SNHG15-mediated feedback loop interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression.

Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.

Cement-augmented locked plate fixation proximal humerus fractures in elderly patient: a systematic review and meta-analysis.

BACKGROUND: This systemic review and meta-analysis aimed to evaluate the clinical outcomes of proximal humeral fracture in elderly patient fixation using locked plate with or without cement augmentation. METHODS: The databases of PubMed, Embase, and Cochrane Library were searched in August 2023 for literature comparing the clinical outcomes of patients with PHFs treated with locked plate alone and locked plate augmented with cement. Data describing study design; level of evidence; inclusion criteria; demographic information; final follow-up; revision rate; implant failure rate; avascular necrosis rate; total complication rate; constant score; and disability of arm, shoulder, and hand (DASH) score were collected. RESULTS: Eight studies (one randomized-controlled trial and seven observational studies), involving 664 patients, were identified. Compared with locked plates alone, using cement-augmented locked plates reduced the implant failure rate (odds ratio (OR) = 0.19; 95% confidence interval (CI) 0.10-0.39; P < 0.0001) and total complication rate (OR = 0.45; 95% CI 0.29-0.69; P = 0.0002) and improved DASH scores (mean difference (MD) = 2.99; 95% CI 1.00-4.98; P = 0.003). However, there was no significant difference in clinical outcomes, including revision rate, avascular necrosis rate, and constant score. CONCLUSION: In this review and meta-analysis, fixation of the PHFs in elderly patients using locked plates with or without cement augmentation has no significant difference in revision rate, but the implant failure and total complication rates may be lesser on using the cement-augmented locked plate for fixation than on using a locked plate alone. Good results are expected for most patients treated with this technique. TRIAL REGISTRATION: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)21 guidelines were followed to conduct this systematic review and meta-analysis and was registered as a protocol in PROSPERO (CRD42022318798).

Regulating effect of miR-132-3p on the changes of MAPK pathway in rat brains and SH-SY5Y cells exposed to excessive fluoride by targeting expression of MAPK1.

BACKGROUND: Although the changes of mitogen-activated protein kinase (MAPK) pathway in the central nervous system (CNS) induced by excessive fluoride has been confirmed by our previous findings, the underlying mechanism(s) of the action remains unclear. Here, we investigate the possibility that microRNAs (miRNAs) are involved in the aspect. METHODS: As a model of chronic fluorosis, SD rats received different concentrations of fluoride in their drinking water for 3 or 6 months and SH-SY5Y cells were exposed to fluoride. Literature reviews and bioinformatics analyses were used to predict and real-time PCR to measure the expression of 12 miRNAs; an algorithm-based approach was applied to identify multiply potential target-genes and pathways; the dual-luciferase reporter system to detect the association of miR-132-3p with MAPK1; and fluorescence in situ hybridization to detect miR-132-3p localization. The miR-132-3p inhibitor or mimics or MAPK1 silencing RNA were transfected into cultured cells. Expression of protein components of the MAPK pathway was assessed by immunofluorescence or Western blotting. RESULTS: In the rat hippocampus exposed with high fluoride, ten miRNAs were down-regulated and two up-regulated. Among these, miR-132-3p expression was down-regulated to the greatest extent and MAPK1 level (selected from the 220 genes predicted) was corelated with the alteration of miR-132-3p. Furthermore, miR-132-3p level was declined, whereas the protein levels MAPK pathway components were increased in the rat brains and SH-SY5Y cells exposed to high fluoride. MiR-132-3p up-regulated MAPK1 by binding directly to its 3'-untranslated region. Obviously, miR-132-3p mimics or MAPK1 silencing RNA attenuated the elevated expressions of the proteins components of the MAPK pathway induced by fluorosis in SH-SY5Y cells, whereas an inhibitor of miR-132-3p just played the opposite effect. CONCLUSION: MiR-132-3p appears to modulate the changes of MAPK signaling pathway in the CNS associated with chronic fluorosis.

Transient kinetics reveal the mechanism of competitive inhibition of the neutral amino acid transporter ASCT2.

