Identification and functional prediction of miRNAs that regulate ROS levels in dielectric barrier discharge plasma-treated boar spermatozoa.

Dielectric barrier discharge (DBD) plasma regulates the levels of reactive oxygen species (ROS), which are critical for sperm quality. MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes, which regulate post-transcriptional gene expression in animals. At present, it is unknown whether DBD plasma can regulate sperm ROS levels through miRNAs. To further understand the regulatory mechanism of DBD plasma on sperm ROS levels, miRNAs in fresh boar spermatozoa were detected using Illumina deep sequencing technology. We found that 25 known miRNAs and 50 novel miRNAs were significantly upregulated, and 14 known miRNAs and 74 novel miRNAs were significantly downregulated in DBD plasma-treated spermatozoa. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that target genes of differentially expressed miRNAs were involved in many activities and pathways associated with antioxidants. We verified that DBD plasma significantly increased boar sperm quality and reduced ROS levels. These results suggest that DBD plasma can improve sperm quality by regulating ROS levels via miRNAs. Our findings provide a potential strategy to improve sperm quality through miRNA-targeted regulation of ROS, which helps to increase male reproduction and protect cryopreserved semen in clinical practice.

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes.

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

The effect and mechanism of low-dose esketamine in neuropathic pain-related depression-like behavior in rats.

BACKGROUND: Clinical evidence suggests that Esketamine (ESK) is an effective treatment for depression. However, the effects of Esketamine in treating depression-like behavior induced by neuropathic pain is unclear. The underlying molecular mechanisms require further investigation to provide new therapeutic targets for the treatment of clinical neuropathic pain-related depression. METHODS: A neuropathic pain-related depression model was established in rats with spared nerve injury (SNI). Male Sprague-Dawley rats were randomly divided into four groups: Sham Group, SNI group, SNI + Normal Saline (NS) Group and SNI + ESK5mg/kg Group. Mechanical pain thresholds were measured to assess pain sensitivity in SNI rats. On the 14th day after surgery a forced swim test and sucrose preference test were used to evaluate the depressive-like behavior of rats in each group. Further, a proteomic analysis was used to quantify differentially expressed proteins. The Gene Onotology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to explore the main protein targets of SNI in the medial prefrontal cortex. The expression of proteins was detected by Western blotting. RESULTS: A neuropathic pain-related depression model was established. Compared with the Sham group, the mechanical pain threshold was decreased significantly (13.2 ±â€¯1.0 vs. 0.7 ±â€¯0.01 g n = 8), while immobility on the forced swim test was also decreased (93.1 ±â€¯7.4 vs. 169.5 ±â€¯9.6 s n = 8), and sucrose preference rate was significantly increased (98.8 ±â€¯0.3 vs. 73.1 ±â€¯1.4n = 7) in SNI group rats. Compared with the SNI + NS group, the mechanical pain threshold was not statistically significant, while immobility on the forced swim test was clearly decreased (161.1 ±â€¯11.6 vs. 77.9 ±â€¯5.0 s n = 8), and sucrose preference rate was significantly increased (53.1 ±â€¯8.9 vs. 96.1 ±â€¯1.4n = 7) in SNI + ESK5mg/kg group rats. To further investigate the underlying mechanism, we employed proteomics to identify proteins exhibiting more than a 1.2-fold difference (P < 0.05) in expression levels within each group for subsequent analysis. Relative to the Sham group, 88 downregulated and 104 up-regulated proteins were identified in the SNI group, while 120 and 84 proteins were up- and down-regulated in the Esketamine treatment group compared with the SNI + NS group. Compared with Sham group, the expressions of mGluR5 and Homer1a were up-regulated in the medial prefrontal cortex (mPFC) in SNI group (mGluR5:0.97 ±â€¯0.05 vs 1.47 ±â€¯0.15, Homer1a:1.03 ±â€¯0.06 vs 1.46 ±â€¯0.16n = 6), and down-regulated after intervention with Esketamine (mGluR5:1.54 ±â€¯0.11 vs 1.06 ±â€¯0.07, Homer1a:1.51 ±â€¯0.13 vs 1.12 ±â€¯0.34n = 6). CONCLUSIONS: Low-dose Esketamine appeared to relieve depression-like behavior induced by neuropathic pain. The Homer1a-mGluR5 signaling pathway might be the mechanism of antidepressant effect of Esketamine.

