell line (A549) and established a drug-resistant lung adenocarcinoma cell line (A549/PEM). The findings demonstrated that PGRMC1 expression was elevated in the A549/PEM cells. It has been hypothesized that PGRMC1 regulates iron absorption through heme binding, resulting in a preference for iron-related cell death pathways (ferroptosis). Our findings indicate that drug-resistant lung adenocarcinoma cells with high PGRMC1 levels exhibit elevated antioxidant activity on the cell membrane and increased reliance on iron-dependent cell death pathways. This suggests a correlation between PGRMC1 and pemetrexed-induced iron-dependent cell death. Our study contributes to the development of more effective therapeutic strategies to improve the prognosis of patients with lung adenocarcinoma, particularly those facing drug resistance challenges.

3.
Curr Med Sci ; 2024 Oct 05.
Article in English | MEDLINE | ID: mdl-39368054

ABSTRACT

OBJECTIVE: This study aimed to evaluate and compare the effectiveness of knowledge base-optimized and unoptimized large language models (LLMs) in the field of orthopedics to explore optimization strategies for the application of LLMs in specific fields. METHODS: This research constructed a specialized knowledge base using clinical guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and authoritative orthopedic publications. A total of 30 orthopedic-related questions covering aspects such as anatomical knowledge, disease diagnosis, fracture classification, treatment options, and surgical techniques were input into both the knowledge base-optimized and unoptimized versions of the GPT-4, ChatGLM, and Spark LLM, with their generated responses recorded. The overall quality, accuracy, and comprehensiveness of these responses were evaluated by 3 experienced orthopedic surgeons. RESULTS: Compared with their unoptimized LLMs, the optimized version of GPT-4 showed improvements of 15.3% in overall quality, 12.5% in accuracy, and 12.8% in comprehensiveness; ChatGLM showed improvements of 24.8%, 16.1%, and 19.6%, respectively; and Spark LLM showed improvements of 6.5%, 14.5%, and 24.7%, respectively. CONCLUSION: The optimization of knowledge bases significantly enhances the quality, accuracy, and comprehensiveness of the responses provided by the 3 models in the orthopedic field. Therefore, knowledge base optimization is an effective method for improving the performance of LLMs in specific fields.

5.
Angew Chem Int Ed Engl ; : e202415789, 2024 Oct 04.
Article in English | MEDLINE | ID: mdl-39363716

ABSTRACT

Photoelectron spectroscopy and theoretical calculations have identified the global minimum structure of the 16-valence electron Si3Cu3- cluster, which features a planar tetracoordinate silicon (ptSi) in a rhombic arrangement. The Si3 and Cu3 triangles are interconnected by an Si2/Cu2 edge, forming an ordered chain-like structure. Besides the conventional 2c-2e σ-bond connecting Si3 and Cu3, the stability of this cluster is reinforced by a delocalized 3c-2e σ-bond in Cu3 and a π-bond in Si3. Our study provides rare experimental confirmation of a planar hypercoordinate heavier Group 14 element, opening possibilities for exploring similar structures in two-dimensional materials.

6.
Curr Med Sci ; 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39347924

ABSTRACT

The brain-computer interface (BCI) system serves as a critical link between external output devices and the human brain. A monitored object's mental state, sensory cognition, and even higher cognition are reflected in its electroencephalography (EEG) signal. Nevertheless, unprocessed EEG signals are frequently contaminated with a variety of artifacts, rendering the analysis and elimination of impurities from the collected EEG data exceedingly challenging, not to mention the manual adjustment thereof. Over the last few decades, the rapid advancement of artificial intelligence (AI) technology has contributed to the development of BCI technology. Algorithms derived from AI and machine learning have significantly enhanced the ability to analyze and process EEG electrical signals, thereby expanding the range of potential interactions between the human brain and computers. As a result, the present BCI technology with the help of AI can assist physicians in gaining a more comprehensive understanding of their patients' physical and psychological status, thereby contributing to improvements in their health and quality of life.

