Dysregulation of protein succinylation and disease development.

As a novel post-translational modification of proteins, succinylation is widely present in both prokaryotes and eukaryotes. By regulating protein translocation and activity, particularly involved in regulation of gene expression, succinylation actively participates in diverse biological processes such as cell proliferation, differentiation and metabolism. Dysregulation of succinylation is closely related to many diseases. Consequently, it has increasingly attracted attention from basic and clinical researchers. For a thorough understanding of succinylation dysregulation and its implications for disease development, such as inflammation, tumors, cardiovascular and neurological diseases, this paper provides a comprehensive review of the research progress on abnormal succinylation. This understanding of association of dysregulation of succinylation with pathological processes will provide valuable directions for disease prevention/treatment strategies as well as drug development.

Knowledge, attitude and practice towards insomnia and sleep hygiene among patients with chronic insomnia in Northwest China in 2023: a cross-sectional survey.

OBJECTIVES: To investigate the knowledge, attitude and practice (KAP) towards insomnia and sleep hygiene among patients with chronic insomnia. DESIGN: Web-based cross-sectional survey. SETTING: Shaanxi Provincial People's Hospital (northwest China) between January 2023 and May 2023. PARTICIPANTS: Patients with chronic insomnia. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic characteristics and KAP towards insomnia and sleep hygiene were collected by distributing a questionnaire developed by the authors. RESULTS: A total of 613 people participated in this study, with a Mean Knowledge Score of 7.63±2.56 (total score of 12), a Mean Attitude Score of 48.39±6.643 (total score of 70) and a Mean Practice Score of 42.37±8.592 (total score of 70). Knowledge was significantly correlated with attitude (r=0.447, p<0.001) and practice (r=0.327, p<0.001), and attitude was significantly correlated with practice (r=0.486, p<0.001). Multivariable logistic regression showed that higher knowledge (OR=1.181 (1.062-1.314), p=0.002) and better attitude (OR=1.171 (1.124-1.221), p<0.001) were independently associated with good practice. According to the structural equation modelling analysis, knowledge directly influenced practice (ß=0.457, p=<0.001) and attitude (ß=1.160, p=<0.001), while attitude influenced practice (ß=0.550, p=<0.001). CONCLUSION: The KAP towards insomnia and sleep hygiene among patients with chronic insomnia in Northwest China in 2023 was moderate, with better practice showing signs of being influenced by better knowledge and more positive attitudes.

Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals.

C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki-Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp2)-C(sp), C(sp2)-C(sp2), and C(sp2)-C(sp3) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia-reperfusion rats by activating Prkaca-mediated cAMP/PKA-MAPK pathway.

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.

[Discussion on hepatic damage mechanism of Asari Radix et Rhizoma based on network pharmacology and untargeted metabolomics].

