ABSTRACT
BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.
Subject(s)
Hemorrhoids , Polidocanol , Recurrence , Sclerosing Solutions , Sclerotherapy , Humans , Polidocanol/administration & dosage , Polidocanol/therapeutic use , Hemorrhoids/therapy , Hemorrhoids/diagnosis , Hemorrhoids/surgery , Middle Aged , Female , Male , Prospective Studies , Sclerotherapy/methods , Treatment Outcome , Ligation/methods , Sclerosing Solutions/administration & dosage , Adult , Aged , Severity of Illness Index , Pain, Postoperative/etiology , Pain, Postoperative/diagnosis , Patient Satisfaction , Pain Measurement , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic useABSTRACT
BACKGROUND: Acupuncture (AT) is widely used in treatment of ovulatory disorder infertility (ODI), but the safety and efficacy of AT for ODI still lack an evidence-based basis. AIM: To evaluate the feasibility and effectiveness of AT as an adjunct intervention for ODI. METHODS: The Cochrane Library, Embase, PubMed, VIP, China National Knowledge Infrastructure, WanFang Data, and Chinese biomedical literature databases were searched from inception to January 20, 2024. Two reviewers independently selected studies, collected data, and evaluated methodological quality through the Cochrane Risk of Bias tool. Revman 5.4 was used for meta-analysis, and the Grade system was performed to evaluate the level of evidence for the outcomes of the meta-analysis. RESULTS: A total of 20 randomized controlled trials with 1677 ODI patients were included. Compared with the clomiphene citrate (CC) group, the AT plus CC group exhibited significant improvement of the pregnancy rate [relative risk (RR) = 1.68, 95% confidence interval (CI): 1.45-1.95, P < 0.00001, I 2 = 23%], ovulation rate (RR = 1.34, 95%CI: 1.22-1.47, P < 0.00001, I 2 = 32%), serum E2 level [mean difference (MD) = 31.36, 95%CI: 21.83-40.88, P < 0.00001, I 2 = 97%], thickness of endometrium (MD = 1.76, 95%CI: 0.71-2.81, P = 0.001, I 2 = 98%) and decreasing miscarriage rate (RR = 0.25, 95%CI: 0.09-0.65, P = 0.005, I 2 = 0%), serum follicle-stimulating hormone level (MD = -2.10, 95%CI: -3.27 to -0.94, P = 0.0004, I 2 = 99%), serum luteinizing hormone level (MD = -6.94, 95%CI: -9.89 to -4.00, P < 0.00001, I 2 = 100%), and serum progesterone level (MD = -1.66, 95%CI: -2.98 to -0.34, P = 0.01, I 2 = 96%). The AT group had a more favorable effect than CC group for improving pregnancy rate (RR = 1.52, 95%CI: 1.33-1.73, P < 0.00001, I 2 = 0%), thickness of endometrium (MD = 2.48, 95%CI: 2.15-2.81, P < 0.00001, I 2 = 0%) and reducing miscarriage rate (RR = 0.23, 95%CI: 0.13-0.44, P < 0.00001, I 2 = 0%), serum follicle-stimulating hormone level (MD = -0.55, 95%CI: -0.86 to -0.24, P = 0.0005, I 2 = 0%), and serum progesterone level (MD = -0.24, 95%CI: -0.28 to -0.20, P < 0.00001). However, the level of evidence was predominantly assessed as very low to moderate. CONCLUSION: AT can improve the pregnancy outcomes and sex hormone levels for patients with ODI. However, further studies are needed to confirm these findings.
