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1.
Res Pract Thromb Haemost ; 8(4): 102443, 2024 May.
Article in English | MEDLINE | ID: mdl-38993621

ABSTRACT

Background: Salvianolic acid B (SAB) is a major component of Salvia miltiorrhiza root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated. Objective: To delineate the antithrombotic mechanisms of SAB. Methods: We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular in silico docking models to predict the interactions of SAB with thrombin. Results: SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site. Conclusion: Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis.

2.
Article in English | MEDLINE | ID: mdl-38866533

ABSTRACT

Objectives Well-being serves as a crucial indicator of national governance and societal advancement. Consequently, the Better Life Index (BLI) developed by the Organisation for Economic Co-operation and Development (OECD) has emerged as a pivotal multidimensional measure of well-being, surpassing traditional indicators such as Gross Domestic Product (GDP). However, current well-being indicators predominantly focus on national measurements and do not effectively evaluate well-being in smaller regions such as states or prefectures. This study aimed to calculate a Regional Well-Being Index (RWI) tailored to localized areas in Japan.Methods Japanese official statistics, publicly available as open data, were analyzed, focusing on 11 domains similar to those in the BLI: "Income," "Jobs," "Housing," "Health," "Work-Life Balance," "Education," "Community," "Civic Engagement," "Environment," "Safety," and "Life Satisfaction." The RWI scores were calculated for each prefecture in 2010, 2013, 2016, and 2019 using standard normalization techniques. To represent the overall well-being of each prefecture in each year, scores were aggregated across all domains; this aggregate is referred to as the Integrated RWI. The reliability and validity of RWI were assessed by examining time-series changes and Pearson's correlation coefficients.Results Median Integrated RWI scores for Japanese prefectures remained relatively stable across the study period, with slight variations observed: median = 0.67 (Interquartile range [IQR]: -2.48-2.71) in 2010, median = 0.00 (IQR: -2.85-2.76) in 2013, median = 0.13 (IQR: -3.05-2.49) in 2016, and median = 0.19 (IQR: -2.75-3.06) in 2019. Geographical analysis showed lower scores in regions such as Western Kyushu and Shikoku, and higher scores in Chubu and Eastern Kinki. The RWI and the BLI demonstrated construct validity, with Pearson's correlation coefficients ranging from 0.58 to 0.99 across various domains.Conclusion The RWI, based on the OECD's BLI, proved to be a reliable and valid tool for assessing comprehensive well-being at the regional level in Japan. It offers foundational data for identifying challenges to regional well-being and shaping targeted policies, thereby contributing to evidence-based policymaking. Moreover, this methodology has potential applicability in evaluating comprehensive well-being beyond GDP at the regional level in other countries using official statistics.

3.
Nat Commun ; 15(1): 5314, 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38906879

ABSTRACT

The introduction of single-atom catalysts (SACs) into Fenton-like oxidation promises ultrafast water pollutant elimination, but the limited access to pollutants and oxidant by surface catalytic sites and the intensive oxidant consumption still severely restrict the decontamination performance. While nanoconfinement of SACs allows drastically enhanced decontamination reaction kinetics, the detailed regulatory mechanisms remain elusive. Here, we unveil that, apart from local enrichment of reactants, the catalytic pathway shift is also an important cause for the reactivity enhancement of nanoconfined SACs. The surface electronic structure of cobalt site is altered by confining it within the nanopores of mesostructured silica particles, which triggers a fundamental transition from singlet oxygen to electron transfer pathway for 4-chlorophenol oxidation. The changed pathway and accelerated interfacial mass transfer render the nanoconfined system up to 34.7-fold higher pollutant degradation rate and drastically raised peroxymonosulfate utilization efficiency (from 61.8% to 96.6%) relative to the unconfined control. It also demonstrates superior reactivity for the degradation of other electron-rich phenolic compounds, good environment robustness, and high stability for treating real lake water. Our findings deepen the knowledge of nanoconfined catalysis and may inspire innovations in low-carbon water purification technologies and other heterogeneous catalytic applications.

4.
J Nanobiotechnology ; 22(1): 361, 2024 Jun 23.
Article in English | MEDLINE | ID: mdl-38910236

ABSTRACT

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.


