Aerobic fitness as a moderator of acute aerobic exercise effects on executive function.

This study aimed to investigate the moderating role of aerobic fitness on the effect of acute exercise on improving executive function from both behavioral and cerebral aspects. Thirty-four young individuals with motor skills were divided into high- and low-fitness groups based on their maximal oxygen uptake. Both groups completed 30 min of moderate-intensity aerobic exercise on a power bike. Executive function tests (Flanker, N-back, More-odd-shifting) were performed before and after exercise and functional near-infrared spectroscopy was used to monitor prefrontal cerebral blood flow changes during the tasks. The results indicated significant differences between the two groups regarding executive function. Participants with lower aerobic fitness performed better than their higher fitness counterparts in inhibitory control and working memory, but not in cognitive flexibility. This finding suggests that the aerobic fitness may moderate the extent of cognitive benefits gained from acute aerobic exercise. Furthermore, the neuroimaging data indicated negative activation in the frontopolar area and dorsolateral prefrontal cortex in response to three complex tasks. These findings underscore the importance of considering individual aerobic fitness when assessing the cognitive benefits of exercise and could have significant implications for tailoring fitness programs to enhance cognitive performance.

A novel nomogram to predict futile recanalization in patients with acute ischemic stroke undergoing mechanical thrombectomy.

Background and objective: Futile recanalization (FR) is defined as patients with acute ischemic stroke (AIS) due to large vessel occlusion who still exhibits functional dependence although undergoing successful mechanical thrombectomy (MT). We aimed to develop and validate a simple nomogram for predicting the probability of FR after MT treatment in AIS patients. Methods: Clinical data of AIS patients in the Jrecan clinical trial in China from March 2018 to June 2019 were collected as the derivation set (n = 162). Meanwhile, clinical data of AIS patients who underwent MT in Baotou Central Hospital and Ningbo No.2 Hospital from 2019 to 2021 were collected as the validation set (n = 170). Multivariate logistic regression analysis was performed for all variables that had p < 0.2 in the univariate analysis in the derivation set. The independent risk factors of FR were further screened out and a nomogram was constructed. The performance of the nomogram was analyzed in the derivation and validation set using C-index, calibration plots, and decision curves. Results: No significant difference in FR rate was detected between the derivation set and the validation set [88/162 (54.32%) and 82/170 (48.23%), p = 0.267]. Multivariate logistic regression analysis showed that age ≥ 65 years old (OR = 2.096, 95%CI 1.024-4.289, p = 0.043), systolic blood pressure (SBP) ≥ 180 mmHg (OR = 5.624, 95%CI 1.141-27.717, p = 0.034), onset to recanalization time (OTR) ≥ 453 min (OR = 2.759, 95%CI 1.323-5.754, p = 0.007), 24 h intracerebral hemorrhage (ICH; OR = 4.029, 95%CI 1.844 ~ 8.803, p < 0.001) were independent risk factors for FR. The C-index of the nomogram of the derivation set and the verification set were 0.739 (95%CI 0.662~0.816) and 0.703 (95%CI 0.621~0.785), respectively. Conclusion: The nomogram composed of age, SBP, OTR, and 24 h ICH can effectively predict the probability of FR after MT in AIS patients.

Geographic differences in psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease: A multicenter study in China.

OBJECTIVE: We aimed to explore the geographic differences in psychological symptoms, sleep quality, and quality of life (QoL) among adult patients with inflammatory bowel disease (IBD). METHODS: A unified questionnaire was developed to collect data on psychological status and QoL of IBD patients from 42 hospitals across 22 provinces, municipalities, and autonomous regions in China's mainland from September 2021 to May 2022. RESULTS: A total of 2478 patients with IBD were surveyed. The proportions of patients with anxiety (28.5% vs 23.1%), depression (32.3% vs 27.8%), and poor QoL (44.8% vs 32.2%) were significantly higher in patients from the northern region compared to the southern region (all P < 0.05). In the western region, the proportions of patients with anxiety (31.9% vs 23.0%), depression (37.7% vs 26.7%), sleep disturbances (64.5% vs 58.5%), and poor QoL (44.9% vs 34.8%) were significantly higher than in the eastern and central regions (all P < 0.01). Patients from inland regions had significantly higher rates of anxiety (27.1% vs 23.3%), depression (32.5% vs 26.0%), sleep disturbance (62.0% vs 57.7%), and poor QoL (43.5% vs 29.9%) compared to those from coastal regions (all P < 0.05). In economically underdeveloped areas, the proportions of patients with depression (33.1% vs 28.5%) and poor QoL (52.0% vs 32.4%) were significantly higher than in economically (relatively) developed areas (both P < 0.05). CONCLUSION: There are significant geographic differences in psychological symptoms, sleep quality, and QoL among Chinese patients with IBD, which might provide valuable insights for global IBD research and clinical practice.