ABSTRACT
Hyperoxia-induced acute lung injury (HALI) is a complication of oxygen therapy. Ferroptosis is a vital factor in HALI. This paper was anticipated to investigate the underlying mechanism of Wedelolactone (WED) on ferroptosis in HALI. The current study used hyperoxia to injure two models, one HALI mouse model and one MLE-12 cell injury model. We found that WED treatment attenuated HALI by decreasing the lung injury score and lung wet/dry weight ratio and alleviating pathomorphological changes. Then, the inflammatory reaction and apoptosis in HALI mice and hyperoxia-mediated MLE-12 cells were inhibited by WED treatment. Moreover, WED alleviated ferroptosis with less iron accumulation and reversed expression alterations of ferroptosis markers, including MDA, GSH, GPX4, SLC7A11, FTH1, and TFR1 in hyperoxia-induced MLE-12 cells in vitro and in vivo. Nrf2-KO mice and Nrf2 inhibitor (ML385) decreased WED's ability to protect against apoptosis, inflammatory response, and ferroptosis in hyperoxia-induced MLE-12 cells. Collectively, our data highlighted the alleviatory role of WED in HALI by activating the Nrf2/HO-1 pathway.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by unknown etiology. This study employs robust ranking aggregation to identify consistent differential genes across multiple datasets, aiming to enhance prognostic evaluation and facilitate the development of more effective immunotherapy strategies for IPF. Using the GSE10667, GSE110147, and GSE24206 datasets, the analysis identifies 92 robust differentially expressed genes (DEGs), including SPP1, IGF1, ASPN, and KLHL13, highlighted as potential biomarkers through machine learning and experimental validation. Additionally, significant differences in immune cell types between IPF samples and controls, such as Plasma cells, Macrophages M0, Mast cells resting, T cells CD8, and NK cells resting, inform the construction of diagnostic and survival prediction models, demonstrating good applicability. These findings provide insights into IPF pathophysiology and suggest potential therapeutic targets.
Subject(s)
Biomarkers , Idiopathic Pulmonary Fibrosis , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/immunology , Humans , Animals , Machine Learning , Mice , Gene Expression Profiling , Prognosis , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/genetics , Osteopontin/genetics , Osteopontin/metabolism , Lung/pathology , Lung/immunology , Disease Models, AnimalABSTRACT
Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty. Our study examined the association between the two medical conditions and effect modification by sex and neuropsychiatric comorbidities in a nationwide population. To compare the risk of precocious puberty between ASD and non-ASD cases, we conducted a Cox regression analysis using ASD as the exposure and time to precocious puberty as the outcome. We adjusted for sex, attention-deficit/hyperactivity disorder (ADHD), tic disorder, obsessive-compulsive disorder (OCD), anxiety disorder, intellectual disability, and epilepsy. We performed a moderation analysis to examine the potential moderating effects of sex and comorbidities. Patients with ASD were prone to have precocious puberty, with an adjusted hazard ratio (aHR) of 1.80 (95% CI: 1.61-2.01). For effect modification, sex, specifically females, moderated the association between ASD and precocious puberty, with a relative excess risk due to interaction (RERI) of 7.35 (95% CI 4.90-9.80). No significant effect modification was found for any of the comorbidities within the scope of additive effect modification. We found that patients with ASD were prone to precocious puberty, regardless of sex or comorbid neuropsychiatric disorders. Girls with ASD are at a particularly higher risk of developing precocious puberty.
ABSTRACT
Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.
Subject(s)
Base Pair Mismatch , DNA Damage , DNA, Single-Stranded , Sequence Analysis, DNA , Single Molecule Imaging , Humans , Aging/genetics , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Base Pair Mismatch/genetics , Cytidine Deaminase/metabolism , Cytidine Deaminase/genetics , Cytosine/metabolism , Deamination , DNA Damage/genetics , DNA Mismatch Repair/genetics , DNA Replication/genetics , DNA, Single-Stranded/genetics , Genome, Mitochondrial/genetics , Mutation , Neoplasms/genetics , Sequence Analysis, DNA/methods , Sequence Analysis, DNA/standards , Single Molecule Imaging/methods , Male , FemaleABSTRACT
Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. From 2018 to 2023, a surge in severe neonatal cases and fatalities linked to a novel variant of genotype D5 was documented in China, France, and Italy. However, the prevention and control of E11 variants have been hampered by limited background data on the virus circulation and genetic variance. Therefore, the present study investigated the circulating dynamics of E11 and the genetic variation and molecular evolution of genotype D5 through the collection of strains from the national acute flaccid paralysis (AFP) and hand, foot, and mouth disease (HFMD) surveillance system in China during 2000-2022 and genetic sequences published in the GenBank database. The results of this study revealed a prevalent dynamic of E11 circulation, with D5 being the predominant genotype worldwide. Further phylogenetic analysis of genotype D5 indicated that it could be subdivided into three important geographic clusters (D5-CHN1: 2014-2019, D5-CHN2: 2016-2022, and D5-EUR: 2022-2023). Additionally, variant-specific (144) amino acid mutation sites and positive-selection pressure sites (132, 262) were identified in the VP1 region. Cluster-specific recombination patterns were also identified, with CVB5, E6, and CVB4 as the major recombinant viruses. These findings provide a preliminary landscape of E11 circulation worldwide and basic scientific data for further study of the pathogenicity of E11 variants.
