Opioid-induced fragile-like regulatory T cells contribute to withdrawal.

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.

Predicting prognosis and immunotherapy response in colorectal cancer by pericytes insights from single-cell RNA sequencing.

Immunotherapy has revolutionized the treatment of tumors, but there are still a large number of patients who do not benefit from immunotherapy. Pericytes play an important role in remodeling the immune microenvironment. However, how pericytes affect the prognosis and treatment resistance of tumors is still unknown. This study jointly analyzed single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing data of multiple cancers to reveal pericyte function in the colorectal cancer microenvironment. Analyzing over 800 000 cells, it was found that colorectal cancer had more pericyte enrichment in tumor tissues than other cancers. We then combined the TCGA database with multiple public datasets and enrolled more than 1000 samples, finding that pericyte may be closely related to poor prognosis due to the higher epithelial-mesenchymal transition (EMT) and hypoxic characteristics. At the same time, patients with more pericytes have higher immune checkpoint molecule expressions and lower immune cell infiltration. Finally, the contributions of pericyte in poor treatment response have been demonstrated in multiple immunotherapy datasets (n = 453). All of these observations suggest that pericyte can be used as a potential biomarker to predict patient disease progression and immunotherapy response.

Uniform thin ice on ultraflat graphene for high-resolution cryo-EM.

Cryo-electron microscopy (cryo-EM) visualizes the atomic structure of macromolecules that are embedded in vitrified thin ice at their close-to-native state. However, the homogeneity of ice thickness, a key factor to ensure high image quality, is poorly controlled during specimen preparation and has become one of the main challenges for high-resolution cryo-EM. Here we found that the uniformity of thin ice relies on the surface flatness of the supporting film, and developed a method to use ultraflat graphene (UFG) as the support for cryo-EM specimen preparation to achieve better control of vitreous ice thickness. We show that the uniform thin ice on UFG improves the image quality of vitrified specimens. Using such a method we successfully determined the three-dimensional structures of hemoglobin (64 kDa), α-fetoprotein (67 kDa) with no symmetry, and streptavidin (52 kDa) at a resolution of 3.5 Å, 2.6 Å and 2.2 Å, respectively. Furthermore, our results demonstrate the potential of UFG for the fields of cryo-electron tomography and structure-based drug discovery.

OTTM: an automated classification tool for translational drug discovery from omics data.

Omics data from clinical samples are the predominant source of target discovery and drug development. Typically, hundreds or thousands of differentially expressed genes or proteins can be identified from omics data. This scale of possibilities is overwhelming for target discovery and validation using biochemical or cellular experiments. Most of these proteins and genes have no corresponding drugs or even active compounds. Moreover, a proportion of them may have been previously reported as being relevant to the disease of interest. To facilitate translational drug discovery from omics data, we have developed a new classification tool named Omics and Text driven Translational Medicine (OTTM). This tool can markedly narrow the range of proteins or genes that merit further validation via drug availability assessment and literature mining. For the 4489 candidate proteins identified in our previous proteomics study, OTTM recommended 40 FDA-approved or clinical trial drugs. Of these, 15 are available commercially and were tested on hepatocellular carcinoma Hep-G2 cells. Two drugs-tafenoquine succinate (an FDA-approved antimalarial drug targeting CYC1) and branaplam (a Phase 3 clinical drug targeting SMN1 for the treatment of spinal muscular atrophy)-showed potent inhibitory activity against Hep-G2 cell viability, suggesting that CYC1 and SMN1 may be potential therapeutic target proteins for hepatocellular carcinoma. In summary, OTTM is an efficient classification tool that can accelerate the discovery of effective drugs and targets using thousands of candidate proteins identified from omics data. The online and local versions of OTTM are available at http://otter-simm.com/ottm.html.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

The plant peptide hormone phytosulfokine promotes somatic embryogenesis by maintaining redox homeostasis in Cunninghamia lanceolata.

