Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis.

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Metabolomics Analysis and Diagnosis of Lung Cancer: Insights from Diverse Sample Types.

Lung cancer is a highly fatal disease that poses a significant global health burden. The absence of characteristic clinical symptoms frequently results in the diagnosis of most patients at advanced stages of lung cancer. Although low-dose computed tomography (LDCT) screening has become increasingly prevalent in clinical practice, its high rate of false positives continues to present a significant challenge. In addition to LDCT screening, tumor biomarker detection represents a critical approach for early diagnosis of lung cancer; unfortunately, no tumor marker with optimal sensitivity and specificity is currently available. Metabolomics has recently emerged as a promising field for developing novel tumor biomarkers. In this paper, we introduce metabolic pathways, instrument platforms, and a wide variety of sample types for lung cancer metabolomics. Specifically, we explore the strengths, limitations, and distinguishing features of various sample types employed in lung cancer metabolomics research. Additionally, we present the latest advances in lung cancer metabolomics research that utilize diverse sample types. We summarize and enumerate research studies that have investigated lung cancer metabolomics using different metabolomic sample types. Finally, we provide a perspective on the future of metabolomics research in lung cancer. Our discussion of the potential of metabolomics in developing new tumor biomarkers may inspire further study and innovation in this dynamic field.

Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents.

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 µM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.

The value of somatosensory evoked potentials in intraoperative evaluation of indirect decompression effect of oblique lumbar interbody fusion for lumbar spinal stenosis.

PURPOSE: The aim of this study was to explore the relationship between intraoperative somatosensory evoked potential (SEP) amplitude changes and clinical outcomes of OLIF indirect decompression for degenerative lumbar spinal stenosis (DLSS). METHODS: A prospective study was performed on 201 patients who received oblique lumbar interbody fusion (OLIF) in our hospital from July 2017 to May 2021 due to single segmental DLSS. The patients were divided into three groups: group A (mild DLSS), group B (moderate DLSS), and group C (severe DLSS). The P40 amplitude during operation were recorded, and the clinical efficacy was evaluated by JOA score 1 year postoperative. ROC curves for satisfactory efficacy of P40 amplitude improvement rate and CSA improvement rate were established. Pearson correlation was used to analyze the relationship between P40 improvement rate and JOA improvement rate. RESULTS: In group A and group B, the improvement rate of JOA in P40 significantly improved group was significantly greater that in improved group and unimproved group (Pa = 0.009; Pb < 0.000). No significant among-subgroup differences in group C (all P > 0.05). In both groups A and B, there was a significant difference in the improvement rate of P40 amplitude between the satisfactory group and the ineffective group (Pa = 0.013; Pb = 0.001), while in group C, there was no statistical significance (Pc = 0.107). By variable Person correlation analysis, a significant positive correlation was obtained between JOA improvement rate and P40 amplitude improvement rate in groups A and B (r1 = 0.27, P1 = 0.02; r2 = 0.508, P2 = 0.001), no correlation between the two in group C (r3 = 0.243, P3 = 0.056). The area under the ROC for assessing surgical efficacy in terms of CSA improvement rate was 0.813 (95% CI: 0.737-0.889, P < 0.001) and 0.767 (95% CI: 0.677-0.856, P < 0.001) in group A and group B, respectively, with satisfactory efficacy cutoff points of 50.18% and 67.89%. CONCLUSION: For mild and moderate DLSS, the intraoperative P40 amplitude improvement rate can predict the improvement of clinical symptoms after surgery and can be used as a reference index to assess the effect of indirect decompression. For severe DLSS, the P40 amplitude improvement rate has limited significance in guiding indirect decompression, and OLIF indirect decompression is not the right treatment for this type of patients.

[Association between maternal gestational diabetes mellitus and the risk of autism spectrum disorder in offspring]. / æ¯äº²å¦Šå¨ ç³–å°¿ç— ä¸Žå­ä»£å­¤ç‹¬ç—‡è°±ç³»éšœç¢å‘ç”Ÿé£Žé™©çš„å ³è”åˆ†æž.

OBJECTIVES: To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring. METHODS: A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored. RESULTS: The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%, P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54, P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11, P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65, P=0.027). CONCLUSIONS: Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring.

Quantitative evaluation of passive muscle stiffness by shear wave elastography in healthy individuals of different ages.