ASCT2 (alanine serine cysteine transporter 2), a member of the SLC1 (solute carrier 1) family, mediates Na+-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anti-cancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor Lc-BPE with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na+ ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na+ ion cannot bind, due to distortion of its binding site (Na2), thus preventing the formation of a translocation-competent complex. Based on the rapid kinetic analysis, the application of Lc-BPE generated outward transient currents, indicating that, despite its net neutral nature, the binding of Lc-BPE in ASCT2 is weakly electrogenic, most likely because of asymmetric charge distribution within the amino acid moiety of the inhibitor. The pre-incubation with Lc-BPE also led to a decrease of the turnover rate of substrate exchange and a delay in the activation of substrate-induced anion current, indicating relatively slow Lc-BPE dissociation kinetics. Overall, our results provide new insight into the mechanism of binding of a prototypical competitive inhibitor to the ASCT transporters.

Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.

To investigate the significance of atherosclerotic plaque location in hybrid surgery comprising both endovascular recanalization approaches and carotid endarterectomy for symptomatic atherosclerotic non-acute long-segment occlusion of the internal carotid artery (ICA), 162 patients were enrolled, including 120 (74.1%) patients in the proximal plaque group and 42 (25.9%) in the distal plaque group. Surgical recanalization was performed in all patients, with successful recanalization in 119 (99.2%) patients in the proximal and 39 (92.9%) in the distal plaque group. The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162). Periprocedural complications occurred in 5 (4.2% or 5/120) patients in the proximal plaque group, including neck infection in two (1.7%), recurrent nerve injury in 1 (0.8%), and laryngeal edema in 2 (1.7%), and 2 (4.8%) in the distal plaque group, including femoral puncture infection in 2 (4.8%). No severe complications occurred in either group. Univariate analysis showed plaque location was a significant (P = 0.018) risk factor for successful recanalization, and multivariate analysis indicated that the plaque location remained a significant independent risk factor for recanalization success (P = 0.017). In follow-up 6-48 months after the recanalization surgery, reocclusion occurred in two (2.8%) patients in the proximal plaque group and 4 (13.3%) in the distal plaque group. In conclusion, although hybrid surgery achieves similar outcomes in patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques, plaque location may be a significant risk factor for successful recanalization of symptomatic non-acute long-segment ICA occlusion.

Further clarification of cognitive processes of prospective memory in schizophrenia by comparing eye-tracking and ecologically-valid measurements.

The aim of this study is to compare ecologically-valid measure (the Cambridge Prospective Memory Test, CAMPROMPT) and laboratory measure (eye-tracking paradigm) in assessing prospective memory (PM) in individuals with schizophrenia spectrum disorders (SSDs). In addition, eye-tracking indices are used to examine the relationship between PM and other cognitive domains in SSDs patients. Initially, the study sample was formed by 32 SSDs patients and 32 healthy control subjects (HCs) who were matched in sociodemographic profile and the performance on CAMPROMPT. An eye-tracking paradigm was employed to examine the differences in PM accuracy and key cognitive processes (e.g., cue monitoring) between the two groups. Additional 31 patients were then recruited to investigate the relationship between PM cue monitoring, other cognitive functions, and the severity of clinical symptoms within the SSDs group. The monitoring of PM cue was reflected in total fixation time and total fixation counts for distractor words. Cognitive functions were assessed using the Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathology. SSDs patients exhibited fewer total fixation counts for distractor words and lower PM accuracy compared to HCs, even though they were priori matched on CAMPROMPT. Correlation analysis within the SSDs group (63 cases) indicated a negative correlation between PM accuracy and PANSS total score, and a positive correlation with working memory and attention/vigilance. Regression analysis within the SSDs group revealed that higher visual learning and lower PANSS total scores independently predicted more total fixation counts on distractor words. Impairment in cue monitoring is a critical factor in the PM deficits in SSDs. The eye-tracking laboratory paradigm has advantages over the ecologically-valid measurement in identifying the failure of cue detection, making it a more sensitive tool for PM deficits in patients with SSDs.