Exploring the pharmacological mechanisms of the flower of Rhododendron molle in rheumatoid arthritis rats based on metabolomics integrated network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, the flower of Rhododendron molle G. Don (RMF) is record in the Chinese pharmacopoeia, and is commonly utilized for treating rheumatoid arthritis (RA) in clinical practice. However, its precise mechanisms necessitate further exploration. AIM OF THE STUDY: To expound the effective components, targets, metabolites, and pathways participated in RMF's anti-RA effects by metabolomics integrated network pharmacology. MATERIALS AND METHODS: CIA rats were intragastric administered RMF for 2 weeks, following which the therapeutic effects were comprehensively evaluated. Serum metabolomics was adopted to investigate the differential metabolites (DEMs). UHPLC-Q-Exactive-MS method was applied to identify the components of RMF, and then network pharmacology was utilize to select the component-RA-targets. Molecular docking and Western blotting were utilized to validate the key targets. RESULTS: RA symptoms were alleviated by RMF through the inhibition secretion of pro-inflammatory factors IL-1ß, IL-6 and TNF-α, along with relief in bone destruction observed in CIA rats. Four targets, namely AKR1B1, TPH1, CYP1A1, and CYP1A2, were identified, along with their corresponding metabolites, namely D-glucose, D-mannose, L-tryptophan, 11-deoxycorticosterone, and 17α-hydroxyprogesterone. These were found to be involved in three key metabolic pathways: steroid hormone biosynthesis, tryptophan metabolism, and galactose metabolism. Additionally, five significant anti-RA active components were identified from RMF, including Rhodojaponin (Rj)-Ⅱ, Rj-Ⅲ, Rj-Ⅴ, Rj-Ⅵ, and quercetin. CONCLUSIONS: The anti-RA mechanisms of RMF were investigated in this study, focusing on active components, upstream targets, and downstream metabolites. These findings lay a foundation for the clinical practice and drug development of RMF.

Optimal gestational weight gain associated with improved perinatal outcomes in women with gestational diabetes mellitus: a population-based study in the United States.

BACKGROUND: Optimal gestational weight change (GWC) is little known among pregnant women with gestational diabetes mellitus (GDM). OBJECTIVE: This study aimed to explore the optimal GWC ranges for women with GDM and validate these ranges compared to the Institute of Medicine (IOM) guidelines. METHODS: A population-based cohort study using natality data from the National Center for Health Statistics (NCHS) in the United States included 1,338,460 mother-infant pairs with GDM from 2014 to 2020. Poisson regression models were performed to identify GWC ranges (GDM targets) associated with acceptable risks (< 10% increase) for a severity-weighted composite outcome including preterm birth (PTB) < 37 weeks, large for gestational age (LGA, birthweight > 90th percentile) and small for gestational age (SGA, birthweight < 10th percentile). These targets were validated in individual outcomes including PTB, LGA, SGA, hypertensive disorders of pregnancy, neonatal intensive care unit admission and neonatal respiratory morbidity and compared with the IOM guidelines using logistic regression models with population-attributable fractions (PAFs) calculated. RESULTS: The severity-weighted composite outcome had a U-shaped or a J-shaped relationship with GWC across body mass index (BMI) categories. The GDM targets were 14.1-20.3 kg, 9.0-17.0 kg, 4.8-13.8 kg, -0.8-10.8 kg, -2.4-8.2 kg, and -8.3-6.0 kg for underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity, respectively. GWC outside the GDM or the IOM targets was associated with increased adverse perinatal outcomes in validation analyses. PAFs indicated that the IOM guidelines reduced a similar or higher proportion of adverse perinatal outcomes compared to the GDM targets for women with GDM, with the exception of those with class 2 and 3 obesity. CONCLUSIONS: The IOM guidelines are generally applicable for women with GDM, with the exception of women with moderate and severe obesity. The optimal GWC ranges for women with GDM and moderate to severe obesity may be lower than the IOM guidelines.