Subject(s)
Autophagy , Cold Temperature , Exosomes , Mice, Inbred C57BL , MicroRNAs , Osteogenesis , Animals , Autophagy/drug effects , Mice , Exosomes/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Osteogenesis/drug effects , Mesenchymal Stem Cells/metabolism , Osteoporosis/pathology , Cell Differentiation/drug effects , Bone and Bones/metabolism , Female , Bone Density , Sirolimus/pharmacology
5.
Article in English | MEDLINE | ID: mdl-38944198

ABSTRACT

BACKGROUND AND AIMS: Recent evidence suggests that insulin resistance affects asthma outcomes; however, the effect of the homeostatic measure of insulin resistance (HOMA-IR) on airway inflammation and asthma exacerbations (AEs) is poorly understood. OBJECTIVES: To analyze the relationship between HOMA-IR and clinical and inflammatory characteristics in patients with asthma, and the association between HOMA-IR and asthma exacerbations (AEs) in the following year. METHODS: A prospective cohort study recruited participants with asthma, who were classified into the HOMA-IRhigh group and HOMA-IRlow group based on the cutoff value of 3.80 for HOMA-IR and were observed within 12 months. We evaluated the clinical and inflammatory features, and a 1-year follow-up was conducted to study the exacerbations. A negative binomial regression model was used to analyze the association between HOMA-IR and AEs. RESULTS: Compared with the patients in the HOMA-IRlow group (n = 564), patients in the HOMA-IRhigh group (n = 61) had higher levels of BMI, higher waist circumference and waist/hip ratio, higher triglycerides, lower cholesterol high-density lipoproteins (HDL), more neutrophils in the peripheral blood, and elevated IL-5 levels in the induced sputum. Furthermore, patients in the HOMA-IRhigh group had a significantly increased risk for moderate-to-severe AEs (adjusted incidence rate ratio (aIRR) = 2.26, 95% confidence interval (CI) = [1.38, 3.70]), severe AEs (aIRR = 2.42, 95% CI = [1.26, 4.67]), hospitalization(aIRR = 2.54, 95% CI = [1.20, 5.38]), and emergency visits (aIRR = 3.04, 95% CI = [1.80, 8.53]). CONCLUSION: HOMA-IR was associated with asthma-related clinical features, and airway inflammation, as well as being an independent risk factor for future AEs. Therefore, insulin resistance may have important implications for managing asthma as a potential treatable trait.

6.
JAMA Oncol ; 10(7): 932-940, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38869865

ABSTRACT

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Female , Male , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Middle Aged , Aged , Adult , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Prospective Studies , Molecular Targeted Therapy/methods
7.
Blood Coagul Fibrinolysis ; 35(5): 271-278, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38874905

ABSTRACT

Immune-mediated thrombotic thrombocytopenia purpura (iTTP) is a rare microvascular disease characterized by severe disseminated microvascular thrombose-bleeding syndrome. Caplacizumab has been approved for the treatment of iTTP in combination with Plasma Exchange (PE) and immunosuppressive therapy, but its role in iTTP therapy remains uncertain. Therefore, we conducted a meta-analysis to investigate the safety and efficacy of caplacizumab for the treatment of patients with iTTP. We searched electronic databases (PubMed, Embase, Cochrane Library, and Scopus) and reference lists of relevant articles to find articles published from 2015 to 2022. The time to normalization of the platelet count of the group caplacizumab is shorter than the group placebo (SMD = -0.72; 95% CI -0.88 to -0.56; P  < 0.05). Caplacizumab reduced the incidence of mortality (OR = 0.41; 95% CI 0.18-0.92; P  < 0.05), exacerbations (OR = 0.10; 95% CI 0.05-0.18; P  < 0.05), and recurrence (OR = 0.17; 95% CI 0.06-0.50; P  < 0.05). However, the bleeding events in the caplacizumab group were higher than those in the placebo group, especially severe bleeding events. There was no difference in ADAMTS13 activity and thromboembolic events between the two groups. Our analysis indicated that caplacizumab is effective and well tolerated for the treatment of iTTP. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022362370.