Application of a nomogram model for the prediction of 90-day poor outcomes following mechanical thrombectomy in patients with acute anterior circulation large-vessel occlusion.

Background: The past decade has witnessed advancements in mechanical thrombectomy (MT) for acute large-vessel occlusions (LVOs). However, only approximately half of the patients with LVO undergoing MT show the best/independent 90-day favorable outcome. This study aimed to develop a nomogram for predicting 90-day poor outcomes in patients with LVO treated with MT. Methods: A total of 187 patients who received MT were retrospectively analyzed. Factors associated with 90-day poor outcomes (defined as mRS of 4-6) were determined by univariate and multivariate logistic regression analyzes. One best-fit nomogram was established to predict the risk of a 90-day poor outcome, and a concordance index was utilized to evaluate the performance of the model. Additionally, 145 patients from a single stroke center were retrospectively recruited as the validation cohort to test the newly established nomogram. Results: The overall incidence of 90-day poor outcomes was 45.16%, affecting 84 of 186 patients in the training set. Moreover, five variables, namely, age (odds ratio [OR]: 1.049, 95% CI [1.016-1.083]; p = 0.003), glucose level (OR: 1.163, 95% CI [1.038-1.303]; p = 0.009), baseline National Institute of Health Stroke Scale (NIHSS) score (OR: 1.066, 95% CI [0.995-1.142]; p = 0.069), unsuccessful recanalization (defined as a TICI grade of 0 to 2a) (OR: 3.730, 95% CI [1.688-8.245]; p = 0.001), and early neurological deterioration (END, defined as an increase of ≥4 points between the baseline NIHSS score and the NIHSS score at 24 h after MT) (OR: 3.383, 95% CI [1.411-8.106]; p = 0.006), were included in the nomogram to predict the potential risk of poor outcomes at 90 days following MT in LVO patients, with a C-index of 0.763 (0.693-0.832) in the training set and 0.804 (0.719-0.889) in the validation set. Conclusion: The proposed nomogram provided clinical evidence for the effective control of these risk factors before or during the process of MT surgery in LVO patients.

Predictive visual field outcomes after optic chiasm decompressive surgery by retinal vessels parameters using optical coherence tomography angiography.

AIM: To evaluate the predictive value of superficial retinal capillary plexus (SRCP) and radial peripapillary capillary (RPC) for visual field recovery after optic cross decompression and compare them with peripapillary nerve fiber layer (pRNFL) and ganglion cell complex (GCC). METHODS: This prospective longitudinal observational study included patients with chiasmal compression due to sellar region mass scheduled for decompressive surgery. Generalized estimating equations were used to compare retinal vessel density and retinal layer thickness pre- and post-operatively and with healthy controls. Logistic regression models were used to assess the relationship between preoperative GCC, pRNFL, SRCP, and RPC parameters and visual field recovery after surgery. RESULTS: The study included 43 eyes of 24 patients and 48 eyes of 24 healthy controls. Preoperative RPC and SRCP vessel density and pRNFL and GCC thickness were lower than healthy controls and higher than postoperative values. The best predictive GCC and pRNFL models were based on the superior GCC [area under the curve (AUC)=0.866] and the tempo-inferior pRNFL (AUC=0.824), and the best predictive SRCP and RPC models were based on the nasal SRCP (AUC=0.718) and tempo-inferior RPC (AUC=0.825). There was no statistical difference in the predictive value of the superior GCC, tempo-inferior pRNFL, and tempo-inferior RPC (all P>0.05). CONCLUSION: Compression of the optic chiasm by tumors in the saddle area can reduce retinal thickness and blood perfusion. This reduction persists despite the recovery of the visual field after decompression surgery. GCC, pRNFL, and RPC can be used as sensitive predictors of visual field recovery after decompression surgery.

Antioxidant Agriculture for Stress-Resilient Crop Production: Field Practice.

Oxidative stress, resulting from the excessive production of reactive oxygen species, is a common and major cause of cellular damage in plants exposed to various abiotic stresses. To address this challenge, we introduce the concept of antioxidant agriculture as a comprehensive strategy to improve stress tolerance and thus crop productivity by minimizing oxidative stress levels in the field environment. This strategy encompasses a diverse range of approaches, including genetic engineering, the exogenous application of antioxidant agents, microbial inoculation, and agronomic practices, to reinforce the plant's intrinsic antioxidant defense system and mitigate oxidative stress. We present recent successful studies of antioxidant measures that have been validated in field conditions, along with our perspective on achieving antioxidant agriculture.