Differential diagnosis value of sympathetic skin response and cutaneous silent period on early-stage multiple system atrophy and Parkinson disease.

PURPOSE: Early differentiation between Parkinson's disease (PD) and Multiple system atrophy (MSA), particularly the parkinsonian subtypes (MSA-P), is challenging due to similar clinical symptoms. We aimed to evaluate Sympathetic skin response (SSR) and Cutaneous silent period (CSP) parameters in patients with MSA-P and PD to identify possible biomarkers that could distinguish the two groups of patients in early stage. METHODS: 22 individuals with early-stage MSA-P, 29 with early-stage PD, and 28 healthy controls were recruited from Guangdong Provincial People's Hospital. Demographic data was collected for all participants. Their SSR and CSP were evaluated using clinical electromyography equipment. Data were compared between different groups. The diagnostic accuracy of SSR and CSP parameters was calculated using the ROC curve. Logistic regression was used to produce an integration model to enhance diagnostic utility. RESULTS: Foot amplitude, CSP end latency and duration distinguished MSA-P from PD with the area under the curve (AUC) 0.770, 0.806, and 0.776, respectively. Foot and hand SSR amplitude distinguished PD from HC with the AUC 0.871 and 0.768, respectively. Foot SSR amplitude, hand SSR amplitude, and CSP end latency distinguished MSA-P from HC with the AUC 0.964, 0.872, and 0.812, respectively. The combination of SSR and CSP parameters differentiation between MSA-P and PD, PD and HC with the AUC 0.829 and 0.879, respectively. CONCLUSIONS: Analysis of SSR and CSP parameters showed excellent diagnostic accuracy in discriminating patients with early-stage MSA-P from HC and good diagnostic accuracy in discriminating patients with MSA-P from PD with early stages.

Development and reproduction of Scirtothrips dorsalis (Thysanoptera: Thripidae) on six host plant species.

Host plants can strongly influence the population performance of insects. Here, we investigated the development, survival, and oviposition of Scirtothrips dorsalis Hood on 6 host plants-Camellia sinensis ( L.) Kuntze (Ericales: Theaceae), Rosa chinensis Jacq. (Rosales: Rosaceae), Capsicum annuum L. (Solanales: Solanaceae), Eustoma grandiflorum (Hook.) G.Don (Gentianales: Gentianaceae), Glycine max (L.) Merr. (Fabales: Fabaceae), and Cucumis sativus L. (Cucurbitales: Cucurbitaceae), and constructed life tables for S. dorsalis on each plant. Significant differences in S. dorsalis development on the host species were observed. The mean developmental period from egg to adult was 11.45 ±â€…0.12 days, 11.24 ±â€…0.13 days, 12.08 ±â€…0.15 days, 12.28 ±â€…0.12 days, 12.67 ±â€…0.10 days, and 13.03 ±â€…0.11 days on C. sinensis, R. chinensis, C. annuum, E. grandiflorum, G. max, and C. sativus, respectively. Significant differences in survival of S. dorsalis were observed, namely, C. sinensis ≈ R. chinensis > E. grandiflorum ≈ C. annuum > G. max > C. sativus. The highest and lowest fecundities of S. dorsalis were recorded on R. chinensis (60.44 ±â€…1.53) and C. sativus (28.64 ±â€…1.02), respectively. Both of the net reproductive rate (R0) and intrinsic rate of increase (rm) of S. dorsalis were the highest on R. chinensis, with the values of 27.63 ±â€…0.58 and 0.142 ±â€…0.002, respectively; while the lowest on C. sativus, with the values of 8.81 ±â€…0.12 and 0.092 ±â€…0.003, respectively. Thus, R. chinensis was found to be the most suitable host, but C. sativus was the least suitable, for population development of S. dorsalis. Our results provide important information for the key control of S. dorsalis among different host plants.