Spinal microglial M1 polarization contributes paclitaxel-induced neuropathic pain by triggering cells necroptosis.

Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-ß synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.

Targeted metabolomics analysis based on HS-SPME-GC-MS to discriminate geographical origin of 'Muscat Hamburg' grape and wine.

Monoterpenes are typical aroma components in muscat grapes and wines, closely related to its geographical origins. However, the mechanism underlying the geographical differences of monoterpenes remains to be elucidated, especially in the Chinese viticulture regions. This study investigated the diversity of six Chinese viticultural vineyards (YT, XF, SS, XX, WW and CL) in the monoterpene composition of Vitis vinifera L. cv.'Muscat Hamburg' grapes and the resulted wines. Monoterpenes were analyzed by HS-SPME- GC-MS. The total amount of free and bound monoterpenes varied dramatically between grapes of different vineyards, and their contents were obviously higher in YT region grapes. The OAVs for 18 monoterpenes of grapes from the YT vineyard were relative higher than those of other regions, and the floral odor could distinguish grapes from different regions. The total free monoterpenes were highest in the YT region wine. Concentrations of total bound monoterpenes ranged from 711.13 µg/L (XF region) to 1078.30 µg/L (CL region). A correlation analysis showed that all monoterpenes showeda positive correlation with mean relative humidity, sum rainfall, and a negative correlation with sum duration of sunshine and mean temperature. This study would provide some new insights to understand the geographical differences of monoterpenes, and the results would facilitate the effective viticultural treatment of grapes to improve the quality of the aroma.

Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China.

Fabry disease (FD), an X-linked disorder resulting from dysfunction of α-galactosidase A, can result in significant complications. Early intervention yields better outcomes, but misdiagnosis or delayed diagnosis is common, impacting prognosis. Thus, early detection is crucial in the clinical diagnosis and treatment of FD. While newborn screening for FD has been implemented in certain regions, challenges persist in enzyme activity detection techniques, particularly for female and late-onset patients. Further exploration of improved screening strategies is warranted. This study retrospectively analyzed genetic screening results for pathogenic GLA variants in 17,171 newborns. The results indicated an estimated incidence of FD in the Nanjing region of China of approximately 1 in 1321. The most prevalent pathogenic variant among potential FD patients was c.640-801G > A (46.15 %). Furthermore, the residual enzyme activity of the pathogenic variant c.911G > C was marginally higher than that of other variants, and suggesting that genetic screening may be more effective in identifying potential female and late-onset patients compared to enzyme activity testing. This research offers initial insights into the effectiveness of GLA genetic screening and serves as a reference for early diagnosis, treatment, and genetic counseling in FD.

Revealing extracellular protein profile and excavating spoilage-related proteases of Aeromonas salmonicida based on multi-omics investigation.

Aeromonas is a ubiquitous aquatic bacteria, and it is a significant factor contributing to meat spoilage during processing and consumption. The abilities of Aeromonas salmonicida 29 and 57, which exhibit spoilage heterogeneity, to secrete protease, lipase, hemolysin, gelatinase, amylase, and lecithinase were confirmed by plate method. A total of 3948 proteins were identified by ITRAQ in extracellular secretions of A. salmonicida, and 16 proteases were found to be potentially related to spoilage ability. The complete genome sequence of A. salmonicida 57 consists of one circular chromosome and three plasmids, while A. salmonicida 29 consists of one circular chromosome, without a plasmid. Transcriptomic analysis revealed a significant number of DEGs were up-regulated in A. salmonicida 29, which were mainly enriched in metabolic pathways (e.g., amino acid metabolism, carbohydrate metabolism), indicating that A. salmonicida 29 had better potential to decompose and utilize nutrients in meat. Six protease genes (2 pepB, hap, pepA, ftsI, and pepD) were excavated by combined ITRAQ with transcriptome analysis, which potentially contribute to bacterial spoilage ability and exhibit universality among other dominant spoilage bacteria. This investigation provides new insights and evidence for elucidating metabolic and spoilage phenotypic differences and provides candidate genes and strategies for future prevention and control technology development.

