RGS19 activates the MYH9/ß-catenin/c-Myc positive feedback loop in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates ß-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the ß-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/ß-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy.

A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia-reperfusion injury by integrating bioinformatics and machine learning algorithms.

BACKGROUND: Liver ischemia-reperfusion injury (LIRI) is closely associated with immune infiltration, which commonly occurs after liver surgery, especially liver transplantation. Therefore, it is crucial to identify the genes responsible for LIRI and develop effective therapeutic strategies that target immune response. Methylation modifications in mRNA play various crucial roles in different diseases. This study aimed to identify potential methylation-related markers in patients with LIRI and evaluate the corresponding immune infiltration. METHODS: Two Gene Expression Omnibus datasets containing human liver transplantation data (GSE12720 and GSE151648) were downloaded for integrated analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to investigate the functional enrichment of differentially expressed genes (DEGs). Differentially expressed methylation-related genes (DEMRGs) were identified by overlapping DEG sets and 65 genes related to N6-methyladenosine (m6A), 7-methylguanine (m7G), 5-methylcytosine (m5C), and N1-methyladenosine (m1A). To evaluate the relationship between DEMRGs, a protein-protein interaction (PPI) network was utilized. The core DEMRGs were screened using three machine learning algorithms: least absolute shrinkage and selection operator, random forest, and support vector machine-recursive feature elimination. After verifying the diagnostic efficacy using the receiver operating characteristic curve, we validated the expression of the core DEMRGs in clinical samples and performed relative cell biology experiments. Additionally, the immune status of LIRI was comprehensively assessed using the single sample gene set enrichment analysis algorithm. The upstream microRNA and transcription factors of the core DEMRGs were also predicted. RESULTS: In total, 2165 upregulated and 3191 downregulated DEGs were identified, mainly enriched in LIRI-related pathways. The intersection of DEGs and methylation-related genes yielded 28 DEMRGs, showing high interaction in the PPI network. Additionally, the core DEMRGs YTHDC1, METTL3, WTAP, and NUDT3 demonstrated satisfactory diagnostic efficacy and significant differential expression and corresponding function based on cell biology experiments. Furthermore, immune infiltration analyses indicated that several immune cells correlated with all core DEMRGs in the LIRI process to varying extents. CONCLUSIONS: We identified core DEMRGs (YTHDC1, METTL3, WTAP, and NUDT3) associated with immune infiltration in LIRI through bioinformatics and validated them experimentally. This study may provide potential methylation-related gene targets for LIRI immunotherapy.

Non-Contact Blood Pressure Estimation from Radar Signals by a Stacked Deformable Convolution Network.

This study introduces a contactless blood pressure monitoring approach that combines conventional radar signal processing with novel deep learning architectures. During the preprocessing phase, datasets suitable for synchronization are created by integrating Kalman filtering, multiscale bandpass filters, and a periodic extraction method in the time domain. These data comprise data on chest micro variations, encapsulating a complex array of physiological and biomedical information reflective of cardiac micromotions. The Radar-based Stacked Deformable convolution Network (RSD-Net) integrates channel and spatial self attention mechanisms within a deformable convolutional framework to enhance feature extraction from radar signals. The network architecture systematically employs deformable convolutions for initial deep feature extraction from individual signals. Subsequently, continuous blood pressure estimation is conducted using self attention mechanisms on feature map from single source coupled with multi-feature map channel attention. The performance of model is corroborated via the open-source dataset procured using a non-invasive 24GHz six-port continuous wave radar system. The dataset, encompassing readings from 30 healthy individuals subjected to diverse conditions including rest, the Valsalva maneuver, apnea, and tilt-table examinations. It serves to substantiate the validity and resilience of the proposed method in the non-contact assessment of continuous blood pressure. Evaluation metrics reveal Pearson correlation coefficients of 0.838 for systolic and 0.797 for diastolic blood pressure predictions. The Mean Error (ME) and Standard Deviation (SD) for systolic and diastolic blood pressure measurements are -0.32 ±6.14mmHg and -0.20 ±5.50mmHg, respectively. The ablation study assesses the contribution of different structural components of the RSD-Net, validating their significance in the overall of model performance.