Color Duplex Ultrasonography for the Evaluation of Innominate, Subclavian, and Common Carotid Artery Stenosis.

OBJECTIVE: This study aimed to validate the efficiency of Doppler ultrasonography for predicting the innominate, subclavian, and common carotid artery stenosis. METHODS: This retrospective multicenter study between 2013 and 2022 enrolled 636 patients who underwent carotid Doppler ultrasonography and subsequent digital subtraction angiography. And 58 innominate artery stenosis, 147 common carotid artery stenosis, and 154 subclavian artery stenosis were included. The peak systolic velocity at innominate, subclavian, and common carotid artery, and velocity ratios of innominate artery to common carotid artery, innominate artery to subclavian artery, and common carotid artery to internal carotid artery were measured or calculated. The threshold values were determined using receiver operating characteristic analysis. RESULTS: The threshold values of innominate artery stenosis were peak systolic velocity >206 cm/s (sensitivity: 82.8%; specificity: 91.4%) to predict ≥50% stenosis and >285 cm/s (sensitivity: 89.2%; specificity: 94.9%) to predict ≥70% stenosis. The threshold values of common carotid artery stenosis were peak systolic velocity >175 cm/s (sensitivity: 78.2%; specificity: 91.9%) to predict ≥50% stenosis and >255 cm/s (sensitivity: 87.1%; specificity: 87.2%) to predict ≥70% stenosis. The threshold values of subclavian artery stenosis were peak systolic velocity >200 cm/s (sensitivity: 68.2%; specificity: 84.4%) to predict ≥50% stenosis and >305 cm/s (sensitivity: 57.9%; specificity: 91.4%) to predict ≥70% stenosis. CONCLUSIONS: Symptomatic patients with ultrasonic parameters of velocity at innominate artery ≥206 cm/s, velocity at common carotid artery ≥175 cm/s, or velocity at subclavian artery ≥200 cm/s need to be considered for further verification and whether revascularization is necessary.

Establishment and validation of a gene mutation-based risk model for predicting prognosis and therapy response in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is a malignant clonal proliferative disease of hematopoietic system. Despite tremendous progress in uncovering the AML genome, only a small number of mutations have been incorporated into risk stratification and used as therapeutic targets. In this research, we performed to construct a predictive prognosis risk model for AML patients according to gene mutations. Methods: Next-generation sequencing (NGS) technology was utilized to detect gene mutation from 118 patients. mRNA expression profiles and related clinical information were mined from TCGA and GEO databases. Consensus cluster analysis was applied to obtain molecular subtypes, and differences in clinicopathological features, prognosis, and immune microenvironment of different clusters were systematically compared. According to the differentially expressed genes (DEGs) between clusters, univariate and LASSO regression analysis were applied to identify gene signatures to build a prognostic risk model. Patients were classified into high-risk (HR) and low-risk (LR) groups according to the median risk score (RS). Differences in prognosis, immune profile, and therapeutic sensitivity between two groups were analyzed. The independent predictive value of RS was assessed and a nomogram was developed. Results: NGS detected 24 mutated genes, with higher mutation frequencies in CBL (63 %) and SETBP1 (49 %). Two clusters exhibited different immune microenvironments and survival probability (p = 0.0056) were identified. A total of 444 DEGs were screened in two clusters, and a mutation-associated risk model was constructed, including MPO, HGF, SH2B3, SETBP1, HLA-DRB1, LGALS1, and KDM5B. Patients in LR had a superior survival time compared to HR. Predictive performance of this model was confirmed and the developed nomogram further improved the applicability of the risk model with the AUCs for predicting 1-, 3-, 5-year survival rate were 0.829, 0.81 and 0.811, respectively. HR cases were more sensitive to erlotinib, CI-1040, and AZD6244. Conclusion: These findings supplemented the understanding of gene mutations in AML, and constructed models had good application prospect to provide effective information for predicting prognosis and treatment response of AML.