Asari Radix et Rhizoma is a common drug for relieving exterior syndrome in clinics, but its toxicity limits its use. In this study, the mechanism of hepatic damage of Asari Radix et Rhizoma was studied by network pharmacology and metabolomics. The hepatic damage-related dataset, namely GSE54257 was downloaded from the GEO database. The Limma package was used to analyze the differentially expressed genes in the dataset GSE54257. Toxic components and target genes of Asari Radix et Rhizoma were screened by TCMSP, ECTM, and TOXNET. The hepatic damage target genes of Asari Radix et Rhizoma were obtained by mapping with the differentially expressed gene of GSE54257, and a PPI network was constructed. GO and KEGG enrichment analysis of target genes were performed, and a "miRNA-target gene-signal pathway" network was drawn with upstream miRNA information. Thirty rats were divided into a blank group, a high-dose Asari Radix et Rhizoma group, and a low-dose Asari Radix et Rhizoma group, which were administered once a day. After continuous administration for 28 days, liver function indexes and liver pathological changes were detected. Five liver tissue samples were randomly collected from the blank group and high-dose Asari Radix et Rhizoma group, and small molecule metabolites were analyzed by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS). The orthogonal partial least squares-discriminant analysis(OPLS-DA) method was used to screen differential metabolites, and enrichment analysis, correlation analysis, and cluster analysis were conducted for differential metabolites. Finally, the MetaboAnalyst platform was used to conduct pathway enrichment analysis for differential metabolites. It was found that there were 14 toxic components in Asari Radix et Rhizoma, corresponding to 37 target genes, and 12 genes related to liver toxicity of Asari Radix et Rhizoma were obtained by mapping to differentially expressed genes of GSE54257. The animal test results showed that Asari Radix et Rhizoma could significantly increase the liver function index, reduce the activity of the free radical scavenging enzyme, change the liver oxidative stress level, and induce lipid peroxidation damage in rats. The results of untargeted metabolomics analysis showed that compared with the blank group, nine metabolites were up-regulated, and 16 metabolites were down-regulated in the liver tissue of the Asari Radix et Rhizoma group. These 25 metabolites had strong correlations and good clustering. Pathway enrichment analysis showed that these differential metabolites and the 12 hepatotoxic target genes of Asari Radix et Rhizoma were mainly involved in purine metabolism, as well as the biosynthesis and metabolism of valine, leucine, glycine, serine, and threonine. The study confirmed that the hepatica damage effect of Asari Radix et Rhizoma was the result of multi-component, multi-target, and multi-signaling pathways, and its mechanism may be related to inhibiting nucleotide synthesis and affecting protein metabolism.

Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Cholesterol-regulated cellular stiffness may enhance evasion of NK cell-mediated cytotoxicity in gastric cancer stem cells.

Gastric cancer has a high rate of recurrence, and as such, immunotherapy strategies are being investigated as a potential therapeutic strategy. Although the involvement of immune checkpoints in immunotherapy is well studied, biomechanical cues, such as target cell stiffness, have not yet been subject to the same level of investigation. Changes in the cholesterol content of the cell membrane directly influence tumor cell stiffness. Here, we investigated the effect of cholesterol on NK cell-mediated killing of gastric cancer stem-like cells. We report that surviving tumor cells with stem-like properties elevated cholesterol metabolism to evade NK cell cytotoxicity. Inhibition of cholesterol metabolism enhances NK cell-mediated killing of gastric cancer stem-like cells, highlighting a potential avenue for improving immunotherapy efficacy. This study suggests a possible effect of cancer cell stiffness on immune evasion and offers insights into enhancing immunotherapeutic strategies against tumors.

CSPP1 stabilizes microtubules by capping both plus and minus ends.

Although the dynamic instability of microtubules (MTs) is fundamental to many cellular functions, quiescent MTs with unattached free distal ends are commonly present and play important roles in various events to power cellular dynamics. However, how these free MT tips are stabilized remains poorly understood. Here, we report that centrosome and spindle pole protein 1 (CSPP1) caps and stabilizes both plus and minus ends of static MTs. Real-time imaging of laser-ablated MTs in live cells showed deposition of CSPP1 at the newly generated MT ends, whose dynamic instability was concomitantly suppressed. Consistently, MT ends in CSPP1-overexpressing cells were hyper-stabilized, while those in CSPP1-depleted cells were much more dynamic. This CSPP1-elicited stabilization of MTs was demonstrated to be achieved by suppressing intrinsic MT catastrophe and restricting the polymerization. Importantly, CSPP1-bound MTs were resistant to MCAK-mediated depolymerization. These findings delineate a previously uncharacterized CSPP1 activity that integrates MT end capping to orchestrate quiescent MTs.

Effects of ulinastatin combined with dexmedetomidine on cognitive dysfunction and emergence agitation in elderly patients who underwent total hip arthroplasty.