PtCu Alloy-Modified Triptycene-Based Polymer with Charge Separation for Photocatalytic Hydrogen Evolution from Water/Seawater.

Direct photocatalytic hydrogen from earth-abundant seawater is a great potential way to achieve sustainable and clean energy, yet unsatisfactory decomposition and rapid electron-hole pair recombination of catalysts hinder the solar-driven H2 conversion efficiency. Herein, we designed a series of PtCu alloy nanoparticle-modified porous triptycene-based polymers (PtxCu1-TCP) to construct the heterostructure for highly efficient hydrogen generation from photocatalytic water/seawater splitting. Characterizations displayed that TCP with an ultrahigh surface area can confine the agglomeration of PtCu alloy; meanwhile, the PtCu alloy can facilitate the rapid electron transfer from TCP. In addition, TCP with a stable covalent bond structure can resist the corrosion of seawater. Benefiting from these two advantages, Pt7Cu1-TCP showed a remarkably enhanced photocatalytic performance with a maximum H2 evolution rate of 3255 µmol g-1 h-1 in natural seawater with triethanolamine, which is 2.69, 116.25, and 1.08 times that of Pt-TCP, Cu-TCP, and optimal catalyst in pure water, respectively. This study provides an idea for the development of a novel catalytic system for hydrogen production from solar-driven water/seawater splitting.

UV-modification of Ag nanoparticles on α-MoCx for interface polarization engineering in electromagnetic wave absorption.

The design of electromagnetic wave absorbing materials (EWAMs) has aroused great attention with the express development of electromagnetic devices, which pose a severe EM pollution risk to human health. Herein, an Ag-doped MoCx composite was designed and constructed through a UV-light-induced self-reduction process. The UV-reduction time was controlled on the α-MoC polymer for 0.5-2 hours for modifying different amounts of Ag. As a result, α-MoC@Ag-1.5 exhibited the strongest RLmin of -56.51 dB at 8.8 GHz under a thickness of 3.0 mm and the widest EAB of 4.96 GHz (12.16-17.12 GHz) covering a substantial portion of the Ku-band at a thickness of 2.0 mm due to the synergy of the conductivity loss and abundant interfacial polarization sites. Additionally, a new strategy for computer simulation technology was proposed to simulate substantial radar cross-sectional reduction values with real far-field conditions, whereby absorbing coatings with α-MoC@Ag-1.5 were proved to contribute to a remarkable radar cross-sectional reduction of 37.4 dB m2.

Low-phase-noise microwave generation with a free-running dual-pumped Si3N4 soliton microcomb.

Microwave signals can be generated by photodetecting the repetition frequencies of the soliton microcombs. In comparison to other methods, the dual-pumped method allows for the stable generation of the soliton microcombs even with resonators having lower Q-factors. However, introducing an additional pump laser may affect the phase noise of the generated microwave signals when using these dual-pumped soliton microcombs. Here, we investigate the factors that could influence the phase noise of microwave signals generated with dual-pumped soliton microcombs, including the polarization, amplitude noise, and phase noise of the two pumps. We demonstrate a 25.25 (12.63) GHz microwave with phase noise reaching -112(-118) dBc/Hz at a 10 kHz offset frequency, surpassing the performance of previous reports on microwave generation using free-running Si3N4 soliton microcombs, even those generated with higher Q microresonators. We analyze the noise floor of the generated microwave signals and establish a phase noise simulation model to study the limiting factors in our system. Our work highlights the potential of generating low-phase-noise microwave signals using free-running dual-pumped soliton microcombs.

Highly Crystalline Poly(heptazine imide)-Based Carbonaceous Anodes for Ultralong Lifespan and Low-Temperature Sodium-Ion Batteries.