An Epigenomic fingerprint of human cancers by landscape interrogation of super enhancers at the constituent level.

Super enhancers (SE), large genomic elements that activate transcription and drive cell identity, have been found with cancer-specific gene regulation in human cancers. Recent studies reported the importance of understanding the cooperation and function of SE internal components, i.e., the constituent enhancers (CE). However, there are no pan-cancer studies to identify cancer-specific SE signatures at the constituent level. Here, by revisiting pan-cancer SE activities with H3K27Ac ChIP-seq datasets, we report fingerprint SE signatures for 28 cancer types in the NCI-60 cell panel. We implement a mixture model to discriminate active CEs from inactive CEs by taking into consideration ChIP-seq variabilities between cancer samples and across CEs. We demonstrate that the model-based estimation of CE states provides improved functional interpretation of SE-associated regulation. We identify cancer-specific CEs by balancing their active prevalence with their capability of encoding cancer type identities. We further demonstrate that cancer-specific CEs have the strongest per-base enhancer activities in independent enhancer sequencing assays, suggesting their importance in understanding critical SE signatures. We summarize fingerprint SEs based on the cancer-specific statuses of their component CEs and build an easy-to-use R package to facilitate the query, exploration, and visualization of fingerprint SEs across cancers.

Poly (Betulinic Acid) Nanoparticles Loaded with bFGF Improve Functional Recovery After Spinal Cord Injury.

Oxidative stress (OS) is one of the crucial molecular events of secondary spinal cord injury (SCI). Basic fibroblast growth factor (bFGF) is a multipotent cell growth factor with an anti-oxidant effect. However, bFGF has a short half-life in vivo, which limits its therapeutic application. Biodegradable polymers with excellent biocompatibility have been recently applied in SCI. The negative aspect is that polymers cannot provide a significant therapeutic effect. Betulinic acid (BA), a natural anti-inflammatory compound, has been polymerized into poly (betulinic acid) (PBA) to serve as a drug carrier for bFGF. This study explores the therapeutic effects and underlying molecular mechanisms of PBA nanoparticles (NPs) loaded with bFGF (PBA-bFGF NPs) in SCI. Results show that PBA-bFGF NPs produce remarkable biocompatibility in vivo and in vitro. The results also demonstrate that local delivery of PBA-bFGF NPs enhances motor function recovery, inhibits OS, mitigates neuroinflammation, and alleviates neuronal apoptosis following SCI. Furthermore, the results indicate that local delivery of PBA-bFGF NPs activates the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway following SCI. In summary, results suggest that local delivery of PBA-bFGF NPs delivers potential therapeutic advantages in the treatment and management of SCI.

Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway.

Background: Neurons in the ventral tegmental area (VTA) are sensitive to stress and their maladaptation have been implicated in the psychiatric disorders such as anxiety and addiction, etc. The cellular properties of the VTA neurons in response to different stressors related to different emotional processing remain to be investigated. Methods: By combining immediate early gene (IEG)-dependent labeling, rabies virus tracing, ensemble-specific transcriptomic analysis and fiber photometry recording in the VTA of male mice, the spatial distribution, brain-wide connectivity and cellular signaling pathways in the VTA neuronal ensembles in response to morphine (Mor-Ens) or foot shock (Shock-Ens) stimuli were investigated. Results: Optogenetic activation of the Mor-Ens drove approach behavior, whereas chemogenetic activation of the Shock-Ens increased the anxiety level in mice. Mor-Ens were clustered and enriched in the ventral VTA, contained a higher proportion of dopaminergic neurons, received more inputs from the dorsal medial striatum and the medial hypothalamic zone, and exhibited greater axonal arborization in the zona incerta and ventral pallidum. Whereas Shock-Ens were more dispersed, contained a higher proportion of GABAergic neurons, and received more inputs from the ventral pallidum and the lateral hypothalamic area. The downstream targets of the G protein and ß-arrestin pathways, PLCß3 and phosphorylated AKT1Thr308, were relatively enriched in the Mor-Ens and Shock-Ens, respectively. Cariprazine, the G-protein-biased agonist for the dopamine D2 receptor, increased the response of Mor-Ens to sucrose water and decreased the anxiety-like behavior during morphine withdrawal, whereas the ß-arrestin-biased agonist UNC9994 decreased the response of Shock-Ens to tail suspension. Conclusions: Taken together, these findings reveal the heterogeneous connectivity and signaling pathways of the VTA neurons in response to morphine and foot shock, providing new insights for development of specific interventions for psychiatric disorders caused by various stressors associated with different VTA neuronal functions.