BACKGROUND: With the continuous growth of the modern elderly population, the risk of fracture increases. Hip fracture is a common type of fracture in older people. Total hip arthroplasty (THA) has significant advantages in relieving chronic pain and promoting the recovery of hip joint function. AIM: To investigate the effect of ulinastatin combined with dexmedetomidine (Dex) on the incidences of postoperative cognitive dysfunction (POCD) and emergence agitation in elderly patients who underwent THA. METHODS: A total of 397 patients who underwent THA from February 2019 to August 2022. We conducted a three-year retrospective cohort study in Shaanxi Provincial People's Hospital. Comprehensive demographic data were obtained from the electronic medical record system. We collected preoperative, intraoperative, and postoperative data. One hundred twenty-nine patients who were administered Dex during the operation were included in the Dex group. One hundred fifty patients who were intravenously injected with ulinastatin 15 min before anesthesia induction were included in the ulinastatin group. One hundred eighteen patients who were administered ulinastatin combined with Dex during the operation were included in the Dex + ulinastatin group. The patients' perioperative conditions, hemodynamic indexes, postoperative Mini-Mental State Examination (MMSE) scores, Ramsay score, incidence of POCD, and serum inflammatory cytokines were evaluated. RESULTS: There was a significant difference in the 24 h visual analogue scale score among the three groups, and the score in the Dex + ulinastatin group was the lowest (P < 0.05). Compared with the Dex and ulinastatin group, the MMSE scores of the Dex + ulinastatin group were significantly increased at 1 and 7 d after the operation (all P < 0.05). Compared with those in the Dex and ulinastatin groups, incidence of POCD, levels of serum inflammatory cytokines in the Dex + ulinastatin group were significantly decreased at 1 and 7 d after the operation (all P < 0.05). The observer's assessment of the alertness/sedation score and Ramsay score of the Dex + ulinastatin group were significantly different from those of the Dex and ulinastatin groups on the first day after the operation (all P < 0.05). CONCLUSION: Ulinastatin combined with Dex can prevent the occurrence of POCD and emergence agitation in elderly patients undergoing THA.

TFR1 knockdown alleviates iron overload and mitochondrial dysfunction during neural differentiation of Alzheimer's disease-derived induced pluripotent stem cells by interacting with GSK3B.

Iron metabolism disorders are implicated in the pathogenesis of Alzheimer's disease (AD). It was previously reported that transferrin receptor (TFR1) expression was upregulated in AD mouse model. However, the precise biological functions of TFR1 in AD progression remains unclear. Herein, we observed a gradual increase in TFR1 protein expression during the differentiation of AD patient-derived induced pluripotent stem cells (AD-iPS). TFR1 knockdown inhibited the protein expression of ferritin and ferritin heavy chain 1 (FTH1), enhanced the expression of ferroportin 1 (FPN1), and decreased intracellular levels of total iron, labile iron, and reactive oxygen species (ROS). Moreover, TFR1 knockdown improved mitochondrial membrane potential (MMP), increased adenosine triphosphate (ATP) content, downregulated mitochondrial fission proteins, and upregulated mitochondrial fusion proteins. TFR1 knockdown alleviated iron overload and mitochondrial dysfunction in neural cells differentiated from AD-iPS, while TFR1 overexpression showed the opposite results. Additionally, TFR1interacted with glycogen synthase kinase 3 beta (GSK3B) and promoted GSK3B expression. GSK3B overexpression reversed the inhibitory effects of TFR1 knockdown on iron overload and mitochondrial dysfunction in AD-iPS differentiated neural cells. In conclusion, TFR1 knockdown alleviated iron overload and mitochondrial dysfunction in neural cells differentiated from AD-iPS by promoting GSK3B expression. Our findings provide a potential therapeutic target for the treatment of AD.

PbrWRKY62-PbrADC1 module involves in superficial scald development of Pyrus bretschneideri Rehd.fruit via regulating putrescine biosynthesis.