Somatic embryogenesis (SE) is widely used for studying the mechanisms of embryo development. However, little is known about the underlying mechanisms, especially in woody plants. Previous studies have established an SE system for Chinese fir (Cunninghamia lanceolata), but this system is genotype-dependent, which limits its application in practice. Here, we found that phytosulfokine (PSK), a plant peptide hormone, can not only increase SE efficiency, but also establish SE in recalcitrant genotypes of C. lanceolata. Proembryogenic mass (PEM) browning and determination of hydrogen peroxide (H2 O2 ) content by 2',7'-dichlorofluorescein staining indicated that a reactive oxygen species (ROS) burst occurred rapidly after PEMs were transferred to SE induction medium. Transcriptome analysis and quantitative reverse transcriptase-PCR validation showed that PSK treatment helped to maintain ROS homeostasis by decreasing the activity of peroxidases in early SE induction. This PSK-regulated redox microenvironment might be helpful to induce expression of SE-related genes like WOX2 in early SE induction. Further analyses suggested that PSK promotes SE induction in C. lanceolata partially through decreasing H2 O2 levels, which is necessary but not sufficient for SE induction in recalcitrant genotypes of C. lanceolata. Furthermore, heterologous overexpression of ClPSK in Arabidopsis led to enhanced SE induction and resistance to H2 O2 stress. Taken together, our study reveals a biological function for the plant peptide hormone PSK, extends our knowledge about SE in woody trees, and provides a valuable tool for establishing an efficient and genotype-independent SE system in C. lanceolata and other coniferous trees.

Exploring the mechanism underlying the therapeutic effects of butein in colorectal cancer using network pharmacology and single-cell RNA sequencing data.

BACKGROUND: Butein has shown substantial potential as a cancer treatment, but its precise mechanism of action in colorectal cancer (CRC) remains unclear. This study aimed to uncover the underlying mechanisms through which butein operates in CRC and to identify potential biomarkers through a comprehensive investigation. METHODS: Target genes associated with butein were sourced from SwissTargetPrediction, CTD, BindingDB and TargetNet. Gene expression data from the GSE38026 dataset and the single-cell dataset (GSE222300) were retrieved from the Gene Expression Omnibus database. The activation of disease-related pathways was assessed using Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and differential gene analysis. Disease-associated genes were identified through differential analysis and weighted gene co-expression network analysis (WGCNA). The protein-protein interaction network was utilized to pinpoint potential drug targets. Molecular complex detection (MCODE) analysis was employed to uncover relevant genes influenced by butein within key subgroup networks. Machine learning techniques were applied for the screening of potential biomarkers, with receiver operating characteristic curves used to evaluate their clinical significance. Single-cell analysis was conducted to assess the pharmacological targets of butein in CRC, with validation performed using the external dataset GSE40967. RESULTS: A total of 232 target genes for butein were identified. Functional enrichment analysis revealed significant enrichment of signaling pathways, including mitogen-activated protein kinase, JAK-STAT and NF-κB, among these genes. Differential analysis, in conjunction with WGCNA, yielded 520 disease-related genes. Subsequently, a disease-drug-gene network consisting of 727 targets was established, and a subnetwork containing 56 crucial genes was extracted. Important pathways such as the FoxO signaling pathway exhibited significant enrichment within these key genes. Machine learning applied to the 56 important genes led to the identification of a potential biomarker, UBE2C. Receiver operating characteristic analysis demonstrated the excellent clinical predictive utility of UBE2C. Single-cell analysis suggested that butein's therapeutic effects might be linked to its influence on epithelial and T cells, with UBE2C expression associated with these cell types. Validation using the external dataset GSE40967 further confirmed the exceptional clinical predictive capability of UBE2C. CONCLUSION: This study combines network pharmacology with single-cell analysis to unravel the mechanisms underlying butein's effects in CRC. Notably, UBE2C emerged as a promising biomarker with superior clinical efficacy. These research findings contribute significantly to our understanding of specific molecular mechanisms, potentially shaping future clinical practices.

Characteristics of bone mineral density in patients with functional hypothalamic amenorrhoea and its association with reproductive hormones and body composition.

