Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Objective To find out whether photobiomodulation(PBM)can mitigate cognitive dysfunction caused by chronic stress by affecting levels of adenosine triphosphate(ATP)and adenosine receptors.Methods Twenty-four C57BL/6J mice were randomly divided into a control group,a stress group,and a treatment group.Chronic unpredictable mild stress was used to establish a mouse model of stress.Six weeks into modeling,the treatment group was subjected to one week of PBM interventions.Behavioral tests were conducted to observe behavioral changes in the mice.Western blotting(WB)was used to detect the expressions of A1,A2B,and A3 adenosine receptors in the hippocampus and prefrontal cortex of mice in the three groups.Twelve C57BL/6J mice were randomly divided into a control group and an intervention group.The intervention group received a week of PBM interventions and underwent behavioral testing.WB was used to detect the expression changes of A1,A2B,and A3 adenosine receptors in the hippocampus and prefrontal cortex in both groups.Immunofluorescence assay was adopted to detect the expression of c-Fos in the hippocampus of mice in the two groups.The ATP assay kit made by Beyotime Biotechnology Co.,Ltd.was used to measure changes in ATP contents in the hippocampus and prefrontal cortex tissues of mice.Cell experiments were conducted to verify the effect of PBM on intracellular ATP contents.Results Mice in the stress group covered a similar distance to the control group,but finished far fewer platform crossings.There was no significant difference between the treatment group and the control group in the number of times of platform crossings,but compared favorably with the stress group where the levels of adenosine receptors in the hippocampus and prefrontal cortex were lower,but were increased by PBM.After PBM interventions in normal mice,platform crossings were increased significantly compared to the control group.PBM also raised adenosine receptor levels and ATP contents in the hippocampus and prefrontal cortex,and increased hippocampal c-Fos expressions.In vitro,PBM elevated intracellular ATP levels.Conclusion PBM may improve chronic stress-induced cognitive dysfunction by regulating ATP levels and adenosine receptor expressions,thereby modulating neuronal responsiveness in the hippocampus.

Currently, the types of kidney stones before surgery are mainly identified by human beings, which directly leads to the problems of low classification accuracy and inconsistent diagnostic results due to the reliance on human knowledge. To address this issue, this paper proposes a framework for identifying types of kidney stones based on the combination of radiomics and deep learning, aiming to achieve automated preoperative classification of kidney stones with high accuracy. Firstly, radiomics methods are employed to extract radiomics features released from the shallow layers of a three-dimensional (3D) convolutional neural network, which are then fused with the deep features of the convolutional neural network. Subsequently, the fused features are subjected to regularization, least absolute shrinkage and selection operator (LASSO) processing. Finally, a light gradient boosting machine (LightGBM) is utilized for the identification of infectious and non-infectious kidney stones. The experimental results indicate that the proposed framework achieves an accuracy rate of 84.5% for preoperative identification of kidney stone types. This framework can effectively distinguish between infectious and non-infectious kidney stones, providing valuable assistance in the formulation of preoperative treatment plans and the rehabilitation of patients after surgery.
Humans ; Kidney Calculi/classification* ; Deep Learning ; Neural Networks, Computer ; Tomography, X-Ray Computed ; Imaging, Three-Dimensional ; Radiomics

Objective To investigate the effect of MALAT1 expressions on cell proliferation and apoptosis in astrocytes by regulating mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK1,2)pathway.Methods The MALAT1 gene was knocked down and over-expressed in C8-D1A cells by lentiviral and plasmid vectors,respectively.The expressions of MALAT1,cell proliferation-related markers(Ki67,MCM2,PCNA)and apoptosis-related proteins(Caspase-3,Bax,Bcl-2)were detected by quantitative real-time polymerase chain reaction(qPCR).CCK-8 assay and flow cytometry were used for cell proliferation and apoptosis in C8-D1A cells.Immunofluorescence was adopted to detect the protein expressions of Caspase-3 and Ki67.Western blotting was used to detect the protein expressions of Caspase-3,Bax,Bcl-2,ERK1/2,p-ERK1/2,p38MAPK and p-p38MAPK.Results Compared with the control group,over-expressed MALAT1 inhibited cell proliferation and induced cell apoptosis in C8-D1A cells while the knockdown of MALAT1 significantly enhanced cell proliferation and anti-apoptotic ability in C8-D1A cells.The proportion of C8-D1A cells in G0/G1-phase and G2/M-phase was higher than in the control group as evidenced by flow cytometry,but was lower in S-phase.Meanwhile,data showed that Caspase-3 was increased while p-ERK1/2 was decreased in terms of protein levels.The mRNA expressions of Ki67 and PCNA were decreased.After knockdown of MALAT1,the proportion of C8-D1A cells in S-phase was higher,but was lower in G2/M-phase.The protein expressions of Caspase-3 and Bax decreased while those of p-ERK1/2 and p-p38MAPK increased.The mRNA expressions of Ki67,MCM2 and PCNA were increased.The differences were all statistically significant(P＜0.05).Conclusion MALAT1 promotes astrocyte apoptosis and inhibits proliferation by regulating the MAPK/ERK1,2 signaling pathway.