OBJECTIVES: To investigate age-related changes on passive muscle stiffness in healthy individuals and measure the shear modulus in different age groups. METHODS: Shear wave elastography (SWE) movies of gastrocnemius medialis (GM) were collected during passive stretching induced by ankle rotation from plantarflexion (PF) to dorsiflexion (DF). A series of SWE images at ankle angles of PF 40°, PF 30°, PF 20°, PF 10°, 0°, DF 10°, DF 20°, and DF 30° were collected and shear moduli measured accordingly for analyses. RESULTS: Eighty-six healthy volunteers (27 children, 31 middle-aged adults, and 28 older people) were recruited. No significant difference was observed in the shear modulus between the three groups at ankle angles of PF 40°, PF 30°, PF 20°, PF 10°, and 0° (p > 0.05). The difference in the shear modulus among the three groups became significant as DF increased. At ankle angles of DF 10°, DF 20°, and DF 30°, the shear modulus was the greatest in the older group, followed by the middle-aged group and then the children group (p = 0.007, 0.000, and 0.000, respectively). CONCLUSIONS: Passive muscle stiffness increases with age, and the difference between age groups was pronounced only after reaching a certain degree of stretching. KEY POINTS: • The influence of age on passive muscle stiffness becomes pronounced only after reaching a certain degree of stretching. • Age should be considered when evaluating passive muscle stiffness in muscular disorders.

Metformin inhibits cell proliferation in SKM-1 cells via AMPK-mediated cell cycle arrest.

Metformin, a widely used antidiabetic drug, has previously been demonstrated to exert anti-cancer effects in certain hematological malignancies, but its effects on the transformation of myelodysplastic syndromes to acute myeloid leukemia (AML-MDS) remain unclear. The present study aimed to investigate the effects of metformin on SKM-1 cells (an AML-MDS cell line) and its underlying mechanisms. SKM-1 cells were treated with different concentrations of metformin. Cell proliferation was assayed by CCK-8. Apoptosis and cell cycle phases were detected by flow cytometry, while cell cycle related proteins and AMPK were tested by Western blot. SKM-1 cells were transfected with LV-AMPKα1-RNAi to reduce the expression of AMPK. Metformin inhibited cell proliferation in a dose and time dependent manner by inducing G0/G1 phase arrest rather than apoptosis induction. Metformin promoted the expression of p-AMPK, P53, P21CIP1 and P27KIP1, while inhibited the expression of CDK4 and CyclinD1. AMPK knockdown attenuated the effects of metformin on SKM-1 cells. These findings suggested that metformin inhibited proliferation of SKM-1 cells, potentially through an AMPK-mediated cell cycle arrest.

Blocking mammalian target of rapamycin alleviates bladder hyperactivity and pain in rats with cystitis.

BACKGROUND: Bladder disorders associated with interstitial cystitis are frequently characterized by increased contractility and pain. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on the exaggerated bladder activity and pain evoked by cystitis and (2) the underlying mechanisms responsible for the role of mTOR in regulating cystic sensory activity. RESULTS: The expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4 E-binding protein 4 (p-4 E-BP1), as well as phosphatidylinositide 3-kinase (p-PI3K) pathway were amplified in cyclophosphamide rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated bladder hyperactivity and pain. In addition, blocking PI3K signal pathway attenuated activities of mTOR, which was accompanied with decreasing bladder hyperactivity and pain. Inhibition of either mTOR or PI3K blunted the enhanced spinal substance P and calcitonin gene-related peptide in cyclophosphamide rats. CONCLUSIONS: The data for the first time revealed specific signaling pathways leading to cyclophosphamide-induced bladder hyperactivity and pain, including the activation of mTOR and PI3K. Inhibition of these pathways alleviates cystic pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of overactive bladder and pain often observed in cystitis.

Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System.