Subject(s)
Purpura, Thrombotic Thrombocytopenic , Single-Domain Antibodies , Humans , Purpura, Thrombotic Thrombocytopenic/drug therapy , Purpura, Thrombotic Thrombocytopenic/therapy , Single-Domain Antibodies/therapeutic use , Plasma Exchange/methods , Treatment Outcome
8.
Nat Commun ; 15(1): 4887, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849368

ABSTRACT

For di-nitroaromatics hydrogenation, it is a challenge to achieve the multi-step hydrogenation with high activity and selectivity due to the complexity of the process involving two nitro groups. Consequently, many precious metal catalysts suffer from low activity for this multi-step hydrogenation reaction. Herein, we employ a fully exposed Pt clusters catalyst consisting of an average of four Pt atoms on nanodiamond@graphene (Ptn/ND@G), demonstrating excellent catalytic performance for the multi-step hydrogenation of 2,4-dinitrotoluene. The TOF (40647 h-1) of Ptn/ND@G is significantly superior to that of single Pt atoms catalyst, Pt nanoparticles catalyst, and even all the known catalysts. Density functional theory calculations and absorption experiments reveal that the synergetic interaction between the multiple active sites of Ptn/ND@G facilitate the co-adsorption/activation of reactants and H2, as well as the desorption of intermediates/products, which is the key for the higher catalytic activity than single Pt atoms catalyst and Pt nanoparticles catalyst.

9.
bioRxiv ; 2024 May 23.
Article in English | MEDLINE | ID: mdl-38826442

ABSTRACT

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

10.
Cancer Immunol Immunother ; 73(7): 125, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38733402

ABSTRACT

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.


Subject(s)
Chemoradiotherapy , Induction Chemotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Propensity Score , Humans , Male , Female , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/drug therapy , Middle Aged , Chemoradiotherapy/methods , Adult , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/drug therapy , Induction Chemotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Aged , Cisplatin/therapeutic use , Cisplatin/administration & dosage , Cisplatin/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Retrospective Studies , Gemcitabine
11.
Front Immunol ; 15: 1395047, 2024.
Article in English | MEDLINE | ID: mdl-38694500

ABSTRACT

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes.


Subject(s)
Cellular Senescence , Drug Resistance, Neoplasm , Prostatic Neoplasms , Humans , Cellular Senescence/drug effects , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Prostatic Neoplasms/metabolism , Animals
12.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2501-2511, 2024 May.
Article in Chinese | MEDLINE | ID: mdl-38812154

ABSTRACT

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.


Subject(s)
Drugs, Chinese Herbal , Tandem Mass Spectrometry , Ziziphus , Animals , Dogs , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/administration & dosage , Ziziphus/chemistry , Male , Liquid Chromatography-Mass Spectrometry
13.
Cancer Cell ; 42(5): 727-731, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38701791

ABSTRACT

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern-whether it's neoadjuvant, adjuvant, or a combination of both-is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Immunotherapy , Lung Neoplasms , Humans , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Clinical Trials as Topic , Immunotherapy/methods , Lung Neoplasms/immunology , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Neoadjuvant Therapy/methods
14.
Phytochemistry ; 223: 114132, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38714288

ABSTRACT

Honokiol (HK) and magnolol (MAG) are typical representatives of neolignans possessing a wide range of biological activities and are employed as traditional medicines in Asia. In the past few decades, HK and MAG have been proven to be promising chemical scaffolds for the development of novel neolignan drugs. This review focuses on recent advances in the medicinal chemistry of HK and MAG derivatives, especially their structure-activity relationships. In addition, it also presents a comprehensive summary of the pharmacology, biosynthetic pathways, and metabolic characteristics of HK and MAG. This review can provide pharmaceutical chemists deeper insights into medicinal research on HK and MAG, and a reference for the rational design of HK and MAG derivatives.


Subject(s)
Biphenyl Compounds , Lignans , Lignans/chemistry , Lignans/pharmacology , Biphenyl Compounds/antagonists & inhibitors , Biphenyl Compounds/pharmacology , Biphenyl Compounds/chemistry , Structure-Activity Relationship , Humans , Molecular Structure , Allyl Compounds , Phenols
15.
J Transl Med ; 22(1): 488, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773576

ABSTRACT

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.