OBJECTIVE: Bone mineral density (BMD) is typically reduced in patients with female athlete triad (FAT) and anorexia nervosa (AN). However, bone health in most patients with functional hypothalamic amenorrhoea (FHA), who may not suffer from severe energy deficiency, has not received adequate attention in clinical practice. This study aimed to investigate BMD and its association with clinical and endocrine features in individuals with FHA and to provide clinical evidence for improving bone loss and preventing osteoporosis in FHA. DESIGN: To assess the bone status of patients with FHA and investigate its association with various clinical and endocrinological characteristics. PATIENTS: We retrospectively analysed 80 patients with FHA who attended the Obstetrics and Gynecology Hospital of Fudan University from January 2022 to March 2023. MEASUREMENTS: The levels of reproductive hormones, including luteinising hormone (LH), follicle-stimulating hormone, oestradiol (E2 ) and total testosterone (TT), were examined at the time of initial diagnosis, and a body composition analyser was used to measure body fat percentage (BF%), lean body mass (LBM) and segmental muscle/fat. Dual-emission X-ray absorptiometry was used to measure lumbar spine BMD and femoral neck BMD in patients with FHA, and the Z score was calculated. RESULTS: The study cohort consisted of 80 female patients with FHA. The average age of the patients was 24.64 ± 6.02 years, and their body mass index (BMI) was 19.47 ± 2.86 kg/m2 . The duration of weight loss was 12 (6, 24) months, while the duration of oligo/amenorrhoea was 12 (4.5, 24) months. The mean degree of weight loss was 18.39 ± 9.53%. Low BMD were present in 15% of patients with FHA at the lumbar spine and/or femoral neck; 12.5% and 10% had low bone mass at the lumbar spine and femoral neck, respectively. The low bone mass group experienced a longer period of weight loss than the normal group [24 (16.5, 60) vs. 12 (4.5, 24) months, p = .037]. In addition, the abnormal group had a lower BMR (basal metabolic rate, BMR) [1158 ± 85 vs. 1231 ± 91 kcal/day, p = .011] and lower bone mineral content [2.15 ± 0.26 vs. 2.43 ± 0.31 kg, p = .009] than the normal group. Both LBMD and femoral neck BMD (Fn BMD) were positively correlated with BMI, BF%, LBM, and regional muscle/fat mass (all p < .05). There was also a positive correlation between LBMD and basal LH levels (p = .009) and waist-to-hip ratio (p = .034), whereas Fn BMD was positively correlated with TT levels (p = .029). Multiple linear regression analysis showed that LBM was positively associated with LBMD (ß = .007, 95% confidence interval [CI] = 0.004-0.009, p < .001), while trunk muscle mass was positively associated with Fn BMD (ß = .046, 95% CI = 0.013-0.080, p = .008). CONCLUSION: Fifteen percent of the patients with FHA exhibited low bone mass, a condition associated with prolonged weight loss. The basal LH and TT levels showed positive correlations with LBMD and Fn BMD, respectively. Meanwhile, BMR levels, BMI, BF%, and muscle mass were all positively correlated with LBMD and Fn BMD. Clinically, we should be attentive to suboptimal bone health in patients with FHA and take early screening, diagnosis and intervention measures, especially appropriate muscle mass gain, to prevent the onset of osteoporosis and fragility fractures in the long term.

Astaxanthin attenuates cigarette smoke-induced small airway remodeling via the AKT1 signaling pathway.

BACKGROUND: Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and antifibrotic effects. Small airway remodeling is the main pathology of chronic obstructive pulmonary disease (COPD) and is caused by epithelial-to-mesenchymal transition (EMT) and fibroblast differentiation and proliferation. Effective therapies are still lacking. This study aimed to investigate the role of AXT in small airway remodeling in COPD and its underlying mechanisms. METHODS: First, the model of COPD mice was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). The effects of AXT on the morphology of CS combined with CSE -induced emphysema, EMT, and small airway remodeling by using Hematoxylin-eosin (H&E) staining, immunohistochemical staining, and western blot. In addition, in vitro experiments, the effects of AXT on CSE induced-EMT and fibroblast function were further explored. Next, to explore the specific mechanisms underlying the protective effects of AXT in COPD, potential targets of AXT in COPD were analyzed using network pharmacology. Finally, the possible mechanism was verified through molecular docking and in vitro experiments. RESULTS: AXT alleviated pulmonary emphysema, EMT, and small airway remodeling in a CS combined with CSE -induced mouse model. In addition, AXT inhibited the EMT process in airway cells and the differentiation and proliferation of fibroblasts. Mechanistically, AXT inhibited myofibroblast activation by directly binding to and suppressing the phosphorylation of AKT1. Therefore, our results show that AXT protects against small airway remodeling by inhibiting AKT1. CONCLUSIONS: The present study identified and illustrated a new food function of AXT, indicating that AXT could be used in the therapy of COPD-induced small airway remodeling.

HDAC6-selective inhibitor CAY10603 ameliorates cigarette smoke-induced small airway remodeling by regulating epithelial barrier dysfunction and reversing.

