Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Oxygen Vacancy-Enhanced Centrosymmetric Breaking of SrFeO3- x for Piezoelectric-Catalyzed Synthesis of H2O2.

Normally, only noncentrosymmetric structure of the materials can potentially be piezoelectric. Thus, it is limited in the field of piezoelectricity for the centrosymmetric structure of the material. In this work, the performance of piezoelectricity is successfully achieved from centrosymmetric SrFeO3- x by modulating oxygen vacancies, which have a surface piezoelectric potential up to 93 mV by using Kelvin-probe force microscopy (KPFM). Moreover, the piezoelectric effects of SrFeO3- x are also evaluated by piezoelectric catalytic effect and density functional theory calculations (DFT). The results show that the piezo-catalytic degradation of tetracycline reaches 96% after 75 min by ultrasonic mechanical vibration and the production of H2O2 by SrFeO3- x piezoelectric synthesis could reach 1821 µmol L-1. In addition, the DFT results indicate that the intrinsic effect of oxygen vacancies effectively promotes the adsorption and activation of O2 and H2O as well as intermediates and improves the piezoelectric catalytic activity. This work provides an effective basis for realizing the piezoelectricity of centrosymmetric materials and regulating the development of piezoelectric catalytic properties.

Autism spectrum disorders detection based on multi-task transformer neural network.

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders that cause people difficulties in social interaction and communication. Identifying ASD patients based on resting-state functional magnetic resonance imaging (rs-fMRI) data is a promising diagnostic tool, but challenging due to the complex and unclear etiology of autism. And it is difficult to effectively identify ASD patients with a single data source (single task). Therefore, to address this challenge, we propose a novel multi-task learning framework for ASD identification based on rs-fMRI data, which can leverage useful information from multiple related tasks to improve the generalization performance of the model. Meanwhile, we adopt an attention mechanism to extract ASD-related features from each rs-fMRI dataset, which can enhance the feature representation and interpretability of the model. The results show that our method outperforms state-of-the-art methods in terms of accuracy, sensitivity and specificity. This work provides a new perspective and solution for ASD identification based on rs-fMRI data using multi-task learning. It also demonstrates the potential and value of machine learning for advancing neuroscience research and clinical practice.

Synthesis of Acylhydroquinones through Visible-Light-Mediated Hydroacylation of Quinones with α-Keto Acids.

A mild and eco-friendly visible-light-induced protocol for the hydroacylation of quinones with α-keto acids has been developed. In the absence of any catalyst or additive, the decarboxylative hydroacylation proceeded smoothly under visible-light irradiation at room temperature. A wide range of quinones and α-keto acids were well-tolerated and afforded hydroacylation products up to 88% isolated yield. The reaction can be scaled up, and the induced groups are useful for further synthetic applications. Preliminarily, mechanistic studies indicated that photoactive quinones absorb visible light to facilitate the transformation.

Utility of paired plasma and drainage fluid mNGS in diagnosing acute intra-abdominal infections with sepsis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) has been increasingly applied in sepsis. We aimed to evaluate the diagnostic and therapeutic utility of mNGS of paired plasma and peritoneal drainage (PD) fluid samples in comparison to culture-based microbiological tests (CMTs) among critically ill patients with suspected acute intra-abdominal infections (IAIs). METHODS: We conducted a prospective study from October 2021 to December 2022 enrolling septic patients with suspected IAIs (n = 111). Pairwise CMTs and mNGS of plasma and PD fluid were sent for pathogen detection. The mNGS group underwent therapeutic regimen adjustment based on mNGS results for better treatment. The microbial community structure, clinical features, antibiotic use and prognoses of the patients were analyzed. RESULTS: Higher positivity rates were observed with mNGS versus CMTs for both PD fluid (90.0% vs. 48.3%, p < 0.005) and plasma (76.7% vs. 1.6%, p < 0.005). 90% of enrolled patients had clues of suspected pathogens combining mNGS and CMT methods. Gram-negative pathogens consist of most intra-abdominal pathogens, including a great variety of anaerobes represented by Bacteroides and Clostridium. Patients with matched plasma- and PD-mNGS results had higher mortality and sepsis severity. Reduced usage of carbapenem (30.0% vs. 49.4%, p < 0.05) and duration of anti-MRSA treatment (5.1 ± 3.3 vs. 7.0 ± 8.4 days, p < 0.05) was shown in the mNGS group in our study. CONCLUSIONS: Pairwise plasma and PD fluid mNGS improves microbiological diagnosis compared to CMTs for acute IAI. Combining plasma and PD mNGS could predict poor prognosis. mNGS may enable optimize empirical antibiotic use.

Factors influencing DVT formation in sepsis.