Subject(s)
Apoptosis , Colitis, Ulcerative , Dextran Sulfate , Endoplasmic Reticulum Stress , Animals , Endoplasmic Reticulum Stress/drug effects , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/pathology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/metabolism , Apoptosis/drug effects , Male , Mice, Inbred C57BL , Colon/pathology , Colon/drug effects , Triterpenes/pharmacology , Triterpenes/therapeutic use , Mice , Cytokines/metabolism , Permeability/drug effects , Signal Transduction/drug effects
16.
Biochem Biophys Res Commun ; 712-713: 149946, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38643717

ABSTRACT

Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competitive blockade of the αIIbß3 integrin on platelets. ApoA-IV inhibition of platelets was dependent on the N-terminal D5/D13 residues, and enhanced with absence of the C-terminus, suggesting it sterically hinders its N-terminal platelet binding site. The C-terminus is also the site of common apoA-IV polymorphisms apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). Interestingly, both are linked with an increased risk of cardiovascular disease, however, the underlying mechanism remains unclear. Here, we generated recombinant apoA-IV and found that the Q360H or T347S polymorphisms dampened its inhibition of platelet aggregation in human platelet-rich plasma and gel-filtered platelets, reduced its inhibition of platelet spreading, and its inhibition of P-selectin on activated platelets. Using an ex vivo thrombosis assay, we found that Q360H and T347S attenuated its inhibition of thrombosis at both high (1800s-1) and low (300s-1) shear rates. We then demonstrate a conserved monomer-dimer distribution among apoA-IV WT, Q360H, and T347S and use protein structure modelling software to show Q360H and T347S enhance C-terminal steric hindrance over the N-terminal platelet-binding site. These data provide critical insight into increased cardiovascular risk for individuals with Q360H or T347S polymorphisms.


Subject(s)
Apolipoproteins A , Blood Platelets , Platelet Aggregation , Thrombosis , Humans , Thrombosis/genetics , Thrombosis/metabolism , Platelet Aggregation/drug effects , Platelet Aggregation/genetics , Blood Platelets/metabolism , Blood Platelets/drug effects , Polymorphism, Genetic , Apoprotein(a)/genetics , Apoprotein(a)/metabolism , Apoprotein(a)/chemistry , P-Selectin/genetics , P-Selectin/metabolism
17.
J Bone Miner Res ; 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38624186

ABSTRACT

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.


We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

18.
Exp Hematol Oncol ; 13(1): 47, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664743

ABSTRACT

Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.

19.
Med Biol Eng Comput ; 62(7): 1981-1990, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38509350

ABSTRACT

Brain-Computer Interfaces (BCIs) have shown great potential in providing communication and control for individuals with severe motor disabilities. However, traditional BCIs that rely on electroencephalography (EEG) signals suffer from low information transfer rates and high variability across users. Recently, eye movement signals have emerged as a promising alternative due to their high accuracy and robustness. Eye movement signals are the electrical or mechanical signals generated by the movements and behaviors of the eyes, serving to denote the diverse forms of eye movements, such as fixations, smooth pursuit, and other oculomotor activities like blinking. This article presents a review of recent studies on the development of BCI typing systems that incorporate eye movement signals. We first discuss the basic principles of BCI and the recent advancements in text entry. Then, we provide a comprehensive summary of the latest advancements in BCI typing systems that leverage eye movement signals. This includes an in-depth analysis of hybrid BCIs that are built upon the integration of electrooculography (EOG) and eye tracking technology, aiming to enhance the performance and functionality of the system. Moreover, we highlight the advantages and limitations of different approaches, as well as potential future directions. Overall, eye movement signals hold great potential for enhancing the usability and accessibility of BCI typing systems, and further research in this area could lead to more effective communication and control for individuals with motor disabilities.


Subject(s)
Brain-Computer Interfaces , Eye Movements , Humans , Eye Movements/physiology , Electroencephalography/methods , Electrooculography , Signal Processing, Computer-Assisted
20.
Heliyon ; 10(5): e27217, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38449612

ABSTRACT

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

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