Subject(s)
Enterovirus B, Human , Evolution, Molecular , Genetic Variation , Genotype , Phylogeny , China/epidemiology , Humans , Enterovirus B, Human/genetics , Enterovirus B, Human/classification , Enterovirus B, Human/isolation & purification , Infant, Newborn , Echovirus Infections/virology , Echovirus Infections/epidemiology , Hand, Foot and Mouth Disease/virology , Hand, Foot and Mouth Disease/epidemiology , InfantABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that leads to progressive cognitive decline and neuropathological changes. Pericytes, which are vessel mural cells on the basement membrane of capillaries, play a crucial role in regulating cerebrovascular functions and maintaining neurovascular unit integrity. Emerging research substantiates the involvement of pericytes in AD. This review provides a comprehensive overview of pericytes, including their structure, origin, and markers and various functions within the central nervous system. Emphatically, the review explores the intricate mechanisms through which pericytes contribute to AD, including their interactions with amyloid beta and apolipoprotein E, as well as various signaling pathways. The review also highlights potential for targeted pericyte therapy for AD, with a focus on stem cell therapy and drug treatments. Future research directions include the classification of pericyte subtypes, studies related to aging, and the role of pericytes in exosome-related mechanisms in AD pathology. In conclusion, this review consolidates current knowledge on the pivotal roles of pericytes in AD and their potential as therapeutic targets, providing valuable insights for future research and clinical interventions aimed at addressing the impact of AD on patients' lives.
Subject(s)
Alzheimer Disease , Pericytes , Pericytes/pathology , Pericytes/metabolism , Pericytes/physiology , Humans , Alzheimer Disease/therapy , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Animals , Amyloid beta-Peptides/metabolismABSTRACT
BACKGROUND: Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM: To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS: RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS: In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION: We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.
Subject(s)
Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms , Tumor Microenvironment , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/metabolism , Prognosis , Cell Line, Tumor , Tumor Microenvironment/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Protein Processing, Post-Translational , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Adenocarcinoma/immunology , Adenocarcinoma/metabolism , Lactic Acid/metabolism , Symporters/genetics , Symporters/metabolism , Cell Proliferation/genetics , Gene Expression Profiling , Male , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/therapy , Female , Animals , TranscriptomeABSTRACT
Agricultural by-products of sesame are promising bioresources in food processing. This study extracted lignin from the by-products of sesame oil production, namely, the capsules and straw of black and white sesame. Using acid, alkali, and ethanol methods, 12 distinct lignins were obtained to prepare biochar, aiming to investigate both the structural characteristics of lignin-based biochar (LBB) and its ability to remove benzo[a]pyrene (BaP) from sesame oil. The results showed that white sesame straw was the most suitable raw material for preparing biochar. In terms of the preparation method, acid-extracted lignin biochar was more effective in removing BaP than alkaline or ethanol methods. Notably, WS-1LB (white sesame straw acid-extracted lignin biochar) exhibited the highest BaP adsorption efficiency (91.44 %) and the maximum specific surface area (1065.8187 m2/g), characterized by porous structures. The pseudo 2nd and Freundlich models were found to be the best fit for the adsorption kinetics and isotherms of BaP on LBB, respectively, suggesting that a multilayer adsorption process was dominant. The high adsorption of LBB mainly resulted from pore filling. This study provides an economical and highly efficient biochar adsorbent for the removal of BaP in oil.