Effective antitumor immunotherapy depends on evoking a cascade of cancer-immune cycles with lymph nodes (LNs) as the initial sites for activating antitumor immunity, making drug administration through the lymphatic system highly attractive. Here, we describe a nanomedicine with dual responsiveness to pH and enzyme for a programmed activation of antitumor immune through the lymphatic system. The proposed nanomedicine can release the STING agonist diABZI-C2-NH2 in the LNs' acidic environment to activate dendritic cells (DCs) and T cells. Then, the remaining nanomedicine hitchhikes on the activated T cells (PD-1+ T cells) through binding to PD-1, resulting in an effective delivery into tumor tissues owing to the tumor-homing capacity of PD-1+ T cells. The enzyme matrix metalloproteinase-2 (MMP-2) being enriched in tumor tissue triggers the release of PD-1 antibody (aPD-1) which exerts immune checkpoint blockade (ICB) therapy. Eventually, the nanomedicine delivers a DNA methylation inhibitor GSK-3484862 (GSK) into tumor cells, and then the latter combines with granzyme B (GZMB) to trigger tumor cell pyroptosis. Consequently, the pyroptotic tumor cells induce robust immunogenic cell death (ICD) enhancing the DCs maturation and initiating the cascading antitumor immune response. Study on a 4T1 breast tumor mouse model demonstrates the prominent antitumor therapeutic outcome of this nanomedicine through creating a positive feedback loop of cancer-immunity cycles including immune activation in LNs, T cell-mediated drug delivery, ICB therapy, and tumor cell pyroptosis-featured ICD.

Enhanced Toughening of the Lamellar Structure in a Black Coral by Interlocking Spines.

The black corals possess a branched, tree-like skeleton that is composed of chitin fibrils embedded within a protein matrix. This skeleton exhibits growth rings interlocked by spines. The lamellae are tightly wrapped around the spines, creating a structure akin to an onion. The indentation hardness and Young's modulus of the spines are comparable to those of the chitin rings. The compressive stress and the fracture toughness are increased by approximately 14.6% and 32.2% at higher loading rate in the dry state, but remain comparable at different loading rates in the wet state. The lamellar interfaces have a tendency to resist sliding in the dry state. As a result, the lamellae that curve around the spines are prone to fracturing one by one, just like an onion being peeled. This allows the material to absorb more fracture energy, ensuring that the spines can effectively resist the lamellar delamination.

The role of imprinting genes' loss of imprints in cancers and their clinical implications.

Genomic imprinting plays an important role in the growth and development of mammals. When the original imprint status of these genes is lost, known as loss of imprinting (LOI), it may affect growth, neurocognitive development, metabolism, and even tumor susceptibility. The LOI of imprint genes has gradually been found not only as an early event in tumorigenesis, but also to be involved in progression. More than 120 imprinted genes had been identified in humans. In this review, we summarized the most studied LOI of two gene clusters and 13 single genes in cancers. We focused on the roles they played, that is, as growth suppressors and anti-apoptosis agents, sustaining proliferative signaling or inducing angiogenesis; the molecular pathways they regulated; and especially their clinical significance. It is notable that 12 combined forms of multi-genes' LOI, 3 of which have already been used as diagnostic models, achieved good sensitivity, specificity, and accuracy. In addition, the methods used for LOI detection in existing research are classified into detection of biallelic expression (BAE), differentially methylated regions (DMRs), methylation, and single-nucleotide polymorphisms (SNPs). These all indicated that the detection of imprinting genes' LOI has potential clinical significance in cancer diagnosis, treatment, and prognosis.

Breaking barriers in cancer treatment: nanobiohybrids empowered by modified bacteria and vesicles.

Cancer, the leading global cause of mortality, poses a formidable challenge for treatment. The effectiveness of cancer therapies, ranging from chemotherapy to immunotherapy, relies on the precise delivery of therapeutic agents to tumor tissues. Nanobiohybrids, resulting from the fusion of bacteria with nanomaterials, constitute a promising delivery system. Nanobiohybrids offer several advantages, including the ability to target tumors, genetic engineering capabilities, programmed product creation, and the potential for multimodal treatment. Recent advances in targeted tumor treatments have leveraged bacteria-based nanobiohybrids. Here, we outline the progress in cancer treatment using nanobiohybrids. Our focus is particularly on various therapeutic approaches within the context of nanobiohybrid systems, where bacteria are integrated with nanomaterials to combat cancer. It has been demonstrated that bacteria-based nanobiohybrids present a robust and effective method for tumor theranostics.

Design, docking optimization, and evaluation of biotin-PEG4-1,8-naphthalimide as a potent and safe antitumor agent with dual targeting of ferroptosis and DNA.