Objective:To investigate the prognostic value of texture analysis of MRI diffusion weighted imaging (DWI) for neonatal hypoglycemic encephalopathy (HE).Methods:The clinical data and MRI data of 119 patients with neonatal HE admitted to Children′s Hospital of Nanjing Medical University from July 2013 to September 2020 were retrospectively analyzed. The children were followed up to 7—8 months and scored by Bayley scales of infant and toddler development. According to the overall development index, the children were divided into three groups: normal group (≥85, group A, n=42), mild developmental retardation group (70－84, group B, n=46) and developmental retardation group (≤69, group C, n= 31). The whole brain region (except sulcus and cisterna) was delineated as region of interest (ROI) by LIFEx 3.4 software in MRI apparent diffusion coefficient images. A total of 37 parameters were calculated automatically by the software, The clinical data, including gender, gestational age, age at MRI scan, birth weight, mode of delivery, history of asphyxia at birth, maternal preeclampsia or diabetes, minimum blood glucose, duration of hypoglycemia, neonatal behavioral neurological assessment (NBNA), presence or absence of polycythemia); the texture parameters, including histogram, volume, gray level co-occurrence matrix (GLCM), gray level run length matrix (GLRLM), neighborhood gray tone difference matrix (NGTDM), gray level size zone matrix (GLSZM), in the three groups were analyzed; and the diagnostic efficacy of clinical parameters and texture parameters was analyzed. Multivariate Logistic regression was used to analyze statistically significant clinical parameters and texture parameters, and receiver operating characteristic curve (ROC) was used to evaluate the prognostic efficacy of these parameter for neonatal HE. Results:There were no significant differences in gender, gestational age, age at MRI scan, delivery mode and blood glucose minimum among the three groups ( P>0.05). There were significant differences in birth weight [(3 150±130)g, (3 020±220)g, (2 880±140)g, F=-0.31, P=0.015], history of suffocation (10 cases, 18 cases, 20 cases, P=0.001), history of maternal diabetes or preeclampsia (14 cases, 29 cases, 21 cases, P=0.002), blood glucose duration [(5.0±0.2)d, (8.0±0.4)d, (14.0±1.7)d, F=-3.09, P=0.030] and NBNA scores (32.0±3.2, 28.0±2.6, 22.0±1.9, F=-4.21, P=0.010) among three groups. There were significant differences in kurtosis and entropy of histogram (2.57±1.12, 3.66±0.98, 4.23±0.37, F=3.54, P=0.010;5.89±1.09, 7.67±2.12, 8.92±1.62, F=-4.42, P=0.020); energy, contrast and dissimilarity of GLCM (0.48±0.01, 0.36±0.02, 0.23±0.01, F=-3.12, P=0.001;2 419±21, 3 354±31, 4 313±26, F=-4.16, P=0.020;126±14, 153±23, 344±43, F=-3.50, P<0.001); long run emphasis of GLRLM (0.78±0.15, 1.12±0.12, 1.76±0.31, F=-4.13, P=0.006), run length non-uniformity and run percentage (71.7±13.9, 96.6±10.7, 104.1±13.5, F=-0.98, P=0.001;0.91±0.05, 0.84±0.21, 0.72±0.17, F=2.97, P=0.010); coarseness and busyness of NGTDM [0.09±0.01, 0.13±0.03, 0.26±0.07, F=-1.95, P=0.003;0.16(0.04, 4.14), 0.32(0.05, 9.84), 0.45(0.15, 10.14), H=-3.24, P=0.030], short-zone emphasis and short-zone high gray length emphasis of GLSZM (4.74±0.45, 3.44±1.03, 1.88±0.67, F=-3.14, P=0.040; 278 963±239, 164 607±544, 111 653±618, F=-3.84, P=0.001) among three groups. Multivariate Logistic regression showed that duration of hypoglycemia, NBNA score, energy, kurtosis, run percentage and short zone effect were independent risk factors for poor prognosis of neonatal HE ( OR=7.43, 4.09, 1.10, 2.11, 1.36, 1.68, P=0.002, 0.027, 0.001, 0.006, 0.007, 0.010, respectively). ROC curve showed that for combined hypoglycemic duration, NBNA and texture parameters, the area under the curve (AUC) was the highest (AUC=0.94, P<0.001). Conclusion:Texture analysis of the MRI diffusion weighted imaging can predict the prognosis of neonatal hypoglycemic encephalopathy at an early stage, which has better prediction efficiency when combined with clinical features.