Subject(s)
Charcoal , Lignin , Sesame Oil , Lignin/chemistry , Charcoal/chemistry , Adsorption , Sesame Oil/chemistry , Benzo(a)pyrene/chemistry , KineticsABSTRACT
BACKGROUND: Limited evidence exists regarding the association between gestational diabetes mellitus (GDM) and elevated levels of thyroid-stimulating hormone (TSH) in newborns. Therefore, this study aimed to investigate the potential risk of elevated TSH levels in infants exposed to maternal GDM, considering the type and number of abnormal values obtained from the 75-gram oral glucose tolerance test (OGTT). METHODS: A population-based, prospective birth cohort study was conducted in Wuhan, China. The study included women who underwent GDM screening using a 75-g OGTT. Neonatal TSH levels were measured via a time-resolved immunofluorescence assay. We estimated and stratified the overall risk (adjusted Risk Ratio [RR]) of elevated TSH levels (defined as TSH > 10 mIU/L or > 20 mIU/L) in offspring based on the type and number of abnormal OGTT values. RESULTS: Out of 15,236 eligible mother-offspring pairs, 11.5% (1,753) of mothers were diagnosed with GDM. Offspring born to women diagnosed with GDM demonstrated a statistically significant elevation in TSH levels when compared to offspring of non-GDM mothers, with a mean difference of 0.20 [95% CI: 0.04-0.36]. The incidence of elevated TSH levels (TSH > 10 mIU/L) in offspring of non-GDM women was 6.3 per 1,000 live births. Newborns exposed to mothers with three abnormal OGTT values displayed an almost five-fold increased risk of elevated TSH levels (adjusted RR 4.77 [95% CI 1.64-13.96]). Maternal fasting blood glucose was independently and positively correlated with neonatal TSH levels and elevated TSH status (TSH > 20 mIU/L). CONCLUSIONS: For newborns of women with GDM, personalized risk assessment for elevated TSH levels can be predicated on the type and number of abnormal OGTT values. Furthermore, fasting blood glucose emerges as a critical predictive marker for elevated neonatal TSH status.
Subject(s)
Diabetes, Gestational , Glucose Tolerance Test , Thyrotropin , Humans , Female , Thyrotropin/blood , Pregnancy , Diabetes, Gestational/blood , Infant, Newborn , Adult , China/epidemiology , Prospective Studies , Birth Cohort , Male , Cohort StudiesABSTRACT
Environmentally persistent free radicals (EPFRs) can pose exposure risks by inducing the generation of reactive oxygen species. As a new class of pollutants, EPFRs have been frequently detected in atmospheric particulate matters. In this study, the seasonal variations and sources of EPFRs in a severe cold region in Northeastern China were comprehensively investigated, especially for the high pollution events. The geomean concentration of EPFRs in the total suspended particle was 6.58 × 1013 spins/m3 and the mean level in winter was one order of magnitude higher than summer and autumn. The correlation network analysis showed that EPFRs had significantly positive correlation with carbon component, K+ and PAHs, indicating that EPFRs were primarily emitted from combustion and pyrolysis process. The source appointment by the Positive Matrix Factorization (PMF) model indicated that the dominant sources in the heating season were coal combustion (48.4%), vehicle emission (23.1%) and biomass burning (19.4%), while the top three sources in the non-heating season were others (41.4%), coal combustion (23.7%) and vehicle emissions (21.2%). It was found that the high EPFRs in cold season can be ascribed to the extensive use of fossil fuel for heating demand; while the high EPFRs occurred in early spring were caused by the large-scale opening combustion of biomass. In summary, this study provided important basic information for better understanding the pollution characteristics of EPFRs, which suggested that the implementation of energy transformation and straw utilization was benefit for the control of EPFRs in severe cold region.