A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives 4a-4h with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation as antitumor agents. Docking simulation optimization results indicated that biotin-PEG4-piperazine-1,8-naphthalimide 4d should be the best candidate among these designed compounds 4a-4h, and therefore, we synthesized and evaluated it as a novel antitumor agent. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and MGC-803 and U251 xenograft models identified 4d as a good candidate antitumor agent with potent efficacy and safety profiles, compared with amonafide and temozolomide. The findings of the docking simulations, fluorescence intercalator displacement (FID), western blot, comet, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transmission electron microscopy, and BODIPY-581/591-C11, FerroOrange, and dihydroethidium (DHE) fluorescent probe assays revealed that 4d could induce DNA damage, affect DNA synthesis, and cause cell cycle arrest in the S phase in MGC-803 cells. Also, it could induce lipid peroxidation and thus lead to ferroptosis in MGC-803 cells, indicating that it mainly exerted antitumor effects through dual targeting of ferroptosis and DNA. These results suggested that it was feasible to design, optimize using docking simulation, and evaluate the potency and safety of biotin-PEG-1,8-naphthalimide as a antitumor agent with dual targeting of ferroptosis and DNA, based on a multi-target drug strategy.

Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

Roles of Akirin1 in early prediction and treatment of graft kidney ischemia‒reperfusion injury.

Ferroptosis is a predominant contributor to graft kidney ischemia‒reperfusion injury (IRI), resulting in delayed graft function (DGF). However, much less is known about the early predicting biomarkers and therapeutic targets of DGF, especially aiming at ferroptosis. Here, we propose a precise predicting model for DGF, relying on the Akirin1 level in extracellular vesicles (EVs) derived from recipient urine 48 h after kidney transplant. In addition, we decipher a new molecular mechanism whereby Akirin1 induces ferroptosis by strengthening TP53-mediated suppression of SLC7A11 during the graft kidney IRI process, that is, Akirin1 activates the EGR1/TP53 axis and inhibits MDM2-mediated TP53 ubiquitination, accordingly upregulating TP53 in two ways. Meanwhile, we present the first evidence that miR-136-5p enriched in EVs secreted by human umbilical cord mesenchymal stem cells (UM-EVs) confers robust protection against ferroptosis and graft kidney IRI by targeted inhibition of Akirin1 but knockout of miR-136-5p in UM sharply mitigates the protection of UM-EVs. The functional and mechanistic regulation of Akirin1 is further corroborated in an allograft kidney transplant model in wild-type and Akirin1-knockout mice. In summary, these findings suggest that Akirin1, which prominently induces ferroptosis, is a pivotal biomarker and target for early diagnosis and treatment of graft kidney IRI and DGF after kidney transplant.

Inhibition of miR-221-3p promotes axonal regeneration and repair of primary sensory neurons via regulating p27 expression.

This study aimed to explore the key microRNA (miRNA) playing a vital role in axonal regeneration with a hostile microenvironment after spinal cord injury. Based on the theory that sciatic nerve conditioning injury (SNCI) could promote the repair of the injured dorsal column. Differentially expressed miRNAs were screened according to the microarray, revealing that 47 known miRNAs were differentially expressed after injury and perhaps involved in nerve regeneration. Among the 47 miRNAs, the expression of miR-221-3p decreased sharply in the SNCI group compared with the simple dorsal column lesion (SDCL) group. Subsequently, it was confirmed that p27 was the target gene of miR-221-3p from luciferase reporter assay. Further, we found that inhibition of miR-221-3p expression could specifically target p27 to upregulate the expression of growth-associated protein 43 (GAP-43), α-tubulin acetyltransferase (α-TAT1) together with α-tubulin, and advance the regeneration of dorsal root ganglion (DRG) neuronal axons. Chondroitin sulfate proteoglycans (CSPGs) are the main components of glial scar, which can hinder the extension and growth of damaged neuronal axons. After CSPGs were used in this study, the results demonstrated that restrained miR-221-3p expression also via p27 promoted the upregulation of GAP-43, α-TAT1, and α-tubulin and enhanced the axonal growth of DRG neurons. Hence, miR-221-3p could contribute significantly to the regeneration of DRG neurons by specifically regulating p27 in the p27/CDK2/GAP-43 and p27/α-TAT1/α-tubulin pathways even in the inhibitory environment with CSPGs.

Risk Factors and Outcomes of Central Nervous System Infection After Spinal Surgery: A Retrospective Cohort Study.