Carbon nitrides with layered structures and scalable syntheses have emerged as potential anode choices for the commercialization of sodium-ion batteries. However, the low crystallinity of materials synthesized through traditional thermal condensation leads to insufficient conductivity and poor cycling stability, which significantly hamper their practical applications. Herein, a facile salt-covering method was proposed for the synthesis of highly ordered crystalline C3N4-based all-carbon nanocomposites. The sealing environment created by this strategy leads to the formation of poly(heptazine imide) (PHI), the crystalline phase of C3N4, with extended π-conjugation and a fully condensed nanosheet structure. Meanwhile, theoretical calculations reveal the high crystallinity of C3N4 significantly reduces the energy barrier for electron transition and enables the generation of efficient charge transfer channels at the heterogeneous interface between carbon and C3N4. Accordingly, such nanocomposites present ultrastable cycling performances over 5000 cycles, with a high reversible capacity of 245.1 mAh g-1 at 2 A g-1 delivered. More importantly, they also exhibit an outstanding low-temperature capacity of 196.6 mAh g-1 at -20 °C. This work offers opportunities for the energy storage use of C3N4 and provides some clues for developing long-life and high-capacity anodes operated under extreme conditions.

IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer whose incidence and mortality continue to increase, whereas its prognosis remains dismal. Tumor-associated macrophages (TAMs) promote malignant progression and immune microenvironment remodeling through direct contact and secreted mediators. Targeting TAMs has emerged as a promising strategy for ICC treatment. Here, we revealed the potential regulatory function of immune responsive gene 1 (IRG1) in macrophage polarization. We found that IRG1 expression remained at a low level in M2 macrophages. IRG1 overexpression can restrain macrophages from polarizing to the M2 type, which results in inhibition of the proliferation, invasion, and migration of ICC, whereas IRG1 knockdown exerts the opposite effects. Mechanistically, IRG1 inhibited the tumor-promoting chemokine CCL18 and thus suppressed ICC progression by regulating STAT3 phosphorylation. The intervention of IRG1 expression in TAMs may serve as a potential therapeutic target for delaying ICC progression.

Study on ultrasonic quantitative evaluation technique based on BP neural network and D-S evidence theory.

Ultrasonic detection technology is widely used because of its high sensitivity, strong penetrating ability, accurate defect location, simple operation, and harmlessness to the human body. However, it is still challenging to locate and quantify the defects whose shapes are complex based on ultrasonic testing. The amount of data required for ultrasonic imaging is relatively large, and the efficiency is relatively low. This paper proposes a new method that combines the BP neural network and D-S evidence theory fusion technology with the pulse reflection method. The circular and triangular defects are selected for numerical simulation and experimental testing. The diameter range of the circle is 1-5 mm. The base range of the isosceles triangle is 4-5 mm, and the height range is 3-5 mm. Finally, this paper researches the inversion imaging of single and multiple defects using neural networks, image processing technology and data fusion technology. The results show that after fusion, the similarity coefficient of defects can reach 0.96, and the minimum area error can reach 1.2 %. The maximum error of the average centroid x is only 9.25 %, and the minimum error is 6.36 %. The centroid y error is less than 12 %. The average centroid y error is only 8.73 % at the maximum and 5.09 % at the minimum, indicating that the defect-inversion is relatively accurate.

Plasma-Induced 2D Electron Transport at Hetero-Phase Titanium Oxide Interface.

Interfaces of metal oxide heterojunctions display a variety of intriguing physical properties that enable novel applications in spintronics, quantum information, neuromorphic computing, and high-temperature superconductivity. One such LaAlO3 /SrTiO3 (LAO/STO) heterojunction hosts a 2D electron liquid (2DEL) presenting remarkable 2D superconductivity and magnetism. However, these remarkable properties emerge only at very low temperatures, while the heterostructure fabrication is challenging even at the laboratory scale, thus impeding practical applications. Here, a novel plasma-enabled fabrication concept is presented to develop the TiO2 /Ti3 O4 hetero-phase bilayer with a 2DEL that exhibits features of a weakly localized Fermi liquid even at room temperature. The hetero-phase bilayer is fabricated by applying a rapid plasma-induced phase transition that transforms a specific portion of anatase TiO2 thin film into vacancy-prone Ti3 O4 in seconds. The underlying mechanism relies on the screening effect of the achieved high-density electron liquid that suppresses the electron-phonon interactions. The achieved "adiabatic" electron transport in the hetero-phase bilayer offers strong potential for low-loss electric or plasmonic circuits and hot electron harvesting and utilization. These findings open new horizons for fabricating diverse multifunctional metal oxide heterostructures as an innovative platform for emerging clean energy, integrated photonics, spintronics, and quantum information technologies.