Subject(s)
Air Pollutants , Coal , Environmental Monitoring , Seasons , Air Pollutants/analysis , Coal/analysis , China , Free Radicals/analysis , Biomass , Particulate Matter/analysis , Cities , Air Pollution/analysisABSTRACT
Reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) serve as vital mediators essential for preserving intracellular redox homeostasis within the human body, thereby possessing significant implications across physiological and pathological domains. Nevertheless, deviations from normal levels of ROS, RNS, and RSS disturb redox homeostasis, leading to detrimental consequences that compromise bodily integrity. This disruption is closely linked to the onset of various human diseases, thereby posing a substantial threat to human health and survival. Small-molecule fluorescent probes exhibit considerable potential as analytical instruments for the monitoring of ROS, RNS, and RSS due to their exceptional sensitivity and selectivity, operational simplicity, non-invasiveness, localization capabilities, and ability to facilitate in situ optical signal generation for real-time dynamic analyte monitoring. Due to their distinctive transition from their spirocyclic form (non-fluorescent) to their ring-opened form (fluorescent), along with their exceptional light stability, broad wavelength range, high fluorescence quantum yield, and high extinction coefficient, rhodamine fluorophores have been extensively employed in the development of fluorescent probes. This review primarily concentrates on the investigation of fluorescent probes utilizing rhodamine dyes for ROS, RNS, and RSS detection from the perspective of different response groups since 2016. The scope of this review encompasses the design of probe structures, elucidation of response mechanisms, and exploration of biological applications.
Subject(s)
Fluorescent Dyes , Reactive Nitrogen Species , Reactive Oxygen Species , Rhodamines , Fluorescent Dyes/chemistry , Rhodamines/chemistry , Reactive Nitrogen Species/analysis , Humans , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/analysis , Optical Imaging , Animals , Sulfur/chemistry , Sulfur/analysisABSTRACT
BACKGROUND: Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms. METHODS: A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy. RESULTS: A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury. CONCLUSIONS: Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients.
Subject(s)
Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Moxibustion , Primary Ovarian Insufficiency , Humans , Female , Rats , Animals , Mitophagy , Reactive Oxygen Species/metabolism , Carbonyl Cyanide m-Chlorophenyl Hydrazone/adverse effects , Carbonyl Cyanide m-Chlorophenyl Hydrazone/metabolism , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/therapy , Primary Ovarian Insufficiency/pathology , Cyclophosphamide/adverse effects , Mesenchymal Stem Cells/metabolism , Mitochondria/metabolism , Ubiquitin-Protein Ligases/metabolism , Protein Kinases/metabolism , Hormones/adverse effects , Hormones/metabolism , Adenosine Triphosphate/metabolismABSTRACT
BACKGROUND: The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PURPOSE: The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. STUDY DESIGN: Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. METHODS: Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. RESULTS: Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1ß, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. CONCLUSIONS: SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.
Subject(s)
Apoptosis , Endothelial Cells , Heme Oxygenase (Decyclizing) , Pulmonary Artery , Signal Transduction , Animals , Male , Rats , Apoptosis/drug effects , Endothelial Cells/drug effects , Glucosides/pharmacology , Hypertension, Pulmonary/drug therapy , Hypoxia/drug therapy , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Phenols/pharmacology , Pulmonary Artery/drug effects , Rats, Sprague-Dawley , Receptors, Aryl Hydrocarbon/metabolism , Rhodiola/chemistry , Signal Transduction/drug effectsABSTRACT
In this study, three activators and two activation methods were employed to activate sesame lignin-based biochar. The biochar samples were comprehensively characterized, their abilities to adsorb benzo[a]pyrene (BaP) from sesame oil were assessed, and the mechanism was analyzed. The results showed that the biochar obtained by one-step activation was more effective in removing BaP from sesame oil than the biochar produced by two-step activation. Among them, the biochar generated by one-step activation with ZnCl2 as the activator had the largest specific surface area (1068.8776 m3/g), and the richest mesoporous structure (0.7891 m3/g); it removed 90.53 % of BaP from sesame oil. BaP was mainly adsorbed by the mesopores of biochar. Mechanistically, pore-filling, π-π conjugations, hydrogen bonding, and n-π interactions were involved. The adsorption was spontaneous and heat-absorbing. In conclusion, the preparation of sesame lignin biochar using one-step activation with ZnCl2 as the activator was found to be the best for removing BaP from sesame oil. This biochar may be an economical adsorbent for the industrial removal of BaP from sesame oil.