Examining the causal relationship between circulating immune cells and the susceptibility to osteomyelitis: A Mendelian randomization study.

BACKGROUND: Osteomyelitis is considered as a deleterious inflammatory condition affecting the bone, primarily attributed to pathogenic infection. However, the underlying factors predisposing individuals to osteomyelitis remain incompletely elucidated. The immune system plays a multifaceted role in the progression of this condition, yet previous observational studies and randomized controlled trials investigating the association between circulating immune cell counts and osteomyelitis have been constrained. In order to address this knowledge gap, we conducted a Mendelian randomization (MR) analysis to evaluate the impact of diverse immune cell counts on the risk of developing osteomyelitis. METHODS: In our study, we utilized single nucleotide polymorphisms (SNPs) that have been strongly linked to circulating immune cells or specific lymphocyte subtypes, as identified in large-scale genome-wide association studies (GWAS). These SNPs served as instrumental variables (IVs) for our MR analysis. We employed a more relaxed clumping threshold to conduct MR analysis on several related lymphocyte subtypes. To estimate causal effects, we utilized the Wald ratio, as well as the random-effects inverse variance weighted (IVW) and weighted median (WM) methods. To enhance the credibility of our results, we performed F-statistic calculations and a series of sensitivity analyses. RESULTS: Our findings revealed a significant correlation between the absolute count of circulating lymphocytes and the risk of osteomyelitis [odds ratio(OR) 1.20；95 % confidence interval (CI), 1.08-1.32；P = 0.0005]. Furthermore, we identified a causal relationship between the absolute count of CD8+ T cells and susceptibility to osteomyelitis (OR 1.16; 95 % CI, 1.04-1.30; P = 0.0098). Importantly, these findings remained robust across a wide range of sensitivity analyses. CONCLUSION: Through our MR analysis, we have provided evidence supporting a causal relationship between genetic predisposition to higher circulating immune cell counts and an increased risk of osteomyelitis. Specifically, our findings highlight the association between elevated CD8+ T cell counts and a heightened susceptibility to osteomyelitis. These results offer valuable insights for the future exploration of immunotherapy approaches in the management of osteomyelitis.

Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Introduction: Postmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause are its main symptoms. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role. However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear. Methods: In this study, we mainly examined the bone strength of the femur, the structure of the intestinal microbiota, SCFAs in the feces and the level of FOXP3 cells in the colon. To further learn about the inflammation response, the condition of the mucosa and the level of cytokines in the serum also included in the testing. In addition, to get the information of the protein expression, the protein expression of OPG and RANKL in the femur and the protein expression of ZO-1 and Occludin in the colon were taken into account. Results: The osteoporosis was significantly improved in the SG group compared with the OVX group, and the diversity of intestinal flora, the secretion level of SCFAs and the expression level of FOXP3 were significantly increased compared with the OVX group. In terms of inflammatory indicators, the intestinal inflammation scores of the SG group was significantly lower than those in the OVX group. Additionally, the serum expression levels of IL-10 and TGF-ß in the SG group were significantly increased compared with the OVX group, and the expression levels of IL-17 and TNF-α were significantly decreased compared with the OVX group. In terms of protein expression, the expression levels of ZO-1, Occluding and OPG were significantly increased in the SG group compared with the OVX group, and the expression level of RANKL was significantly decreased compared with the OVX group. Discussion: Shengu granules treatment can improve the imbalance of intestinal flora, increase the secretion of SCFAs and the expression of FOXP3, which reduces the inflammatory response and repairs the intestinal barrier, as well as regulates the expression of OPG/RANKL signaling axis. Overall, Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Bacterial isolation and genome analysis of a novel Klebsiella quasipneumoniae phage in southwest China's karst area.