Cavity-Partitioned Self-Assembled Cage for Sequential Separation in Aqueous Solutions.

The concept of pore space partition has emerged as an effective strategy for developing improved coordination-based supramolecular porous materials with exceptional performance. Herein, we report that a water-soluble self-assembled tetrahedral cage 1 with a partitioned cavity shown excellent performance as a multifunctional extractant. The results show that this unique partitioned cavity can efficiently separate halogenated adamantanes, adamantane isomers, and polycyclic aromatic hydrocarbons. Furthermore, the influence of cavity-partitioned cage 1 on the electrochemical properties of redox-active molecules and electrochemically driven reversible host-guest process has also been demonstrated. The findings offer valuable insights into the design and development of new type of materials with controlled phase separation and tailored electrochemical properties.

Dissecting and tracing the gut microbiota of infants with botulism: a cross sectional and longitudinal study.

Background: Infant botulism is caused by botulinum neurotoxin (BoNT), which is mainly produced by Clostridium botulinum. However, there is a lack of longitudinal cohort studies on infant botulism. Herein, we have constructed a cross-sectional and longitudinal cohort of infants infected with C. botulinum. Our goal was to reveal the differences in the intestinal microbiota of botulism-infected and healthy infants as well as the dynamic changes over time through multi-omics analysis. Methods: We performed 16S rRNA sequencing of 20 infants' stools over a period of 3 months and conducted whole genome sequencing of isolated C. botulinum strains from these laboratory-confirmed cases of infant botulism. Through bioinformatics analysis, we focused on the changes in the infants' intestinal microbiota as well as function over time series. Results: We found that Enterococcus was significantly enriched in the infected group and declined over time, whereas Bifidobacterium was significantly enriched in the healthy group and gradually increased over time. 18/20 isolates carried the type B 2 botulinum toxin gene with identical sequences. In silico Multilocus sequence typing found that 20\u00B0C. botulinum isolates from the patients were typed into ST31 and ST32. Conclusion: Differences in intestinal microbiota and functions in infants were found with botulism through cross-sectional and longitudinal studies and Bifidobacterium may play a role in the recovery of infected infants.

Mental simulation of colour properties during language comprehension: influence of context and comprehension stages.

Many studies have shown that mental simulation may occur during language comprehension. Supporting evidence is derived from the matching effects in the sentence-picture verification (SPV) task often used to assess mental simulations of object properties, such as size, orientation, and shape. However, mixed results have been obtained regarding object colour, with researchers reporting matching or mismatching effects. This study investigated the impact of colour information clarity within sentences on the process of mental simulation during language comprehension. Employing the SPV task and using novel objects, we examined whether there is a mental simulation of colour after excluding typical/atypical colour bias and how varying levels of colour information clarity in sentences influence the emergence of matching effects at different stages of comprehension. To address these issues, we conducted two experiments. In Experiment 1, the participants read normal sentences and subsequently engaged in picture verification with a novel object after a 500 ms delay. In Experiment 2, the participants encountered sentences containing both clear and unclear colour information and, after either a 0 ms or 1500 ms interval, completed picture verification tasks with a novel object. Null effects were found in the 500 ms condition for normal sentences and the 0 ms condition for unclear colour information sentences. A mismatching effect appeared in the 0 ms condition after clear colour information sentences, and a matching effect appeared in the 1500 ms condition for all sentences. The results indicated that after excluding colour bias, the participants still formed mental simulations of colour during language comprehension. Our results also indicated that ongoing colour simulation with time pressure impacted the participant responses. The participants ignored unclear colour information under time pressure, but without time pressure, they constructed simulations that were as detailed as possible, regardless of whether the implicit colour information in the sentence was clear.