7.
Front Plant Sci ; 15: 1382768, 2024.
Article in English | MEDLINE | ID: mdl-39263418

ABSTRACT

Introduction: Citrus fruit is rich in important functional constituents such as flavonoids, phenolic acids terpenes and other functional substances that play an important role for treating clinical diseases or controlling major agricultural diseases and pests. Plant secondary metabolites have become one of the most important resources of novel lead compounds, especially young citrus fruits contain multiple functional substances. 'Orah', a type of citrus reticulata, is known for its fine appearance, productivity, delicious sweetness, late-maturing characteristics, and is widely cultivated in China. Fruit thinning and rootstock selection are commonly used agronomic measures in its production to ensure its quality and tree vigor. However, few studies have demonstrated the effects of these agronomic measures on the functional substances of 'Orah'. Methods: In this study, we used HPLC coupled with UV to detect the dynamic changes of fruit quality, 13 main flavonoids, 7 phenolic acids, 2 terpenes, synephrine and antioxidant capacity in both peel and pulp of citrus fruits grafted on four rootstocks (Red orange Citrus reticulata Blanco cv. red tangerine, Ziyang xiangcheng Citrus junos Sieb. ex Tanaka, Trifoliate orange Poncirus trifoliata L. Raf, and Carrizo citrange Citrus sinensis Osb.×P.trifoliate Raf) at six different developmental stages (from 90 DAF to 240 DAF). Results: The results indicated that rootstock can significantly affect the contents of functional constituents and antioxidant capacity in 'Orah'. Additionally, it was found that pruning at either 90 DAF (days after flowering) or 150 DAF produced the most favorable outcomes for extracting functional substances. We also identified rootstock 'Trifoliate orange' has the highest total soluble solids (TSS) and 'Ziyang xiangcheng' to be the optimal in terms of comprehensive sensory of fruit quality, while 'Red orange' and 'Ziyang xiangcheng' are optimal in terms of functional substance quality, and 'Red orange' excels in antioxidant capacity. Discussion: Overall, the findings demonstrate the important role of rootstocks and developmental stage in shaping fruit sensory quality and functional substance synthesis, providing valuable insights for guiding rootstock selection, determining thinning time, and utilizing pruned fruits in a more informed manner.

8.
Ann Med ; 56(1): 2397090, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39221748

ABSTRACT

BACKGROUND: The quick sequential [sepsis-related] organ failure assessment (qSOFA) acts as a prompt to consider possible sepsis. The contributions of individual qSOFA elements to assessment of severity and for prediction of mortality remain unknown. METHODS: A total of 3974 patients with community-acquired pneumonia were recruited to an observational prospective cohort study. The area under the receiver operating characteristic curve (AUROC), odds ratio, relative risk and Youden's index were employed to assess discrimination. RESULTS: Respiratory rate ≥22/min demonstrated the most superior diagnostic value, indicated by largest odds ratio, relative risk and AUROC, and maximum Youden's index for mortality. However, the indices for altered mentation and systolic blood pressure (SBP) ≤100 mm Hg decreased notably in turn. The predictive validities of respiratory rate ≥22/min, altered mentation and SBP ≤100 mm Hg were good, adequate and poor for mortality, indicated by AUROC (0.837, 0.734 and 0.671, respectively). Respiratory rate ≥22/min showed the strongest associations with SOFA scores, pneumonia severity index, hospital length of stay and costs. However, SBP ≤100 mm Hg was most weakly correlated with the indices. CONCLUSIONS: Respiratory rate ≥22/min made the greatest contribution to parsimonious qSOFA to assess severity and predict mortality. However, the contributions of altered mentation and SBP ≤100 mm Hg decreased strikingly in turn. It is the first known prospective evidence of the contributions of individual qSOFA elements to assessment of severity and for prediction of mortality, which might have implications for more accurate clinical triage decisions.


Respiratory rate ≥22/min demonstrated the most superior diagnostic value.Respiratory rate ≥22/min showed the strongest association with severity.Respiratory rate ≥22/min, altered mentation and SBP ≤100 mm Hg predicted mortality well, adequately and poorly, respectively.


Subject(s)
Organ Dysfunction Scores , ROC Curve , Humans , Male , Female , Prospective Studies , Aged , Middle Aged , Pneumonia/mortality , Pneumonia/diagnosis , Severity of Illness Index , Community-Acquired Infections/mortality , Community-Acquired Infections/diagnosis , Sepsis/mortality , Sepsis/diagnosis , Respiratory Rate , Aged, 80 and over , Blood Pressure , Predictive Value of Tests , Prognosis
9.
Adv Sci (Weinh) ; : e2406248, 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39297323