BACKGROUND: Small airway remodelling is a vital characteristic of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial-mesenchymal transition (EMT). Recent studies have indicated that histone deacetylase 6 (HDAC6) plays an important role in the dysregulation of epithelial function. In this study, we investigated the therapeutic effects and underlying mechanisms of an inhibitor with high selectivity for HDAC6 in COPD. METHODS: Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 against CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using hematoxylin and eosin (H&E) staining, Masson's trichrome staining, immunohistochemical staining, and western blot. The human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of action of CAY10603. RESULTS: HDAC6 levels in the lung homogenates of CS-exposed mice were higher than that those in control mice. Compared to the CS group, the mean linear intercept (MLI) of the CAY10603 treatment group decreased and the mean alveolar number (MAN)increased. Collagen deposition was reduced in groups treated with CAY10603. The expression of α-SMA was markedly upregulated in the CS group, which was reversed by CAY10603 treatment. Conversely, E-cadherin expression in the CS group was further downregulated, which was reversed by CAY10603 treatment. CAY10603 affects the tight junction protein expression of ZO-1 and occludin. ZO-1 and occludin expression were markedly downregulated in the CS group. After CAY10603treatment, the protein expression level of ZO-1 and occludin increased significantly. In HBE cells, Cigarette smoke extract (CSE) increased HDAC6 levels. CAY10603 significantly attenuated the release of TGF-ß1 induced by CSE. CAY10603 significantly increased the E-cadherin levels in TGF-ß1 treated HBE cells, while concurrently attenuated α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. CAY10603 also inhibited TGF-ß1 induced cell migration. CONCLUSIONS: These findings suggested that CAY10603 inhibited CS induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-ß1/Smad2/3 signalling pathway.

Early Experience With Fenestration Modification of Castor Branched Stent-Graft for Aortic Arch Diseases.

PURPOSE: This study aimed to assess the safety and viability of combining branched stent graft with fenestrated thoracic endovascular aortic repair (TEVAR) in treating aortic arch lesions. MATERIALS AND METHODS: The cohort included patients presenting with aortic arch lesions who underwent treatment with a combination of branched stent graft and fenestrated TEVAR between July 2020 and November 2022. Technical success was defined as the precise deployment of the stent graft, maintenance of branch vessel patency, and the absence of type I endoleak. The secondary outcomes examined were complications and all-cause mortality. RESULTS: The study cohort comprised 21 patients (average age: 61.0±14.8 years) with aortic arch lesions from 3 tertiary care hospitals. The aortic arch lesions encompassed aortic dissection (N=8), aortic aneurysm (N=8), pseudoaneurysm (N=1), intramural hematoma (N=1), and penetrating aortic ulcer (N=3). The technical success rate achieved was 95.2% (20/21). Failure in one case was due to an intraoperative type I endoleak, which was rectified with an additional stent graft placement. The 30-day mortality rate was 4.8% (1/21). One patient suffered a stroke but responded well to medical intervention. The median hospital stay was 10.9±5.4 days. During the follow-up period, one death (4.8%) was associated with aortic complications. A type II endoleak was observed and managed with close monitoring. Two patients underwent re-interventions for retrograde type A dissection and stent migration, respectively. No occlusions were observed in the target branch arteries. CONCLUSIONS: The combination of branched stent graft with fenestrated TEVAR emerges as a viable strategy for addressing specific lesions in the aortic arch. CLINICAL IMPACT: This study demonstrates the feasibility of using branched stent grafts with fenestrated TEVAR for treating aortic arch lesions, achieving a technical success rate of 95.2%. Compared to traditional open surgery, this innovative, minimally invasive approach reduces perioperative mortality and complications, such as stroke and spinal cord ischemia. For clinicians, it offers a viable alternative for patients unfit for open repair, particularly in complex aortic arch cases. While the initial outcomes are promising, further research is needed to assess long-term durability and risks, including stent graft migration and late endoleak, ensuring the technique's safety and efficacy over time.

Rhodium(III)-Catalyzed C-H Cascade Annulation of Arylhydrazines with 2-Diazo-1,3-indandiones for the Synthesis of Tetracyclic Indeno[1,2-b]indoles.

An efficient approach for the preparation of tetracyclic indeno[1,2-b]indoles via Rh(III)-catalyzed C-H cascade annulation between arylhydrazines and diazo indan-1,3-diones has been established. In addition, a series of indeno[1,2-b]indoles were obtained in up to 96% yield with a wide range of substrates and high functional group tolerance. Finally, the diverse transformations of the desired products demonstrate the synthetic utility and utilization of this protocol.

Rhodium(III)-Catalyzed C-H Activation/[5 + 2] Cascade Annulation of Aroyl Hydrazides with Iodonium Ylides for the Synthesis of Seven-Membered Dibenzodiazepinediones.