Subject(s)
Benzo(a)pyrene , Charcoal , Lignin , Sesame Oil , Sesamum , Charcoal/chemistry , Lignin/chemistry , Benzo(a)pyrene/chemistry , Adsorption , Sesame Oil/chemistry , Sesamum/chemistry , Zinc Compounds/chemistry , Chlorides/chemistryABSTRACT
Clonal hematopoiesis (CH) represents the clonal expansion of hematopoietic stem cells and their progeny driven by somatic mutations. Accurate risk assessment of CH is critical for disease prevention and clinical decision-making. The size of CH has been showed to associate with higher disease risk, yet, factors influencing the size of CH are unknown. In addition, the characteristics of CH in long-lived individuals are not well documented. Here, we report an in-depth analysis of CH in longevous (≥90 y old) and common (60~89 y old) elderly groups. Utilizing targeted deep sequencing, we found that the development of CH is closely related to age and the expression of aging biomarkers. The longevous elderly group exhibited a significantly higher incidence of CH and significantly higher frequency of TET2 and ASXL1 mutations, suggesting that certain CH could be beneficial to prolong life. Intriguingly, the size of CH neither correlates significantly to age, in the range of 60 to 110 y old, nor to the expression of aging biomarkers. Instead, we identified a strong correlation between large CH size and the number of mutations per individual. These findings provide a risk assessment biomarker for CH and also suggest that the evolution of the CH is influenced by factor(s) in addition to age.
Subject(s)
Clonal Hematopoiesis , Hematopoiesis , Humans , Aged , Clonal Hematopoiesis/genetics , Hematopoiesis/genetics , Aging/genetics , Mutation , BiomarkersABSTRACT
OBJECTIVE: To observe and verify the changes of transcriptome in hyperoxia-induced acute lung injury (HALI), and to further clarify the changes of pathways in HALI. METHODS: Twelve healthy male C57BL/6J mice were randomly divided into normoxia group and HALI group according to the random number table, with 6 mice in each group. The mice in the normoxia group were fed normally in the room, and the mice in the HALI group was exposed to 95% oxygen to reproduce the HALI animal model. After 72 hours of hyperoxia exposure, the lung tissues were taken for transcriptome sequencing, and then Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathway enrichment analysis was performed. The pathological changes of lung tissue were observed under light microscope after hematoxylin-eosin (HE) staining. Real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to verify the key molecules in the signal pathways closely related to HALI identified by transcriptomics analysis. RESULTS: Transcriptomic analysis showed that hyperoxia induced 537 differentially expressed genes in lung tissue of mice as compared with the normoxia group including 239 up-regulated genes and 298 down-regulated genes. Further KEGG pathway enrichment analysis identified 20 most significantly enriched pathway entries, and the top three pathways were ferroptosis signaling pathway, p53 signaling pathway and glutathione (GSH) metabolism signaling pathway. The related genes in the ferroptosis signaling pathway included the up-regulated gene heme oxygenase-1 (HO-1) and the down-regulated gene solute carrier family 7 member 11 (SLC7A11). The related genes in the p53 signaling pathway included the up-regulated gene tumor suppressor gene p53 and the down-regulated gene murine double minute 2 (MDM2). The related gene in the GSH metabolic signaling pathway was up-regulated gene glutaredoxin 1 (Grx1). The light microscope showed that the pulmonary alveolar structure of the normoxia group was normal. In the HALI group, the pulmonary alveolar septum widened and thickened, and the alveolar cavity shrank or disappeared. RT-RCR and Western blotting confirmed that compared with the normoxia group, the mRNA and protein expressions of HO-1 and p53 in lung tissue of the HALI group were significantly increased [HO-1 mRNA (2-ΔΔCt): 2.16±0.17 vs. 1.00±0.00, HO-1 protein (HO-1/ß-actin): 1.05±0.01 vs. 0.79±0.01, p53 mRNA (2-ΔΔCt): 2.52±0.13 vs. 1.00±0.00, p53 protein (p53/ß-actin): 1.12±0.02 vs. 0.58±0.03, all P < 0.05], and the mRNA and protein expressions of Grx1, MDM2, SLC7A11 were significantly decreased [Grx1 mRNA (2-ΔΔCt): 0.53±0.05 vs. 1.00±0.00, Grx1 protein (Grx1/ß-actin): 0.54±0.03 vs. 0.93±0.01, MDM2 mRNA (2-ΔΔCt): 0.48±0.03 vs. 1.00±0.00, MDM2 protein (MDM2/ß-actin): 0.57±0.02 vs. 1.05±0.01, SLC7A11 mRNA (2-ΔΔCt): 0.50±0.06 vs. 1.00±0.00, SLC7A11 protein (SLC7A11/ß-actin): 0.72±0.03 vs. 0.98±0.01, all P < 0.05]. CONCLUSIONS: HALI is closely related to ferroptosis, p53 and GSH metabolism signaling pathways. Targeting the key targets in ferroptosis, p53 and GSH metabolism signaling pathways may be an important strategy for the prevention and treatment of HALI.