BACKGROUND: Southwest China is one of the largest karst regions in the world. Karst environment is relatively fragile and vulnerable to human activities. Due to the discharge of sewage and domestic garbage, the karst system may be polluted by pathogenic bacteria. The detection of bacterial distribution and identification of phage capable of infecting them is an important approach for environmental assessment and resource acquisition. METHODS: Bacteria and phages were isolated from karst water in southwest China using the plate scribing and double plate method, respectively. Isolated phage was defined by transmission electron microscopy, one-step growth curve and optimal multiplicity of infection (MOI). Genomic sequencing, phylogenetic analysis, comparative genomic and proteomic analysis were performed. RESULTS: A Klebsiella quasipneumoniae phage was isolated from 32 isolates and named KL01. KL01 is morphologically identified as Caudoviricetes with an optimal MOI of 0.1, an incubation period of 10 min, and a lysis period of 60 min. The genome length of KL01 is about 45 kb, the GC content is 42.5%, and it contains 59 open reading frames. The highest average nucleotide similarity between KL01 and a known Klebsiella phage 6939 was 83.04%. CONCLUSIONS: KL01 is a novel phage, belonging to the Autophagoviridae, which has strong lytic ability. This study indicates that there were not only some potential potentially pathogenic bacteria in the karst environment, but also phage resources for exploration and application.

Utility, benefits, and risks of newborn genetic screening carrier reports for families.

Background: Newborn genetic screening (NBGS) based on next-generation sequencing offers enhanced disease detection and better detection rates than traditional newborn screening. However, challenges remain, especially around reporting the NBGS carrier results. Therefore, we aimed to investigate the NBGS carrier parents' views on NBGS and NBGS reports in China. Methods: We distributed a survey querying demographic information, knowledge and perceptions of NBGS, the impact of NBGS on a total of 2930 parents, and their decision-making to parents of newborns reported as carriers in NBGS in Nanjing, China in 2022. Results: The average age of the survey respondents was 30.7 years (standard deviation = 3.6). Most (68.38%) felt informed about NBGS, especially women, the highly educated, and high earners. Nearly all (98.74%) saw NBGS as crucial for early disease detection, with 73.18% believing it positively impacts their future. However, 19.16% felt it might cause anxiety, especially among the less educated. Concerns included potential discrimination due to exposed genetic data and strained family ties. Many suggested NBGS coverage by medical insurance to ease financial burdens. Conclusions: Through our study, we gained insights into parents' perspectives and concerns regarding the NBGS carrier result reporting, thus providing relevant information for further refinement and clinical promotion of the NBGS project.

ELM combined with differential Raman spectroscopy for the detection of microplastics in organisms.

Aiming at the problems of low extraction efficiency, high false detection rate, weak Raman signal and serious interference by fluorescence signal in the detection of microplastics in marine organisms, this paper establishes a set of rapid detection methods for microplastics in organisms, including confocal Raman spectroscopy, fluorescence imaging, differential Raman spectroscopy, and rapid identification of microplastics based on the ELM modeling assistance. Firstly, to address the problem of low extraction efficiency of microplastics, we explored and optimized the digestion method of tissues, which effectively improved the digestion effect of fish tissues and excluded the influence of tissues on microplastics detection. Aiming at the problems of high misdetection rate and low pre-screening efficiency of microplastics, fluorescence imaging technology is adopted to realize the visualization and detection of microplastics, which effectively improves the detection efficiency and precision of microplastics. Based on the confocal microscopy Raman spectroscopy detection system built independently in the laboratory, using 784/785 nm as the excitation light, the differential Raman spectroscopy technique effectively excludes the interference of fluorescence signals in the Raman spectra, and improves the signal-to-noise ratio of the Raman spectra, and the recovery rate of the Raman characteristic peaks in the differential Raman spectroscopy reaches 100 % compared to the traditional baseline correction method, which is 33.3 % higher than that of the baseline correction method. Finally, a microplastic identification model is constructed based on ELM to assist in realizing the rapid and accurate identification of microplastics. The more complete detection method of microplastics in marine organisms proposed in this paper can realize the rapid and nondestructive, efficient and accurate detection of microplastics in fish, which can help to further promote the development of marine microplastics monitoring technology.