O-GlcNAcylation mediates H2O2-induced apoptosis through regulation of STAT3 and FOXO1.

The O-linked-ß-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H2O2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H2O2-induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H2O2-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H2O2-induced apoptosis of N2a cells.

The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS: We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS: Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS: HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

Leveraging Historical Medical Records as a Proxy via Multimodal Modeling and Visualization to Enrich Medical Diagnostic Learning.

Simulation-based Medical Education (SBME) has been developed as a cost-effective means of enhancing the diagnostic skills of novice physicians and interns, thereby mitigating the need for resource-intensive mentor-apprentice training. However, feedback provided in most SBME is often directed towards improving the operational proficiency of learners, rather than providing summative medical diagnoses that result from experience and time. Additionally, the multimodal nature of medical data during diagnosis poses significant challenges for interns and novice physicians, including the tendency to overlook or over-rely on data from certain modalities, and difficulties in comprehending potential associations between modalities. To address these challenges, we present DiagnosisAssistant, a visual analytics system that leverages historical medical records as a proxy for multimodal modeling and visualization to enhance the learning experience of interns and novice physicians. The system employs elaborately designed visualizations to explore different modality data, offer diagnostic interpretive hints based on the constructed model, and enable comparative analyses of specific patients. Our approach is validated through two case studies and expert interviews, demonstrating its effectiveness in enhancing medical training.

Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury.

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity, damaging the neurons. However, how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear. Herein, we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury. We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice. Lipid droplet accumulation could be induced by myelin debris in HT22 cells. Myelin debris degradation by phospholipase led to massive free fatty acid production, which increased lipid droplet synthesis, ß-oxidation, and oxidative phosphorylation. Excessive oxidative phosphorylation increased reactive oxygen species generation, which led to increased lipid peroxidation and HT22 cell apoptosis. Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway, thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells. Motor function, lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury. The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

Tissue Identification of Intervertebral Disc Anatomy Using Forward-oriented Ultrasound Endoscopic System: A Feasibility Study.

Minimally invasive surgery is widely used for spine surgery, however the commonly used optical endoscopes cannot identity tissues under surface. In this study, a forward-oriented ultrasound endoscopic system was proposed to detect and identity different types of tissues for surgical approaches. A total of 150 ultrasound image data were collected from 6 types of intervertebral disc tissue using a custom-developed endoscopic probe. The gray-level co-occurrence matrix (GLCM) properties including energy (angular second moment, ASM), contrast, entropy, and homogeneity (inverse difference moment, IDM) were calculated on the acquired ultrasound images, and the single-parameter and combined parameter were applied for tissue classification. The classification accuracies of fibrous ring, nerve roots and bone were 100%, and the overall accuracy for all tissues was 73.33%. The results indicated that the combined parameter method provided more accurate classification output. It demonstrated that the proposed endoscopic ultrasonography system had the potential of identifying different tissues under surface during the endoscopic spine surgery.Clinical Relevance-This study establishes that the forward-oriented ultrasound endoscopic system was feasible to identify different types of tissues under surface during the endoscopic spine surgery.

"Moderate" adjuvant chemotherapy-induced leukopenia is beneficial for survival of patients with early breast cancer: a retrospective study.

BACKGROUND: The association between chemotherapy-induced leukopenia (CIL) and survival for patients with early breast cancer (EBC) is not known. We investigated the relationship between different grades of CIL and survival in patients with EBC receiving adjuvant chemotherapy. METHODS: A total of 442 patients with EBC receiving a regimen containing an anthracycline (A) and taxane (T) were included into our analysis. Survival analyses were undertaken using Kaplan-Meier curves. The P-value was calculated using the log rank test. Subgroup analysis was conducted to investigate the correlation of CIL grade and survival based on the clinicopathological characteristics of patients. Afterwards, univariate and multivariate analyses screened out independent prognostic factors to construct a prognostic model, the robustness of which was verified. RESULTS: Patients with EBC who experienced grade 2-4 ("moderate" and "severe") CIL were associated with longer overall survival (OS) than those with grade 0-1 (mild) CIL (P = 0.021). Compared with patients with mild CIL, OS was longer in patients with severe CIL (P = 0.029). Patients who suffered from moderate CIL tended to have longer OS than those with mild CIL (P = 0.082). Nevertheless, there was no distinguishable difference in OS between moderate- or severe-CIL groups. Subgroup analysis revealed that patients with moderate CIL had longer OS than those with mild CIL among patients who were premenstrual, or with human epidermal growth factor receptor 2-positive (HER2+), > 3 lymph nodes with metastases, a tumor diameter > 5 cm. A prognostic model based on menstrual status, N stage, and CIL grade showed satisfactory robustness. CONCLUSION: The grade of CIL was strongly associated with the prognosis among patients with EBC who received a regimen containing both anthracyclines and taxanes. Patients with a "moderate" CIL grade tended to have better survival outcomes.