Controlled hypotension technology can improve patient recovery in the early postoperative period after total knee arthroplasty: A prospective, randomized controlled clinical study.

OBJECTIVES: The study aimed to analyze the application of controlled hypotension and tourniquets in total knee arthroplasty (TKA) to evaluate their early postoperative period effects in TKA. PATIENTS AND METHODS: A total of 183 patients (43 males, 140 females; mean age: 67.8±6.4 years; range, 50 to 84 years) with knee osteoarthritis who needed TKA were recruited for this prospective, randomized controlled clinical study between August 2022 and May 2023. The study included a tourniquet group (group T, 94 patients) and a controlled hypotension group (group H, 89 patients). In group T, an inflatable tourniquet was used throughout the operation, with the pressure of the tourniquet set at 300 mmHg. In group H, controlled hypotension was used, with the mean arterial pressure controlled at 55-65 mmHg. The outcome measures of this study included blood loss, coagulation function, inflammatory mediators, knee joint function, permeation thickness of bone cement around the tibial prosthesis, and cognitive function. RESULTS: The baseline demographics and clinical characteristics of the two groups of patients were comparable (p>0.05). Intraoperative blood loss in group H was higher than that in group T (p<0.05), whereas hemoglobin decrease, postoperative drainage flow, hidden blood loss, and total blood loss in group T were higher than in group H (p<0.05). Fibrinogen, D-dimer, C-reactive protein, and interleukin-6 levels were higher in group T than in group H on the first and third postoperative days (p<0.05). The knee joint function of group H was significantly better than that of group T on the fifth day and one month after the operation (p<0.05). There was no significant difference in the penetration thickness of bone cement around the tibial prosthesis between the two groups (p>0.05). There was no significant difference in Mini-Mental State Examination scores between the two groups on the same day (p>0.05). CONCLUSION: Controlled hypotension technology in TKA can reduce total blood loss by reducing hidden blood loss and can help to alleviate the postoperative hypercoagulable state, relieve inflammatory reactions, and facilitate early recovery of knee joint function after surgery.

Identification of MIR600HG/hsa-miR-342-3p/ANLN network as a potential prognosis biomarker associated with lmmune infiltrates in pancreatic cancer.

Pancreatic cancer is one of the tumors with the worst prognosis, causing serious harm to human health. The RNA network and immune response play an important role in tumor progression. While a systematic RNA network linked to the tumor immune response remains to be further explored in pancreatic cancer. Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, the MIR600HG/hsa-miR-342-3p/ANLN network was determined. WB and IHC were used to confirm the high expression of ANLN in pancreatic cancer. The prognostic model based on the RNA network could effectively predict the survival prognosis of patients. The analysis of immune infiltration showed that the MIR600HG/hsa-miR-342-3p/ANLN network altered the level of infiltration of T helper 2 (Th2) and effector memory T (Tem) cells. Furthermore, we found that the chemokines chemokine ligand (CCL) 5 and CCL14 may play a key role in immune cell infiltration mediated by the RNA network. In conclusion, this study constructed a prognostic model based on the MIR600HG/hsa-miR-342-3p/ANLN network and found that it may function in tumor immunity.

FTZ polysaccharides ameliorate kidney injury in diabetic mice by regulating gut-kidney axis.