Objective:To assess the efficacy and security of 2 940 nm Er∶YAG laser combined with electronic injection of collagen in treatment of striae gravidarum.Methods:The symmetrical spots on both sides of abdomen of 21 subjects with striae gravidarum were divided into treatment and control groups by simple randomization method in the Department of Burn and Plastic Surgery, 903 Hospital from November 2017 to May 2019. The treatment group were treated with 2 940 nm Er∶YAG laser combined with electronic injection of collagen every 2 months for 3 sessions, and control group were received 2 940 nm Er∶YAG laser combined with electronic injection of physiological saline. The total effective rate, satisfaction, striae width, histopathology, and the adverse reaction were evaluated at 6 months after treatment.Results:A total of 19 subjects completed the whole trail. The clinical effective rate of the treatment group was 89.47% and the control group was 68.42%. In the treatment group, 11 cases were satisfied with and 6 cases were very satisfied with treatment outcome. In the treatment group, 8 cases were satisfied with and 3 cases were very satisfied with treatment outcome. The difference of total effective rate and satisfaction was statistically significant ( χ2 was 3.91 and 5.54, P was 0.045 and 0.019). The maximum width decreased by (1.53±0.97) mm on treatment side, and (1.37±1.01) mm on control side. The difference of striae width was statistically significant. No adverse effect was observed on both sides. Conclusions:The combination of the 2 940 nm Er∶YAG laser with electronic injection of collagen for treatment of striae gravidarum is a safe and effective approach for improving of striae gravidarum.

Cultivating salt-alkali tolerant rice varieties is one of the important ways to meet the increasing food demand of growing global population. In this study, twenty-one rice germplasms with different salt-alkali tolerance were treated with six salt-alkali concentrations at germination and seedling stages. The germination potential, germination rate, shoot length, root length, root number, fresh weight of shoot and seedlings were measured. The average value of salt damage rate was used to evaluate the salt-alkali tolerance. As the salt-alkali concentration increases, the inhibition on seed germination and growth became more obvious. Upon treatment with 1% NaCl plus 0.25% NaHCO₃, the salt damage rate of germination rate has the largest variation, ranging from 0% to 89.80%. The salt damage rate of each trait shows a similar trend at all concentrations. Four germplasm resources with strong salt-alkali tolerance (Dajiugu, Nippobare, Mowanggu and 02428) and 7 sensitive germplasms were screened. The salt-tolerant gene sequence of 4 salt-alkali tolerant varieties and 3 sensitive germplasms were analyzed. OSHAL3 and OsRR22 were identical among the 7 germplasms, but SKC1 and DST showed clear variations between the salt-alkali tolerant and sensitive germplasms. Besides the salt-alkali tolerant germplasm resources, this study can also serve as a reference for mining of genes involved in salt-alkali tolerance and breeding of salt-alkali tolerant rice varieties.
Alkalies ; Germination ; Oryza/genetics* ; Plant Breeding ; Seedlings/genetics*

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
Chromatin ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; Histones/metabolism* ; Humans ; Neoplasms/therapy*

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*

Objective To explore the clinical effect of microendoscopic discectomy through posterior approach in old patients with multilevel lumber spinal stenosis and analyze the influence factors that related to clinical effect .Methods 64 old patients with multilevel lumber spinal stenosis were selected and divided into microendoscopic group and open group based on different operation method ,each group contained 32 patients .Comparison was made between two groups in respects of operation time ,amount of bleed-ing ,hospital time post-operation and Nakai scores .Analyzed the influence factors that related to clinical effect .Results The opera-tion time ,amount of bleeding ,hospital time post-operation in microendoscopic group were lower than open group ,the differences had statistical significance .Based on the Nakei score ,the curative effect in microendoscopic group was slightly lower than open group ,but the differences had no statistical significance .The JOA score pre-operation ,walking distances and complication were rela-tive factors that could influence the clinical effect of microendoscopic discectomy through posterior approach method .Conclusion Microendoscopic discectomy through posterior approach in old patients with multilevel lumber spinal stenosis had quicker postoper-ative recovery than conventional operation ,and the JOA score pre-operation ,walking distances and complication were relative fac-tors that could influence the clinical effect of microendoscopic discectomy through posterior approach method .