Subject(s)
Acute Lung Injury , Hyperoxia , Rats , Mice , Male , Animals , Tumor Suppressor Protein p53 , Hyperoxia/complications , Rats, Sprague-Dawley , Actins , Mice, Inbred C57BL , Signal Transduction , Gene Expression Profiling , RNA, MessengerABSTRACT
Gut microbiota and their metabolic products might play important roles in regulating the pathogenesis of autism spectrum disorder (ASD). The purpose of this study was to characterize gut microbiota and serum amino acid metabolome profiles in children with ASD. A non-randomized controlled study was carried out to analyze the alterations in the intestinal microbiota and their metabolites in patients with ASD (n = 30) compared with neurotypical controls (NC) (n = 30) by metagenomic sequencing to define the gut microbiota community and liquid chromatography/mass spectrometry (LC/MS) analysis to characterize the metabolite profiles. Compared with children in the NC group, those in the ASD group showed lower richness, higher evenness, and an altered microbial community structure. At the class level, Deinococci and Holophagae were significantly lower in children with ASD compared with TD. At the phylum level, Deinococcus-Thermus was significantly lower in children with ASD compared with TD. In addition, the functional properties (such as galactose metabolism) displayed significant differences between the ASD and NC groups. Five dominant altered species were identified and analyzed (LDA score > 2.0, P < 0.05), including Subdoligranulum, Faecalibacterium_praushitzii, Faecalibacterium, Veillonellaceae, and Rumminococcaceae. The peptides/nickel transport system was the main metabolic pathway involved in the differential species in the ASD group. Decreased ornithine levels and elevated valine levels may increase the risk of ASD through a metabolic pathway known as the nickel transport system. The microbial metabolism in diverse environments was negatively correlated with phascolarctobacterium succinatutens. Our study provides novel insights into compositional and functional alterations in the gut microbiome and metabolite profiles in ASD and the underlying mechanisms between metabolite and ASD.
Subject(s)
Autism Spectrum Disorder , Gastrointestinal Microbiome , Child , Humans , Gastrointestinal Microbiome/physiology , Nickel , Metabolome , Amino Acids/metabolismABSTRACT
BACKGROUND: Previous studies of singletons evaluating prenatal phthalate exposure and early neurodevelopment reported mixed results and the associations could be biased by parental, obstetrical, and genetic factors. METHODS: A co-twin control design was employed to test whether prenatal phthalate exposure was associated with children's neurocognitive development. We collected information from 97 mother-twin pairs enrolled in the Wuhan Twin Birth Cohort between March 2016 and October 2018. Fourteen phthalate metabolites were measured in maternal urine collected at each trimester. Neurodevelopmental differences in twins at the age of two were examined as the outcome of interest. Multiple informant model was used to examine the covariate-adjusted associations of prenatal phthalate exposure with mental development index (MDI) and psychomotor development index (PDI) scores assessed at 2 years of age based on Bayley Scales of Infant Development (Second Edition). This model also helps to identify the exposure window of susceptibility. RESULTS: Maternal urinary levels of mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (ß = 1.91, 95% CI: 0.43, 3.39), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (ß = 1.56, 95% CI: 0.33, 2.79), and the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) (ß = 1.85, 95% CI: 0.39, 3.31) during the first trimester showed the strongest and significant positive associations with intra-twin MDI difference. When stratified with twin chorionicity, the positive associations of monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), individual DEHP metabolites, and ∑DEHP exposure during pregnancy with intra-twin neurodevelopmental differences were more significant in monochorionic diamniotic (MCDA) twins than those in dichorionic diamniotic (DCDA) twins. CONCLUSIONS: Neurodevelopmental differences in MCDA twins were strongly associated with prenatal phthalate exposure. Our findings warrant further confirmation in longitudinal studies with larger sample sizes.