Putrescine plays a role in superficial scald development during the cold storage of pear fruit. However, the molecular mechanism behind this phenomenon has not been un-fully clarified until recently. In this study, a conjoint analysis of metabolites and gene expression profiles in the putrescine-metabolic pathway of P. bretschneideri Rehd. fruit followed by experimental validation revealed that PbrADC1, forming a homodimer in the chloroplast, was involved in putrescine biosynthesis and thus fruit chilling resistance. Additionally, the substrate-binding residue Cys546 in PbrADC1, whose activity was modified by H2O2, played a crucial role in arginine decarboxylation into agmatine. Through a combined analysis of the distribution of cis-acting elements in the PbrADC1 promoter as well as the expression profiles of related transcription factors (TFs), several TFs were identified as upstream regulators of PbrADC1 gene. Further investigation revealed that the nuclear PbrWRKY62 could directly bind to the W-box elements in the PbrADC1 promoter, activate its expression, enhance putrescine accumulation, and thus increase fruit chilling tolerance. In conclusion, our results suggest that the PbrWRKY62-PbrADC1 module is involved in the development of superficial scald in P. bretschneideri Rehd. fruit via regulating putrescine biosynthesis. Consequently, these findings could serve as valuable genetic resources for breeding scald-resistant pear fruit.

MRPS9-Mediated Regulation of the PI3K/Akt/mTOR Pathway Inhibits Neuron Apoptosis and Protects Ischemic Stroke.

Neuronal apoptosis is crucial in the pathophysiology of ischemic stroke (IS), albeit its underly24ing mechanism remaining elusive. Investigating the mechanism of neuronal apoptosis in the context of IS holds substantial clinical value for enhancing the prognosis of IS patients. Notably, the MRPS9 gene plays a pivotal role in regulating mitochondrial function and maintaining structural integrity. Utilizing bioinformatic tactics and the extant gene expression data related to IS, we conducted differential analysis and weighted correlation network analysis (WGCNA) to select important modules. Subsequent gene interaction analysis via the STRING website facilitated the identification of the key gene-mitochondrial ribosomal protein S9 (MRPS9)-that affects the progression of IS. Moreover, possible downstream signaling pathways, namely PI3K/Akt/mTOR, were elucidated via Kyoto Encyclopedia of Gene and Genomes (KEGG) and Gene Ontology (GO) pathway analysis. Experimental models were established utilizing oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Changes in gene and protein expression, as well as cell proliferation and apoptosis, were monitored through qPCR, WB, CCK8, and flow cytometry. An OGD/R cell model was further employed to investigate the role of MRPS9 in IS post transfusion of MRPS9 overexpression plasmids into cells. Further studies were conducted by transfecting overexpressed cells with PI3K/Akt/mTOR signaling pathway inhibitor LY294002 to unveil the mechanism of MRPS9 in IS. Bioinformatic analysis revealed a significant underexpression of MRPS9 in ischemic stroke patients. Correspondingly, in vitro experiments with HN cells subjected to OGD/R treatment demonstrated a marked reduction in MRPS9 expression, accompanied by a decline in cell viability, and an increase cell apoptosis. Notably, the overexpression of MRPS9 mitigated the OGD/R-induced decrease in cell viability and augmentation of apoptosis. In animal models, MRPS9 expression was significantly lower in the MCAO/R group compared to the sham surgery group. Further, the KEGG pathway analysis associated MRPS9 expression with the PI3K/Akt/mTOR signaling pathway. In cells treated with the specific PI3K/Akt/mTOR inhibitor LY294002, phosphorylation levels of Akt and mTOR were decreased, cell viability decreased, and apoptosis increased compared to the MRPS9 overexpression group. These findings collectively indicate that MRPS9 overexpression inhibits PI3K/Akt/mTOR pathway activation, thereby protecting neurons from apoptosis and impeding IS progression. However, the PI3K/Akt/mTOR inhibitor LY294002 is capable of counteracting the protective effect of MRPS9 overexpression on neuronal apoptosis and IS. Our observations underscore the potential protective role of MRPS9 in modulating neuronal apoptosis and in attenuating the pathophysiological developments associated with IS. This is achieved through the regulation of the PI3K/Akt/mTOR pathway. These insights forge new perspectives and propose novel targets for the strategic diagnosis and treatment of IS.