A novel Rh(III)-catalyzed C-H activation/[5 + 2] cascade annulation of aroyl hydrazides with iodonium ylides is accomplished, in which diverse seven-membered dibenzodiazepinediones were afforded in moderate to excellent yields. This annulation reaction features an ideal functional group tolerance and a wide substrate scope. Large-scale and derivatization reactions were conducted to demonstrate the potential utility of this transformation.

Exploration of rich-club reorganization in facial synkinesis: insights from structural and functional brain network analysis.

Facial palsy therapies based on cortical plasticity are in development, but facial synkinesis progress is limited. Studying neural plasticity characteristics, especially network organization and its constitutive elements (nodes/edges), is the key to overcome the bottleneck. We studied 55 participants (33 facial synkinesis patients, 22 healthy controls) with clinical assessments, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). We analyzed rich-club organization and metrics of structural brain networks (rich-club coefficients, strength, degree, density, and efficiency). Functional brain network metrics, including functional connectivity and its coupling with the structural network, were also computed. Patients displayed reduced strength and density of rich-club nodes and edges, as well as decreased global efficiency. All nodes exhibited decreased nodal efficiency in patients. Patients had significantly increased functional connectivity and decreased structural-functional coupling strength in rich-club nodes, rich-club edges, and feeder edges. Our study indicates that facial synkinesis patients have weakened structural connections but enhanced functional transmission from rich-club nodes. The loss of connections and efficiency in structural network may trigger compensatory increases in functional connectivity of rich-club nodes. Two potential biomarkers, rich-club edge density and structural-functional coupling strength, may serve as indicators of disease outcome. These findings provide valuable insights into synkinesis mechanisms and offer potential targets for cortical intervention.

Systemic metabolic engineering of Enterobacter aerogenes for efficient 2,3-butanediol production.

2,3-Butanediol (2,3-BDO) is an important gateway molecule for many chemical derivatives. Currently, microbial production is gradually being recognized as a green and sustainable alternative to petrochemical synthesis, but the titer, yield, and productivity of microbial 2,3-BDO remain suboptimal. Here, we used systemic metabolic engineering strategies to debottleneck the 2,3-BDO production in Enterobacter aerogenes. Firstly, the pyruvate metabolic network was reconstructed by deleting genes for by-product synthesis to improve the flux toward 2,3-BDO synthesis, which resulted in a 90% increase of the product titer. Secondly, the 2,3-BDO productivity of the IAM1183-LPCT/D was increased by 55% due to the heterologous expression of DR1558 which boosted cell resistance to abiotic stress. Thirdly, carbon sources were optimized to further improve the yield of target products. The IAM1183-LPCT/D showed the highest titer of 2,3-BDO from sucrose, 20% higher than that from glucose, and the yield of 2,3-BDO reached 0.49 g/g. Finally, the titer of 2,3-BDO of IAM1183-LPCT/D in a 5-L fermenter reached 22.93 g/L, 85% higher than the wild-type strain, and the titer of by-products except ethanol was very low. KEY POINTS: Deletion of five key genes in E. aerogenes improved 2,3-BDO production The titer of 2,3-BDO was increased by 90% by regulating metabolic flux Response regulator DR1558 was expressed to increase 2,3-BDO productivity.

Application of 18ß-glycyrrhetinic acid in the structural modification of natural products: a review.

18ß-Glycyrrhetinic acid (GA) is an oleane-type pentacyclic triterpene saponin obtained from glycyrrhizic acid by removing 2 glucuronic acid groups. GA and its analogues are active substances of glycyrrhiza aicd, with similar structure and important pharmacological effects such as anti-inflammatory, anti-diabetes, anti-tumor and anti-fibrosis. Although GA combined compounds are in the clinical trial stages, its application potential is severely restricted by its low bioavailability, water solubility and membrane permeability. In this article, synthetic methods and structure-activity relationships (SARs) of GA derivatives from 2018 to present are reviewed based on pharmacological activity. It is hoped that this review can provide reference for the future development of potential GA preclinical candidate compounds, and furnish ideas for the development of pentacyclic triterpenoid lead compounds.