Reactive oxygen/nitrogen species scavenging and inflammatory regulation by renal-targeted bio-inspired rhodium nanozymes for acute kidney injury theranostics.

Acute kidney injury (AKI) results from the rapid deterioration of renal function, which is mainly treated by transplantation and dialysis, and has a high mortality rate. Inflammation induced by excess reactive oxygen/nitrogen species (RONS) plays a crucial role in AKI. Although small molecule antioxidants have been utilized to alleviate AKI, low bioavailability and side-effect of these drugs tremendously limit their clinical use. Hence, we successfully construct ultra-small (2-4 nm) rhodium nanoparticles modified with l-serine (denoted as Rh-Ser). Our results show that Rh-Ser with multiple enzyme-mimicking activities, allows remove various RONS to protect damaged kidney cells. Additionally, the ultrasmall size of Rh-Ser is conducive to enrichment in the renal tubules, and the modification of l-serine enables Rh-Ser to bind to kidney injury molecule-1, which is highly expressed on the surface of damaged renal cells, thereby targeting the damaged kidney and increasing the retention time. Moreover, Rh-Ser allows the production of oxygen at the inflammatory site, thus further improving hypoxia and inhibiting pro-inflammatory macrophages to relieve inflammation, and increasing the survival rate of AKI mice from 0 to 80%, which exhibits a better therapeutic effect than that of small molecule drug. Photoacoustic and fluorescence imaging can effectively monitor and evaluate the enrichment and therapeutic effect of Rh-Ser. Our study provides a promising strategy for the targeted treatment of AKI via RONS scavenging and inflammatory regulation.

Identifying squalene epoxidase as a metabolic vulnerability in high-risk osteosarcoma using an artificial intelligence-derived prognostic index.

BACKGROUND: Osteosarcoma (OSA) presents a clinical challenge and has a low 5-year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high-risk OSA patients and guide treatment. METHODS: We combined 10 machine-learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single-cell RNA sequencing (scRNA-seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA-seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways. RESULTS: The artificial intelligence-derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high-AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K-Akt signalling, and diminished immune infiltration. ScRNA-seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE-specific inhibitor FR194738 demonstrated anti-OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents. CONCLUSIONS: AIDPI is a robust biomarker for identifying the high-risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential.

ICBP90, an epigenetic regulator, induces DKK3 promoter methylation, promotes glioma progression, and reduces sensitivity to cis-platinum.

Glioma is the most common brain malignancy, characterized by high morbidity, high mortality, and treatment-resistance. Inverted CCAAT box Binding Protein of 90 kDa (ICBP90) has been reported to be involved in tumor progression and the maintenance of DNA methylation. Herein, we constructed ICBP90 over-expression and knockdown glioma cell lines, and found that ICBP90 knockdown inhibited glioma cell proliferation, migration, and invasion. ICBP90 silencing potentially enhanced cellular sensitivity to cis-platinum (DDP) and exacerbated DDP-induced pyroptosis, manifested by the elevated levels of gasdermin D-N-terminal and cleaved caspase 1; whereas, ICBP90 over-expression exhibited the opposite effects. Consistently, ICBP90 knockdown inhibited tumor growth in an in vivo mouse xenograft study using U251 cells stably expressing sh-ICBP90 and oe-ICBP90. Further experiments found that ICBP90 reduced the expression of Dickkopf 3 homolog (DKK3), a negative regulator of ß-catenin, by binding its promoter and inducing DNA methylation. ICBP90 knockdown prevented the nuclear translocation of ß-catenin and suppressed the expression of c-Myc and cyclin D1. Besides, DKK3 over-expression restored the effects of ICBP90 over-expression on cell proliferation, migration, invasion, and DDP sensitivity. Our findings suggest that ICBP90 inhibits the expression of DKK3 in glioma by maintaining DKK3 promoter methylation, thereby conducing to ICBP90-mediated carcinogenesis and drug insensitivity.

Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.

Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidences and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.