ABSTRACT

Experimentally achieving the first-ever electric field periodic poling of single crystal barium titanate oxide (BTO, or BaTiO3) thin film on-insulator is reported. Owing to the outstanding optical nonlinearities of BTO, this result is a key step toward achieving quasi-phase-matching (QPM). First, the BTO thin film is grown on a dysprosium scandate substrate using pulsed laser deposition with a thin layer of strontium ruthenate later serving as the bottom electrode for poling. The characterization of the BTO thin film using x-ray diffraction (XRD) and piezo-response force microscopy to demonstrate single crystal, single domain growth of the film that enables the desired periodic poling, are presented. To investigate the poling quality, both non-destructive piezo force response microscopy and destructive etching-assisted scanning electron microscopy (SEM) are applied, and it is shown that high quality, uniform, and intransient poling with 50% duty cycle and periods ranging from 2 µm to 10 µm is achieved. The successful realization of periodic poling in BTO thin film unlocks the potential for highly efficient nonlinear processes under QPM that seemed far-fetched with prior polycrystalline BTO thin films which predominantly relied on efficiency-limited random or non-phase matching conditions and is a key step toward integration of BTO photonic devices.

10.
Clin Psychol Psychother ; 31(5): e3053, 2024.
Article in English | MEDLINE | ID: mdl-39307835

ABSTRACT

OBJECTIVE: The objective of this study was to provide an updated analysis of suicide characteristics in China from 2002 to 2021, with the aim of informing the development of evidence-based suicide prevention strategies. METHODS: The Ministry of Health-Vital Registration System (MOH-VR) provided the data on suicide mortality, which enabled us to examine the average annual percentage change (AAPC) in suicide rates using a Poisson regression model. RESULTS: Notably, there has been a significant decline in suicide rates observed in both urban and rural areas. In the early years of the study period, higher suicide rates were observed among females compared to males; however, a shift occurred after 2005, with male suicide rates surpassing those of females. Except for 2005, rural areas consistently exhibited higher suicide rates than urban areas. Furthermore, suicide rates exhibited an increasing trend with age, irrespective of gender or region. CONCLUSION: These findings highlight a decreasing trend in suicide rates in China over the past two decades, although gender and regional disparities persist. Going forward, sustained efforts in suicide prevention, with a specific focus on mental health, are warranted.


Subject(s)
Rural Population , Suicide , Urban Population , Humans , China/epidemiology , Male , Female , Suicide/statistics & numerical data , Suicide/trends , Adult , Middle Aged , Rural Population/statistics & numerical data , Adolescent , Young Adult , Urban Population/statistics & numerical data , Aged , Sex Distribution , Sex Factors
11.
Plant Cell Environ ; 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39262278

ABSTRACT

Plants have developed various resistance mechanisms against herbivorous insects through prolonged coevolution. Plant defence responses can be triggered by specific compounds present in insect saliva. Apyrase, a known enzyme that catalyzes the hydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP) and inorganic phosphorus, has recently been identified in some herbivorous insects. However, whether insect salivary apyrase induces or inhibits plant responses remains poorly understood. In this study, we identified an apyrase-like protein in the salivary proteome of the fall armyworm, Spodoptera frugiperda, named Sfapyrase. Sfapyrase was primarily expressed in the salivary gland and secreted into plants during insect feeding. Transient expression of Sfapyrase in tobacco and maize enhanced plant resistance and resulted in decreased insect feeding. Knockdown of Sfapyrase through RNA interference led to increased growth and feeding of S. frugiperda. Furthermore, we showed that Sfapyrase activates the jasmonic acid signalling pathway and promotes the synthesis of secondary metabolites, especially benzoxazinoids, thereby enhancing resistance to S. frugiperda. In summary, our findings demonstrated that Sfapyrase acts as a salivary elicitor, inducing maize jasmonic acid defence responses and the production of insect-resistant benzoxazinoids. This study provides valuable insights into plant-insect interactions and offers potential targets for developing innovative insect pest management strategies.

12.
J Youth Adolesc ; 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39302609

ABSTRACT

During adolescence, empathy and prosocial behavior contribute to the establishment of positive interpersonal relationships and social connections, promoting holistic development in youth. A substantial amount of research has provided compelling evidence that there is a relationship between peer relationships and empathy and prosocial behavior. Empathy, as a key mediating factor, links the influence of peers with prosocial behavior in adolescents, yet there is currently a lack of robust meta-analytic evidence regarding this mediating role. This study employed a two-stage structural equation modeling approach to synthesize existing research on peer influence, empathy, and prosocial behavior during adolescence. Systematic searches were conducted across three databases (PubMed, Web of Science, and PsycINFO), identifying a total of 49 studies, with a systematic assessment of study quality. The results indicated that empathy plays a mediating role between peer influence and prosocial behavior. Positive peer influence is positively correlated with empathy and prosocial behavior, while negative peer influence is negatively correlated with empathy and prosocial behavior, and empathy is positively correlated with prosocial behavior. This meta-analysis demonstrates that during adolescence, empathy mediates the connection between peer influence and prosocial behavior, representing a potential process that can explain the relationship between peer influence and prosocial behavior.