Cross-cultural adaptation and validation of the positive and negative social exchange scale in older adults with disabilities in China.

PURPOSE: This study translated the Positive and Negative Social Exchange (PANSE) scale into Chinese, examined its psychometric characteristics, and explored its feasibility for use among older adults with disabilities from China. MATERIALS AND METHODS: A two-stage study procedure was employed. In the first stage, the English version of the PANSE scale was translated and cross-culturally adapted. In the second stage, the reliability and validity of the scale were assessed based on item-total correlation, internal consistency, test-retest reliability, content validity, structural validity, concurrent criterion validity, and known group validity. RESULTS: A total of 357 older adults with disabilities participated in the survey. The Chinese version of the PANSE scale consisted of two parts, the Positive Social Exchange Scale and the Negative Social Exchange Scale. Exploratory factor analysis extracted six communal factors. The cumulative contribution of the two parts of the scale was 69.90% and 77.88%, respectively. The item-total correlation was 0.353 to 0.802, the internal consistency of the PANSE was 0.653 to 0.886. The PANSE demonstrated good content validity and it was correlated with the SSRS scale. CONCLUSION: The Chinese version of the PANSE is a valid and reliable instrument for assessing social exchange in Chinese older adults with disabilities.Implication for rehabilitationDespite the growing number of older adults with disabilities being a concern in China, the lack of tools to measure the type of social support limits research related to the health status of these people.This study cross-culturally adapted, translated into Chinese and validated the Positive and Negative Social Exchange (PANSE) scale as the measurement tool to be used in the cultural context of China.The two subscales of PANSE were validated in the Chinese population of older adults with disabilities.The PANSE scale measures social exchange among older adults with disabilities in China, which can guide the development of interventions to address issues in the social exchange of these people.

In Situ Vaccination with An Injectable Nucleic Acid Hydrogel for Synergistic Cancer Immunotherapy.

Recently, therapeutic cancer vaccines have emerged as promising candidates for cancer immunotherapy. Nevertheless, their efficacies are frequently impeded by challenges including inadequate antigen encapsulation, insufficient immune activation, and immunosuppressive tumor microenvironment. Herein, we report a three-in-one hydrogel assembled by nucleic acids (NAs) that can serve as a vaccine to in situ trigger strong immune response against cancer. Through site-specifically grafting the chemodrug, 7-ethyl-10-hydroxycamptothecin (also known as SN38), onto three component phosphorothioate (PS) DNA strands, a Y-shaped motif (Y-motif) with sticky ends is self-assembled, at one terminus of which an unmethylated cytosine-phosphate-guanine (CpG) segment is introduced as an immune agonist. Thereafter, programmed cell death ligand-1 (PD-L1) siRNA that performs as immune checkpoint inhibitor is designed as a crosslinker to assemble with the CpG- and SN38-containing Y-motif, resulting in the formation of final NA hydrogel vaccine. With three functional agents inside, the hydrogel can remarkably induce the immunogenic cell death to enhance the antigen presentation, promoting the dendritic cell maturation and effector T lymphocyte infiltration, as well as relieving the immunosuppressive tumor environment. When inoculated twice at tumor sites, the vaccine demonstrates a substantial antitumor effect in melanoma mouse model, proving its potential as a general platform for synergistic cancer immunotherapy.

Magnetic Resonance Imaging-Based Classification Systems for Informing Better Outcomes of Adenomyosis After Ultrasound-Guided High-Intensity Focused Ultrasound Ablating Surgery.