BACKGROUND: The Fufang-zhenzhu-tiaozhi formula (FTZ), a traditional Chinese medicine (TCM) commonly used to treat metabolic diseases, potentially impacts the microbial ecosystem. Increasing evidence suggests that polysaccharides, bioactive components of TCMs, have great potential on kinds of diseases such as DKD by regulating intestinal flora. PURPOSE: This study aimed to investigate whether the polysaccharide components in FTZ (FTZPs) have beneficial effects in DKD mice via the gut-kidney axis. STUDY DESIGN AND METHODS: The DKD model in mice was established by streptozotocin combined with a high-fat diet (STZ/HFD). Losartan was used as a positive control, and FTZPs were administered at doses of 100 and 300 mg/kg daily. Renal histological changes were measured by H&E and Masson staining. Western blotting, quantitative real-time polymerase chain reaction (q-PCR) and immunohistochemistry were performed to analyze the effects of FTZPs on renal inflammation and fibrosis, which were further confirmed using RNA sequencing. Immunofluorescence was used to analyze the effects of FTZPs on colonic barrier function in DKD mice. Faecal microbiota transplantation (FMT) was used to evaluate the contribution of intestinal flora. 16S rRNA sequencing was utilized to analyze the composition of intestinal bacteria, and UPLC-QTOF-MS-based untargeted metabolomics was used to identify the metabolite profiles. RESULTS: Treatment with FTZPs attenuated kidney injury, as indicated by the decreased urinary albumin/creatinine ratio and improved renal architecture. FTZPs downregulated the expression of renal genes associated with inflammation, fibrosis, and systematically blunted related pathways. FTZPs also restored the colonic mucosal barrier and increased the expression of tight junction proteins (E-cadherin). The FMT experiment confirmed the substantial contribution of the FTZPs-reshaped microbiota to relieving DKD symptoms. Moreover, FTZPs elevated the content of short-chain fatty acids (propionic acid and butanoic acid) and increased the level of the SCFAs transporter Slc22a19. Intestinal flora disorders caused by diabetes, including the growth of the genera Weissella, Enterococcus and Akkermansia, were inhibited by FTZPs treatment. Spearman's analysis revealed that these bacteria were positively correlated with indicators of renal damage. CONCLUSION: These results show that oral administration of FTZPs, by altering SCFAs levels and the gut microbiome, is a therapeutic strategy for the treatment of DKD.

RNF125 attenuates hepatocellular carcinoma progression by downregulating SRSF1-ERK pathway.

Hepatocellular carcinoma (HCC) is one of the most deadly malignant cancers worldwide. Research into the crucial genes responsible for maintaining the aggressive behaviour of cancer cells is important for the clinical treatment of HCC. The purpose of this study was to determine whether the E3 ubiquitin ligase Ring Finger Protein 125 (RNF125) plays a role in the proliferation and metastasis of HCC. RNF125 expression in human HCC samples and cell lines was investigated using TCGA dataset mining, qRT‒PCR, western blot, and immunohistochemistry assays. In addition, 80 patients with HCC were studied for the clinical value of RNF125. Furthermore, the molecular mechanism by which RNF125 contributes to hepatocellular carcinoma progression was determined with mass spectrometry (MS), coimmunoprecipitation (Co-IP), dual-luciferase reporter assays, and ubiquitin ladder assays. We found that RNF125 was markedly downregulated in HCC tumour tissues, which was associated with a poor prognosis for patients with HCC. Moreover, the overexpression of RNF125 inhibited HCC proliferation and metastasis both in vitro and in vivo, whereas the knockdown of RNF125 exerted antithetical effects. Mechanistically, mass spectrometry analysis revealed a protein interaction between RNF125 and SRSF1, and RNF125 accelerated the proteasome-mediated degradation of SRSF1, which impeded HCC progression by inhibiting the ERK signalling pathway. Furthermore, RNF125 was detected to be the downstream target of miR-103a-3p. In this study, we identified that RNF125 is a tumour suppressor in HCC and inhibits HCC progression by inhibiting the SRSF1/ERK pathway. These findings provide a promising treatment target for HCC.

Comprehensive analysis of transcriptome-wide M6A methylation for hepatic ischaemia reperfusion injury in mice.