13.
J Affect Disord ; 367: 573-582, 2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39242042

ABSTRACT

AIM: To investigate the impact of public health emergencies on the prevalence of suicidal ideation among healthcare workers (HCWs) and medical students. METHODS: The prevalence of suicidal ideation among HCWs and medical students was searched for analysis. The platforms included PubMed, medRVix, bioRvix, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. Interrupted time-series analysis was employed to determine whether the COVID-19 pandemic influenced the prevalence and trends of suicidal ideation. To account for autocorrelation and heteroskedasticity, Newey-West standard errors were utilized with a lag of order one. RESULTS: Seventy studies with 145,641 HCWs and medical students from 30 countries were included in the final analysis, with 30 studies before COVID-19 and 40 studies during the pandemic. Before the pandemic outbreak (April 2020), the monthly increasing rate was 0.063 % (95 % CI: -0.009 %, 0.135 %, z = 1.73, P = 0.084). The tendency of suicidal ideation prevalence increased by 1.116 % (95%CI: 0.888 %, 1.344 %, z = 9.60, P < 0.001). In other words, the calculated monthly growth rate of suicidal ideation after the pandemic outbreak is 1.179 % (95%CI: 0.968 %, 1.391 %, z = 10.93, P < 0.001) per month. The overall growing trend of prevalence of suicidal ideation during the pandemic is 1.896 % per month in America; 1.590 % in Europe; 0.443 % (95%CI: 0.213 %, 0.673 %, z = 3.77, P < 0.001) in Asia; 1.055 % in HCWs; and 0.645 % in medical students. CONCLUSION: This study highlights that the COVID-19 pandemic can significantly impact the prevalence of suicidal ideation among HCWs and medical students, and the prevalence showed an upward trend.

14.
J Clin Med ; 13(17)2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39274552

ABSTRACT

Background: Functional recovery following the surgical fixation of acetabular posterior wall fractures remains a challenge. This study compares outcomes of posterior wall fracture reconstruction using an anatomical posterior acetabular plate (APAP) versus conventional reconstruction plates. Methods: Forty patients with acetabular fractures involving the posterior wall or column underwent surgery, with 20 treated using APAPs (APAP group) and 20 with conventional pelvic reconstruction plates (control group). Baseline patient characteristics, intraoperative blood loss and time, reduction quality, postoperative function, and postoperative complications were compared using appropriate non-parametric statistical tests. A general linear model for repeated measures analysis of variance was employed to analyze trends in functional recovery. Results: No significant differences were observed in baseline characteristics. APAP significantly reduced surgical time by 40 min (186.5 ± 51.0 versus 225.0 ± 47.7, p =0.004) and blood loss (695 ± 393 versus 930 ± 609, p = 0.049) compared to conventional plates. At 3 and 6 months following surgery, the APAP group exhibited higher functional scores (modified Merle d'Aubigné scores 10 ± 1.8 versus 7.8 ± 1.4, p < 0.001; 13.4 ± 2.8 versus 10.1 ± 2.1, p = 0.001), converging with the control group by 12 months (modified Merle d'Aubigné scores 14.2 ± 2.6 versus 12.7 ± 2.6, p = 0.072; OHS 31.6 ± 12.3 versus 30.3 ± 10.1, p = 0.398). Radiologically, the APAP group demonstrated superior outcomes (p = 0.047). Complication and conversion rates to hip arthroplasty did not significantly differ between groups (10% versus 15%, p = 0.633). Conclusions: The use of an APAP in reconstructing the posterior acetabulum significantly reduces surgical time, decreases intraoperative blood loss, and leads to earlier functional recovery compared to conventional reconstruction plates. The APAP provides stable fixation of the posterior wall and ensures the durable maintenance of reduction, ultimately yielding favorable surgical outcomes.

15.
Integr Cancer Ther ; 23: 15347354241273962, 2024.
Article in English | MEDLINE | ID: mdl-39223822

ABSTRACT

BACKGROUND: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. MATERIALS AND METHODS: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. RESULTS: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p-PI3K and p-Akt were notably downregulated. CONCLUSION: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.