BACKGROUND: A referenced MRI-based classification associated with focused ultrasound ablation surgery (FUAS) outcomes is lacking in adenomyosis. PURPOSE: To identify an MRI-based classification system for informing the FUAS outcomes. STUDY TYPE: Retrospective. POPULATION: Patients with FUAS for adenomyosis, were divided into a training set (N = 643; 355 with post-FUAS gonadotropin-releasing hormone/levonorgestrel, 288 without post-FUAS therapy) and an external validation set (N = 135; all without post-FUAS therapy). FIELD STRENGTH/SEQUENCE: 1.5 T, turbo spin-echo T2-weighted imaging and single-shot echo-planar diffusion-weighted imaging sequences. ASSESSMENT: Five MRI-based adenomyosis classifications: classification 1 (C1) (diffuse, focal, and mild), C2 (intrinsic, extrinsic, intramural, and indeterminate), C3 (internal, adenomyomas, and external), C4 (six subtypes on areas [internal or external] and volumes [<1/3 or ≥2/3]), and C5 (internal [asymmetric or symmetric], external, intramural, full thickness [asymmetric or symmetric]) for FUAS outcomes (symptom relief and recurrence). STATISTICAL TESTS: The optimal classification was significantly associated with the most subtypes of FUAS outcomes. Relating to the timing of recurrence was measured using Cox regression analysis and median recurrence time was estimated by a Kaplan-Meier curve. A P value <0.05 was considered statistically significant. RESULTS: Dysmenorrhea relief and recurrence were only associated with C2 in training patients undergoing FUAS alone. Compared with other subtypes, the extrinsic subtype of C2 was significantly associated with dysmenorrhea recurrence in the FUAS group. Besides, the median dysmenorrhea recurrence time of extrinsic subtype was significantly shorter than that of other subtypes (42.0 months vs. 50.3 months). In the validation cohort, C2 was confirmed as the optimal system and its extrinsic subtype was confirmed to have a significantly shorter dysmenorrhea recurrence time than other subtypes. DATA CONCLUSION: Classification 2 can inform dysmenorrhea relief and recurrence in patients with adenomyosis undergoing FAUS only. Itsextrinsic subtype was associated with an earlier onset of dysmenorrhea recurrence after treatment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Bioinformatics analysis of differentially expressed genes related to ischemia and hypoxia in spinal cord injury and construction of miRNA-mRNA or mRNA-transcription factor interaction network.

BACKGROUND: Previous studies show that spinal cord ischemia and hypoxia is an important cause of spinal cord necrosis and neurological loss. Therefore, the study aimed to identify genes related to ischemia and hypoxia after spinal cord injury (SCI) and analyze their functions, regulatory mechanism, and potential in regulating immune infiltration. METHODS: The expression profiles of GSE5296, GSE47681, and GSE217797 were downloaded from the Gene Expression Omnibus database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to determine the function and pathway enrichment of ischemia- and hypoxia-related differentially expressed genes (IAHRDEGs) in SCI. LASSO model was constructed, and support vector machine analysis was used to identify key genes. The diagnostic values of key genes were evaluated using decision curve analysis and receiver operating characteristic curve analysis. The interaction networks of miRNAs-IAHRDEGs and IAHRDEGs-transcription factors were predicted and constructed with the ENCORI database and Cytoscape software. CIBERSORT algorithm was utilized to analyze the correlation between key gene expression and immune cell infiltration. RESULTS: There were 27 IAHRDEGs identified to be significantly expressed in SCI at first. These genes were mostly significantly enriched in wound healing function and the pathway associated with lipid and atherosclerosis. Next, five key IAHRDEGs (Abca1, Casp1, Lpl, Procr, Tnfrsf1a) were identified and predicted to have diagnostic value. Moreover, the five key genes are closely related to immune cell infiltration. CONCLUSION: Abca1, Casp1, Lpl, Procr, and Tnfrsf1a may promote the pathogenesis of ischemic or hypoxic SCI by regulating vascular damage, inflammation, and immune infiltration.

Hybrid Membrane Camouflaged Chemodrug-Gene Nanoparticles for Enhanced Combination Therapy of Ovarian Cancer.