N6-Methyladenosine (m6A) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs. However, little is known about the underlying mechanisms of m6A-modified mRNAs in hepatic IR injury. In mouse models, liver samples were subjected to methylated RNA immunoprecipitation with high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). In total, 16917 m6A peaks associated with 4098 genes were detected in the sham group, whereas 21,557 m6A peaks associated with 5322 genes were detected in the IR group. There were 909 differentially expressed m6A peaks, 863 differentially methylated transcripts and 516 differentially m6A modification genes determined in both groups. The distribution of m6A peaks was especially enriched in the coding sequence and 3'UTR. Furthermore, we identified a relationship between differentially m6A methylated genes (fold change≥1.5/≤ 0.667, p value≤0.05) and differentially expressed genes (fold change≥1.5 and p value≤0.05) to obtain three overlapping predicted target genes (Fnip2, Phldb2, and Pcf11). Our study revealed a transcriptome-wide map of m6A mRNAs in hepatic IR injury and might provide a theoretical basis for future research in terms of molecular mechanisms.

Machine learning reveals sex differences in clinical features of acute exacerbation of chronic obstructive pulmonary disease: A multicenter cross-sectional study.

Introduction: Intrinsically, chronic obstructive pulmonary disease (COPD) is a highly heterogonous disease. Several sex differences in COPD, such as risk factors and prevalence, were identified. However, sex differences in clinical features of acute exacerbation chronic obstructive pulmonary disease (AECOPD) were not well explored. Machine learning showed a promising role in medical practice, including diagnosis prediction and classification. Then, sex differences in clinical manifestations of AECOPD were explored by machine learning approaches in this study. Methods: In this cross-sectional study, 278 male patients and 81 female patients hospitalized with AECOPD were included. Baseline characteristics, clinical symptoms, and laboratory parameters were analyzed. The K-prototype algorithm was used to explore the degree of sex differences. Binary logistic regression, random forest, and XGBoost models were performed to identify sex-associated clinical manifestations in AECOPD. Nomogram and its associated curves were established to visualize and validate binary logistic regression. Results: The predictive accuracy of sex was 83.930% using the k-prototype algorithm. Binary logistic regression revealed that eight variables were independently associated with sex in AECOPD, which was visualized by using a nomogram. The AUC of the ROC curve was 0.945. The DCA curve showed that the nomogram had more clinical benefits, with thresholds from 0.02 to 0.99. The top 15 sex-associated important variables were identified by random forest and XGBoost, respectively. Subsequently, seven clinical features, including smoking, biomass fuel exposure, GOLD stages, PaO2, serum potassium, serum calcium, and blood urea nitrogen (BUN), were concurrently identified by three models. However, CAD was not identified by machine learning models. Conclusions: Overall, our results support that the clinical features differ markedly by sex in AECOPD. Male patients presented worse lung function and oxygenation, less biomass fuel exposure, more smoking, renal dysfunction, and hyperkalemia than female patients with AECOPD. Furthermore, our results also suggest that machine learning is a promising and powerful tool in clinical decision-making.

Sodium hydrosulfide inhibits hemin-induced ferroptosis and lipid peroxidation in BV2 cells via the CBS/H2S system.

Ferroptosis is a form of iron-dependent programmed cell death discovered in recent years that has been shown to be involved in diverse neurological disorders. Hydrogen sulfide (H2S) is an important signaling molecule with neuroprotective effects, including antioxidation. However, whether the protective mechanism of H2S is related to ferroptosis remains unknown. Therefore, in this study, we focused on the protective mechanisms of sodium hydrosulfide (NaHS, a donor of H2S) against ferroptosis caused by intracerebral hemorrhage (ICH) using a hemin-induced BV2 cell injury model in vitro. Our results indicated that NaHS enhanced cell viability and reduced hemin-induced lactate dehydrogenase (LDH) release. NaHS suppressed ferroptosis after hemin treatment, which was confirmed by attenuated reactive oxygen species (ROS) and lipid peroxidation, maintained iron homeostasis, recovery of the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7-member 11 (SLC7A11), and increased glutathione (GSH) production. Moreover, we demonstrated that inhibiting ferroptosis improved cell survival and prevented hemin-induced oxidative stress. In addition, NaHS was also able to block ferroptosis inducer RSL3-induced ferroptotic cell death. We also found that NaHS increased cystathionine-ß-synthase (CBS) expression and H2S levels after hemin treatment. Furthermore, NaHS-induced ferroptosis reduction was inhibited by the CBS inhibitor aminooxyacetic acid (AOAA) as well as by CBS small interference RNA (siCBS). In summary, these findings demonstrated that NaHS protects against hemin-induced ferroptosis by reducing lipid peroxidation, inhibiting iron overload, increasing GSH production, and improving GPX4 and SLC7A11 via the CBS/H2S system. The CBS/H2S system may be a promising target for preventing ferroptosis after ICH.