Subject(s)
Adenocarcinoma of Lung , Drugs, Chinese Herbal , Lung Neoplasms , Mice, Inbred C57BL , Tumor Microenvironment , Animals , Drugs, Chinese Herbal/pharmacology , Tumor Microenvironment/drug effects , Mice , Adenocarcinoma of Lung/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Humans , Cell Line, Tumor , Cell Proliferation/drug effects , Vascular Endothelial Growth Factor A/metabolism , Male , Pemetrexed/pharmacology , Neovascularization, Pathologic/drug therapy , Cell Movement/drug effects , Medicine, Chinese Traditional/methods
16.
Plants (Basel) ; 13(16)2024 Aug 14.
Article in English | MEDLINE | ID: mdl-39204695

ABSTRACT

The benefits of citrus fruits are strongly associated with their secondary metabolites. In this study, we conducted widely targeted metabolomics analyses to compare the variability of the ingredients in four scion-rootstock combinations. A total of 376 differential metabolites were obtained by a multivariate statistical analysis, and a KEGG pathway analysis showed that the enriched metabolic pathways were mainly related to the biosynthesis of flavonoids as well as lipid metabolism. The anthocyanin-targeted metabolomic features showed that cyanidin 3-O-glucoside, cyanidin 3-O-(6-O-malonyl-beta-D-glucoside), cyanidin 3-O-sophoroside, and cyanidin 3-O-xyloside were the pigments responsible for the red color of Tarocco. A lipid metabolomics analysis revealed that when Tarocco was hetero-grafted with rootstock H, there was an increase in the content of each lipid subclass, accompanied by an increase in the levels of unsaturated fatty acids, including polyunsaturated linoleic and linolenic acids, thus impacting the ratio of unsaturated fatty acids to saturated fatty acids. Additionally, we determined their antioxidant capacity ('Trifoliate orange' (Z) > 'Citrange' (ZC) > 'Hongju' (H) > 'Ziyang Xiangcheng' (X)) using in vitro assays. Finally, we utilized a network pharmacology analysis to explore the antioxidant mechanisms and potential pharmacological ingredients; we obtained 26 core targets proteins and 42 core metabolites associated with oxidative damage, providing a basis for future preventive and therapeutic applications of these metabolites.

18.
Acta Pharmacol Sin ; 2024 Aug 19.
Article in English | MEDLINE | ID: mdl-39160244

ABSTRACT

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC50 value of 4.23 µM. Treatment with OB (2.5, 5 mg·kg-1·d-1, i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-ß/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.

19.
Technol Cancer Res Treat ; 23: 15330338241277699, 2024.
Article in English | MEDLINE | ID: mdl-39161322

ABSTRACT

Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577-1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216-1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.


Subject(s)
Body Mass Index , Genetic Predisposition to Disease , Genome-Wide Association Study , Mendelian Randomization Analysis , Humans , Female , Odds Ratio , Polymorphism, Single Nucleotide , Genital Neoplasms, Female/genetics , Genital Neoplasms, Female/etiology , Genital Neoplasms, Female/epidemiology , Risk Factors , Receptors, Estrogen/metabolism , Receptors, Estrogen/genetics
20.
Sci Rep ; 14(1): 18190, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39107362

ABSTRACT

The objective of this work was to investigate the sorption behavior of gases, namely CO2, CH4, and N2, by molecules of coal sampled from Linglu mine under different water inclusion rates. To this end, the adsorption, diffusion, adsorption heat, and potential energy distribution characteristics of the gases in the coal pores at different water inclusion rates were analyzed using molecular dynamics and grand canonical ensemble Monte Carlo methods. The results showed that the adsorption relationship of the coal molecules on CO2, CH4, and N2 exhibited a downtrend followed by an uptrend when the water content was increased from 0 to 3.6%. The adsorption amount of CO2 was approximately twice as much as those of CH4 and N2, indicating that the competitive adsorption advantage of CO2 compared with those of CH4 and N2 was unaffected by the water content. The trend in the average heat of adsorption was generally consistent with the trend in the density of coal molecules under different moisture contents. Under the same conditions, the diffusion coefficient within a coal molecule was negatively related to the water content in the system. The layer spacing of the water molecules (2.875 Å) was greater than the liquid-water layer spacing, indicating the formation of a water molecule layer at this point, which inhibited gas adsorption. This study lays a theoretical foundation for further investigating the microscopic mechanism of coal-water interaction.

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