Long-Term Subjective Efficacy of Female Stress Urinary Incontinence with Tension-Free Vaginal Tape-Obturator Technique.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the long-term subjective efficacy of the tension-free vaginal tape-obturator (TVT-O) technique in the treatment of female stress urinary incontinence (SUI). METHODS: A retrospective analysis was performed on 84 patients who underwent TVT-O surgery for SUI in a tertiary center between January 2007 and December 2013. All patients filled in the Urinary Incontinence Quality of Life Questionnaire (I-QOL), the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form (PISQ-12). Subjective efficacy, including surgical efficacy, clinical severity of SUI, improvement in quality of life (QoL), and sexual activity with regard to TVT-O were compared before and after surgery (≥ 10 years). RESULTS: The average postoperative follow-up time was 12.6 ± 1.9 years, range, 10-16 years. The overall subjective effectiveness of the surgery was 94.0% (79 out of 84). The subjective clinical severity significantly improved more than 10 years after surgery compared with the preoperative value (p = 0.000). The median I-QOL score was 88.1 (84.1-92.0) preoperatively and 98.3 (94.3-99.7) postoperatively, and the long-term QoL of postoperative patients was significantly improved (p < 0.05). The median ICIQ-SF score was 10.5 (8-15) preoperatively, and 3 (0-5) postoperatively, and the ICIQ-SF score before and after surgery showed significant improvement in urinary incontinence symptoms (p < 0.05). No difference was observed in the PISQ-12 scores before and after surgery in the sexually active population. CONCLUSIONS: The TVT-O technique still has good subjective efficacy in SUI more than 10 years after surgery and significantly improves the QoL of patients.

Strategic disruption of cancer's powerhouse: precise nanomedicine targeting of mitochondrial metabolism.

Mitochondria occupy a central role in the biology of most eukaryotic cells, functioning as the hub of oxidative metabolism where sugars, fats, and amino acids are ultimately oxidized to release energy. This crucial function fuels a variety of cellular activities. Disruption in mitochondrial metabolism is a common feature in many diseases, including cancer, neurodegenerative conditions and cardiovascular diseases. Targeting tumor cell mitochondrial metabolism with multifunctional nanosystems emerges as a promising strategy for enhancing therapeutic efficacy against cancer. This review comprehensively outlines the pathways of mitochondrial metabolism, emphasizing their critical roles in cellular energy production and metabolic regulation. The associations between aberrant mitochondrial metabolism and the initiation and progression of cancer are highlighted, illustrating how these metabolic disruptions contribute to oncogenesis and tumor sustainability. More importantly, innovative strategies employing nanomedicines to precisely target mitochondrial metabolic pathways in cancer therapy are fully explored. Furthermore, key challenges and future directions in this field are identified and discussed. Collectively, this review provides a comprehensive understanding of the current state and future potential of nanomedicine in targeting mitochondrial metabolism, offering insights for developing more effective cancer therapies.

New frontiers in salivary extracellular vesicles: transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases.

Salivary extracellular vesicles (EVs) have emerged as key tools for non-invasive diagnostics, playing a crucial role in the early detection and monitoring of diseases. These EVs surpass whole saliva in biomarker detection due to their enhanced stability, which minimizes contamination and enzymatic degradation. The review comprehensively discusses methods for isolating, enriching, quantifying, and characterizing salivary EVs. It highlights their importance as biomarkers in oral diseases like periodontitis and oral cancer, and underscores their potential in monitoring systemic conditions. Furthermore, the review explores the therapeutic possibilities of salivary EVs, particularly in personalized medicine through engineered EVs for targeted drug delivery. The discussion also covers the current challenges and future prospects in the field, emphasizing the potential of salivary EVs in advancing clinical practice and disease management.

Successful treatment of mixed pulmonary Aspergillus and Mucor infection using intrabronchial amphotericin B infusion: a case report and literature review.

BACKGROUND: Reports of pulmonary aspergillosis and mucormycosis co-infections are rare; thus, limited guidance is available on early diagnosis and treatment. We present a case of mixed pulmonary Aspergillus and Mucor infection and review the literature regarding this co-infection. The diagnosis and treatment methods are summarized to improve clinicians' understanding of the disease and to facilitate early diagnosis and treatment. CASE PRESENTATION: A 60-year-old male farmer with poorly controlled diabetes mellitus was admitted to hospital with a fever of unknown origin that had been present for 15 days and pulmonary aspergillosis complicated by Mucor spp. INFECTION: Because multiple lobes were involved, the infection worsened despite surgical resection and antifungal therapy. Finally, we treated this patient with a bronchoscopic infusion of amphotericin B. After four courses of bronchoscopic amphotericin B infusion, we observed rapid clinical improvement and subsequent resolution of pulmonary infiltrates. CONCLUSION: Our case highlights the use of bronchoscopy in the successful clinical treatment of invasive fungal diseases of the lung.