Epigallocatechin gallate alleviates osteoporosis by regulating the gut microbiota and serum metabolites in rats.

Osteoporosis, one of the serious public health problems worldwide, can lead to degeneration of the bone structure and increased risk of fractures. Epigallocatechin gallate (EGCG) is a natural product with potential efficacy in inhibiting bone loss. However, the specific mechanism remains unclear. This study first investigated the role of EGCG in preventing dexamethasone (DEX)-induced osteoporosis by regulating intestinal microbiota and serum metabolites. We detected the bone density, bone microstructure, and changes in intestinal microorganisms and serum metabolites. According to our results, EGCG inhibited the decline of bone density, protected the bone microstructure, increased microbial diversity, promoted the abundance of beneficial bacteria such as Prevotellaceae and Ruminococcus, and inhibited the abundance of pathogenic bacteria such as Peptostreptococcaceae. There were also significant changes in serum metabolites among different treatments. Differential metabolites were mainly involved in sphingolipid metabolism and glycerophospholipid metabolism pathways, especially ceramide (d18:0/16:0(2OH)), phosphatidylserine (P-20:0/20:4(5Z,8Z,11Z,14Z)), phosphatidylserine (18:2(9Z,12Z)/12:0), and phosphatidylethanolamine (O-16:0/0:00), which were increased after EGCG treatment. Notably, most of the above metabolites were positively correlated with bone mineral density, BV/TV and Tb·Th, and negatively correlated with Tb·Sp. In summary, EGCG can prevent bone damage, promote the production of beneficial bacteria and metabolites, and enhance immune function. This study provides a basis and reference for the prevention and treatment of osteoporosis, as well as the application of EGCG in maintaining body health.

Osteonectin bidirectionally regulates osteoblast mineralization.

OBJECTIVE: The aim of this study was to investigate whether Osteonectin/Secreted protein acidic and rich in cysteine (ON/SPARC) had a two-way dose-dependent regulatory effect on osteoblast mineralization and its molecular mechanism. METHODS: Initially, different concentrations of ON were added in osteoblasts, and the gene of bone sialoprotein (BSP), osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP) were detected using reverse-transcription quantitative polymerase chain reaction (RT-PCR). Secondly, based on the above results, the Optima and inhibitory concentration of ON for osteoblast mineralization were determined and regrouped, the Control group was also set up, and the gene detections of Collagen 1 (Col 1), Discoidin domain receptor 2 (DDR2) and p38 mitogen­activated protein kinase were added using RT-PCR. In the third stage of the experiment, osteoblasts were pretreated with 0.4Mm ethyl-3,4-dihydroxybenzoate (DHB) (a specific inhibitor of collagen synthesis) for 3 h before adding the optima SPARC, the gene and protein expressions of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 were detected by RT­qPCR and western blot analysis, and the mineralized nodules were observed by alizarin red staining. RESULTS: The results showed that the expression of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 genes and proteins in osteoblasts were significantly enhanced by 1 ug/ml ON, 100 ug/ml ON or 1 ug/ml ON added with 3,4 DHB significantly inhibited the expressions of DDR2, P38 and the above-mentioned mineralization indexes, and significantly reduced the formation of mineralized nodules. CONCLUSION: This study suggested that ON had a bidirectional dose-dependent regulatory effect on osteoblast mineralization, and the activation of P38 pathway by collagen binding to DDR2 was also an important molecular mechanism.

Characteristics of amino acid metabolism in colorectal cancer.

In recent years, metabolomics research has become a hot spot in the screening and treatment of cancer. It is a popular technique for the quantitative characterization of small molecular compounds in biological cells, tissues, organs or organisms. Further study of the tumor revealed that amino acid changes may occur early in the tumor. The rapid growth and metabolism required for survival result in tumors exhibiting an increased demand for amino acids. An abundant supply of amino acids is important for cancer to maintain its proliferative driving force. Changes in amino acid metabolism can be used to screen malignant tumors and improve therapeutic outcomes. Therefore, it is particularly important to study the characteristics of amino acid metabolism in colorectal cancer. This article reviews several specific amino acid metabolism characteristics in colorectal cancer.

ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy.

Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of ß-catenin and activates the ß-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.