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.

BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

Non-coordinating counteranion as a powerful tool to tune the activity of copper water oxidation catalysts.

Ten copper-bipyridine-type catalysts, [(bpyR)Cu(OH)2]2+, featuring diverse counteranions (OAc-, Cl-, SO42-, NO3-, OTf-) were synthesized. The observed substantial variations in turnover frequency (TOF) among these catalysts, coupled with insights gained from electrochemical investigations, underscore the pivotal influence of counteranions in fine-tuning the catalytic activity of metal complexes during water oxidation. The TOF value follows the trend of OAc- > Cl- > SO42- > NO3- > OTf-, which is the same as the change of coordinating ability index, a™. Density Functional Theory (DFT) calculations reveal that counteranion coordination plays an important role in influencing the catalytic performance of these complexes.

Therapeutic potential of extracellular vesicles from diverse sources in cancer treatment.

Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive proliferation, uncontrolled growth, invasion of nearby tissues, and spread to distant organs. Its progression involves a complex interplay of several elements and processes. Extracellular vesicles (EVs) serve as critical intermediaries in intercellular communication, transporting critical molecules such as lipids, RNA, membrane, and cytoplasmic proteins between cells. They significantly contribute to the progression, development, and dissemination of primary tumors by facilitating the exchange of information and transmitting signals that regulate tumor growth and metastasis. However, EVs do not have a singular impact on cancer; instead, they play a multifaceted dual role. Under specific circumstances, they can impede tumor growth and influence cancer by delivering oncogenic factors or triggering an immune response. Furthermore, EVs from different sources demonstrate distinct advantages in inhibiting cancer. This research examines the biological characteristics of EVs and their involvement in cancer development to establish a theoretical foundation for better understanding the connection between EVs and cancer. Here, we discuss the potential of EVs from various sources in cancer therapy, as well as the current status and future prospects of engineered EVs in developing more effective cancer treatments.

Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.

BACKGROUND AND AIMS: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Men's symptom experience throughout androgen deprivation therapy for prostate cancer: A systematic review and meta-aggregation.

BACKGROUND: Androgen deprivation therapy is a common treatment for men with advanced prostate cancer. They have experienced many complex symptoms that affect their quality of life. However, qualitative reviews that synthesize the symptom experience for men with prostate cancer are lacking. OBJECTIVE: To explore the men's symptom experience throughout androgen deprivation therapy for prostate cancer. DESIGN: A qualitative evidence synthesis using meta-aggregation. DATA RESOURCES: Published and unpublished literature between January 2001 and August 2023 were identified from PubMed, Embase (Ovid), Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, ProQuest, Google Scholar, China National Knowledge Infrastructure (CNKI), Wang Fang, and VIP. REVIEW METHODS: Two reviewers independently conducted screening, study selection and data extraction, and quality appraisal was performed using the Joanna Briggs Institutes Critical Appraisal Checklist for Qualitative Research. Data synthesis was conducted using meta-aggregative approach. RESULTS: 24 articles of moderate to high methodological quality were included. A total of 98 findings were extracted with 59 unequivocal or equivocal findings eligible for meta-aggregation, aggregated into nine categories, and developed four synthesized findings: (1) production of symptoms: unrecognized and underestimated, (2) perception of symptoms: varied and complicated, (3) meaning of symptoms: threatened and affected, and (4) response to symptoms: push and pull. CONCLUSIONS: Men throughout androgen deprivation for prostate cancer experience the four crisis-packed stages in their symptomatic journey. Health care provider need to understand the men's thoughts whether in the process of shared decision-making or in the course of the chosen therapy. Future research should develop individual suitable interventions and offer practical strategies for managing symptom. PROSPERO registration: CRD42023449129.

Cathepsins and cancer risk: a Mendelian randomization study.

Background: Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis. Methods: We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis. Results: After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, P = 0.001, PFDR = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, P = 0.0002, P FDR = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, P = 0.006). Conclusion: Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.