HLTF promotes hepatocellular carcinoma progression by enhancing SRSF1 stability and activating ERK/MAPK pathway.

Helicase-like transcription factor (HLTF) has been found to be involved in the progression of several tumors, but the role of HLTF in hepatocellular carcinoma (HCC) progression has not been studied. Here, our study explored the underlying mechanism of HLTF in HCC progression for the first time. Database analysis and clinical sample examination indicated that HLTF was upregulated in HCC tissues and was related to poor clinicopathological features in patients. Upregulation of HLTF accelerated the growth and metastasis of HCC cells both in vitro and in vivo. Bioinformatics analysis and subsequent experiments revealed that ERK/MAPK signaling pathway activation was vital to HLTF-mediated proliferation and metastasis in HCC cells. Moreover, HLTF was demonstrated to interact with SRSF1 and contribute to its protein stability to activate the ERK/MAPK signaling pathway and enhance HCC growth and metastasis. In addition, miR-511-5p was expressed at a low level in HCC tissues, was negatively correlated HLTF, and regulated HLTF expression. Our study shows that HLTF plays an oncogenic role in HCC progression and provides a novel biomarker and therapeutic target for the diagnosis and treatment of HCC.

Comprehensive analysis of the prognostic value and functions of prefoldins in hepatocellular carcinoma.

Prefoldins (PFDNs), a group of proteins known to be associated with cytoskeletal rearrangement, are involved in tumor progression in various cancer types. However, little is known about the roles of PFDNs in hepatocellular carcinoma (HCC). Herein, we investigated the transcriptional and survival data of PFDNs from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the potential functions of PFDN1/2/3/4. We also detected the expression of PFDN1/2/3/4 via immunohistochemistry (IHC), Western blotting, and real-time PCR in our clinical samples. We found that the PFDN family showed elevated expression in HCC tissues, while only PFDN1/2/3/4 were found to be significantly correlated with poor prognosis of patients with HCC in the TCGA database. Further investigation was associated with PFDN1-4. We found that the expression of PFDN1/2/3/4 was significantly associated with advanced clinicopathologic features. Apart from the TCGA database, IHC, real-time PCR, and immunoblotting identified the overexpression of PFDN1/2/3/4 in HCC tissues and HCC cell lines. Taken together, these results indicated that PFDN1/2/3/4 might be novel prognostic biomarkers and treatment targets for patients with HCC.

LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression.

LncRNAs are involved in the pathophysiologic processes of multiple diseases, but little is known about their functions in hepatic ischemia/reperfusion injury (HIRI). As a novel lncRNA, the pathogenetic significance of hepatic nuclear factor 4 alpha, opposite strand (Hnf4αos) in hepatic I/R injury remains unclear. Here, differentially expressed Hnf4αos and Hnf4α antisense RNA 1 (Hnf4α-as1) were identified in liver tissues from mouse ischemia/reperfusion models and patients who underwent liver resection surgery. Hnf4αos deficiency in Hnf4αos-KO mice led to improved liver function, alleviated the inflammatory response and reduced cell death. Mechanistically, we found a regulatory role of Hnf4αos-KO in ROS metabolism through PGC1α upregulation. Hnf4αos also promoted the stability of Hnf4α mRNA through an RNA/RNA duplex, leading to the transcriptional activation of miR-23a and miR-23a depletion was required for PGC1α function in hepatoprotective effects on HIRI. Together, our findings reveal that Hnf4αos elevation in HIRI leads to severe liver damage via Hnf4αos/Hnf4α/miR-23a axis-mediated PGC1α inhibition.