Recently, cell membrane camouflaged nanoparticles (NPs) endowed with natural cellular functions have been extensively studied in various biomedical fields. However, there are few reports about such biomimetic NPs used to codeliver chemodrug and genes for synergistic cancer treatment up to now. Herein, we first prepare chemodrug-gene nanoparticles (Mito-Her2 NPs) by the electrostatic interaction coself-assembly of mitoxantrone hydrochloride (Mito) and human epidermal growth factor receptor-2 antisense oligonucleotide (Her2 ASO). Then, Mito-Her2 NPs are coated by a hybrid membrane (RSHM), consisting of the red blood cell membrane (RBCM) and the SKOV3 ovarian cancer cell membrane (SCM), to produce biomimetic chemodrug-gene nanoparticles (Mito-Her2@RSHM NPs) for combination therapy of ovarian cancer. Mito-Her2@RSHM NPs integrate the advantages of RBCM (e.g., good immune evasion capability and long circulation lifetime in the blood) and SCM (e.g., highly specific cognate recognition) together and improve the anticancer efficacy of Mito-Her2 NPs. The results show that Mito-Her2@RSHM NPs can be devoured by SKOV3 ovarian cancer cells and effectively degraded to release Her2 ASOs and Mito simultaneously. Her2 ASOs can inhibit the expression of endogenous Her2 genes and recover cancer cells' sensitivity to Mito, which ultimately led to a high apoptosis rate of 75.7% in vitro. Mito-Her2@RSHM NPs also show a high tumor suppression rate of 83.33 ± 4.16% in vivo without significant damage to normal tissues. In summary, Mito-Her2@RSHM NPs would be expected as a versatile and safe nanodrug delivery platform with high efficiency for chemo-gene combined cancer treatment.

Differential analysis of phytochemistry and antioxidant activity in five citrus by-products based on chromatography, mass spectrometry, and spectrum-effect relationships.

The unripe fruit or peel of Citrus aurantium L., Citrus sinensis Osbeck, and Citrus reticulata Blanco are often disregarded due to perceptions of their marginal value. The present study was undertaken to explore the differences in phytochemical composition and bioactive properties of five citrus by-products in China and demonstrate their potential value. 214 compounds were systematically identified using LC-Orbitrap-MS analysis. Among them, narirutin, naringin, hesperidin, and neohesperidin were established as essential compounds for the discrimination and authentication of the five by-products via a combination of LC-MS, HPLC, and TLC techniques. Variations in the antioxidant activity of the by-products were observed, which correlated with their maturity and were attributable to differences in their active ingredients. Moreover, spectrum-effect relationship analysis revealed that the four previously identified differential markers, along with nobiletin and tangeretin, significantly contributed to the differences in antioxidant activity. The results highlight the potential for citrus by-product enhancement and utilization.

Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure.

Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals 'turn-on', enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.

Photoredox Nickel-Catalysed Stille Cross-Coupling Reactions.

The Stille cross-coupling reaction is one of the most common strategies for the construction of C-C bonds. Despite notable strides in the advancement of the Stille reaction, persistent challenges persist in hindering its greener evolution. These challenges encompass multiple facets, such as the high cost of precious metals and ligands, the demand for various additives, and the slow reaction rate. In comparison to the dominant palladium-catalysed Stille reactions, cost-effective nickel-catalysed systems lag behind, and enantioconvergent Stille reactions of racemic stannanes remain undeveloped. Herein, we present a pioneering instance of nickel-catalysed enantioconvergent Stille cross-coupling reactions of racemic stannane reagents, resulting in the formation of C-C bonds in good to high yields with excellent stereoselectivity. This strategy provides a practical, scalable, and operationally straightforward method for the synthesis of C(sp3 )-C(sp3 ), C(sp3 )-C(sp2 ), and C(sp3 )-C(sp) bonds under exceptionally mild conditions (without additives and bases, ambient temperature). The innovative use of synergistic photoredox/nickel catalysis enables a novel single-electron transmetalation process of stannane reagents, providing a new research paradigm of Stille reactions.