OBJECTIVE: To investigate the risk factor associated with central nervous system infection, a rare and dire complication after spinal surgery. METHODS: Univariate and multivariate logistic regression analyses were performed to screen for the independent risk factors. According to the different administration methods of antibiotics, patients were divided into intravenous and intrathecal groups. The differences in time needed for body temperature, white blood cells (WBC), and C-reactive protein (CRP) to return to normal and the time of antibiotic application were compared between the 2 groups. In addition, the differences in WBC, neutrophil ratio, CRP, procalcitonin in blood, and WBC in cerebrospinal fluid were compared before intrathecal injection, after the first one, and the last one. The incidence of complications in the 2 groups was observed. RESULTS: Dural tears, laminectomy, and operation time >3 hours were identified as independent risk factors. The time needed for body temperature, WBC, and CRP to return to normal and the antibiotic application time were significantly different between the 2 groups (all P < 0.05). Before and after the first intrathecal injection and after the last intrathecal injection, the differences in WBCs, neutrophil ratios, CRP, procalcitonin in blood, and cerebrospinal fluid-WBC were statistically significant in overall and pairwise comparisons (P < 0.05). Complications occurred in 2 and 14 cases, respectively. CONCLUSIONS: The independent risk factors for central nervous system infection after spinal surgery were a dural tear, laminectomy, and operation time > 3 hours. Combined intravenous and intrathecal injections of antibiotics led to a better effect than intravenous injection alone; however, this approach was associated with more complications.

Autistic clinical profiles, age at first concern, and diagnosis among children with autism spectrum disorder.

Background: To explore the relationship between autistic clinical profiles and age at first concern and diagnosis among children with autism spectrum disorder. The clinical profiles included the severity of autism, cognition, adaptability, language development, and regression. Methods: The multivariate linear regression model was used to examine the association of diagnostic age and first-concern age with autistic clinical profiles and with further stratification analysis. Results: A total of 801 autistic children were included. Language delay and regression were associated with earlier diagnostic age (language delay: crudeß: -0.80, 95%CI%: -0.92--0.68; regression: crudeß: -0.21, 95%CI%: -0.43--0.00) and the age of first concern of autistic children (language delay: crudeß: -0.55, 95%CI%: -0.65--0.45; regression: crudeß: -0.17, 95%CI%: -0.34--0.00). After stratification by sex, language delay tended to be more associated with the earlier diagnostic age among boys (crudeß: -0.85, 95%CI%: -0.98--0.72) than among girls (crudeß: -0.46, 95%CI%: -0.77--0.16). After stratification by maternal education level or family income level, language delay was most associated with the earlier diagnostic age in autistic children from families with higher socioeconomic levels. Conclusion: Language delay, rather than other symptoms, promoted an earlier diagnostic age. Among male autistic children or children from families with higher socioeconomic levels, language delay was most significantly associated with an earlier age of diagnosis. Cognitive delay, or adaptive delay, was associated with a later age at diagnosis and presented only in autistic children from families with lower socioeconomic levels. There may be sex or socioeconomic inequality in the diagnostic age for autistic children. More publicity and public education about the diversity of autistic symptoms are urgently needed in the future, especially for low-socioeconomic families.

Small extracellular vesicles delivering lncRNA WAC-AS1 aggravate renal allograft ischemia‒reperfusion injury by inducing ferroptosis propagation.

Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ferroptosis among cell populations in a wave-like manner, developing the "wave of ferroptosis" causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the "wave of ferroptosis" in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the "wave of ferroptosis" propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant.

Albumin-Consolidated AIEgens for Boosting Glioma and Cerebrovascular NIR-II Fluorescence Imaging.

The application of an exogenous polymer matrix to construct aggregation-induced emission (AIE) nanoprobes promotes the utility of AIE luminogens (AIEgens) in diagnosing brain diseases. However, the limited fluorescence (FL) and low active-targeting abilities of AIE-based nanoprobes impede their imaging application. Here, we employed endogenous albumin as an effective matrix to encapsulate AIEgens to enhance FL quantum yield (QY) and active-targeting ability. The albumin-consolidated strategy effectively inhibited the intramolecular vibration of AIEgens and enhanced endocytosis mediated by the gp60 receptor. The QYs of three kinds of albumin-based AIE nanoprobes with FL emissions ranging from the visible (400-650 nm) to the second near-infrared (NIR-II, 1000-1700 nm) region was at least 10% higher, and the tumor-targeting efficiency was ∼25% higher, compared with those of nanoprobes constructed by the exogenous polymer. Albumin-based AIE nanoprobes have achieved active-targeting NIR-II imaging of brain tumors and cerebrovascular imaging with a high signal-to-background ratio (SBR, ∼90) and high resolution (∼70 µm) in mouse models. Therefore, the albumin-based AIE nanoprobes will enable FL imaging-guided surgery of brain tumors and cerebral ischemia, which will improve surgical efficacy to prevent recurrence and side effects.