INTRODUCTION: Sepsis is a global public health burden. Deep vein thrombosis (DVT) is the third most common cause of death from cardiovascular disease after heart attacks and strokes. We designed this experiment to investigate the factors influencing DVT formation in patients with sepsis. METHODS: In this survey, 918 septic patients admitted to Peking Union Medical College Hospital, who underwent DVT screening were enrolled. The data were collected from June 8, 2013 to October 12, 2022. The differences between septic patients with and without DVT were studied from following aspects: basic information, comorbidities, inflammatory cytokines, albumin, source of infection, sequential organ failure assessment (SOFA) score, coagulation and prognosis. MAIN RESULTS: In this study, the prevalence of DVT in patients with sepsis was 0.23. Elderly patients with sepsis were prone to DVT (p value < 0.001). In terms of comorbidities, septic patients with hypertension and atrial fibrillation were prone to DVT (p value 0.045 and 0.048). Inflammatory cytokines, such as procalcitonin (PCT), C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, had no significant correlation with DVT in patients with sepsis (p value 0.364, 0.882, 0.912, 0.789, 0.245, and 0.780). Levels of serum albumin correlated with DVT in patients with sepsis (p value 0.003). The SOFA total score had no relationship with DVT formation (p value 0.254). Coagulation and respiration function were negatively correlated with DVT (p value 0.018). Liver function was positively correlated with DVT (p value 0.020). Patients in the DVT group had longer duration of mechanical ventilation and longer intensive care unit (ICU) stays (p value < 0.001 and 0.006). There was no significant difference in survival in septic patients with and without DVT (p value 0.868). CONCLUSIONS: The SOFA total score had no relationship with DVT formation. The function of each organ had different effects on DVT formation. Better coagulation and respiration function, easier DVT formation. Poorer liver function, easier DVT formation. DVT was associated with longer duration of mechanical ventilation and longer ICU stays.

Synergistic dual cell therapy for atherosclerosis regression: ROS-responsive Bio-liposomes co-loaded with Geniposide and Emodin.

The development of nanomaterials for delivering natural compounds has emerged as a promising approach for atherosclerosis therapy. However, premature drug release remains a challenge. Here, we present a ROS-responsive biomimetic nanocomplex co-loaded with Geniposide (GP) and Emodin (EM) in nanoliposome particles (LP NPs) for targeted atherosclerosis therapy. The nanocomplex, hybridized with the macrophage membrane (Møm), effectively evades immune system clearance and targets atherosclerotic plaques. A modified thioketal (TK) system responds to ROS-rich plaque regions, triggering controlled drug release. In vitro, the nanocomplex inhibits endothelial cell apoptosis and macrophage lipid accumulation, restores endothelial cell function, and promotes cholesterol effluxion. In vivo, it targets ROS-rich atherosclerotic plaques, reducing plaque area ROS levels and restoring endothelial cell function, consequently promoting cholesterol outflow. Our study demonstrates that ROS-responsive biomimetic nanocomplexes co-delivering GP and EM exert a synergistic effect against endothelial cell apoptosis and lipid deposition in macrophages, offering a promising dual-cell therapy modality for atherosclerosis regression.

Maintaining moderate versus lower PEEP after cardiac surgery: a propensity-scored matched analysis.

BACKGROUND: Setting positive end-expiratory pressure (PEEP) at around 5 cm H2O in the early postoperative period seems a common practice for most patients. It remains unclear if the routine application of higher levels of PEEP confers any meaningful clinical benefit for cardiac surgical patients. The aim of this study was to compare moderate versus conventional lower PEEP on patient-centered outcomes in the intensive care unit (ICU). METHODS: This is a single-center retrospective study involving patients receiving cardiac surgery from June 2022 to May 2023. Propensity-score matching (PSM) was used to balance the baseline differences. Primary outcomes were the duration of mechanical ventilation and ICU length of stay. Secondary outcomes included PaO2/FiO2 ratio at 24 h and the need for prone positioning during ICU stay. RESULTS: A total of 334 patients were included in the study, 102 (31%) of them received moderate PEEP (≥ 7 cm H2O) for the major time in the early postoperative period (12 h). After PSM, 79 pairs of patients were matched with balanced baseline data. The results showed that there was marginal difference in the distribution of mechanical ventilation duration (p = 0.05) and the Moderate PEEP group had a higher extubation rate at the day of T-piece trial (65 [82.3%] vs 52 [65.8%], p = 0.029). Applying moderate PEEP was also associated with better oxygenation. No differences were found regarding ICU length of stay and patients requiring prone positioning between groups. CONCLUSION: In selective cardiac surgical patients, using moderate PEEP compared with conventional lower PEEP in the early postoperative period correlated to better oxygenation, which may have potential for earlier liberation of mechanical ventilation.

The level of partial pressure of carbon dioxide affects respiratory effort in COVID-19 patients undergoing pressure support ventilation with extracorporeal membrane oxygenation.

BACKGROUND: Patients with COVID-19 undergoing pressure support ventilation (PSV) with extracorporeal membrane oxygenation (ECMO) commonly had high respiratory drive, which could cause self-inflicted lung injury. The aim of this study was to evaluate the influence of different levels of partial pressure of carbon dioxide(PaCO2) on respiratory effort in COVID-19 patients undergoing PSV with ECMO. METHODS: ECMO gas flow was downregulated from baseline (respiratory rate < 25 bpm, peak airway pressure < 25 cm H2O, tidal volume < 6 mL/kg, PaCO2 < 40 mmHg) until PaCO2 increased by 5 - 10 mmHg. The pressure muscle index (PMI) and airway pressure swing during occlusion (ΔPOCC) were used to monitor respiratory effort, and they were measured before and after enforcement of the regulations. RESULTS: Ten patients with COVID-19 who had undergone ECMO were enrolled in this prospective study. When the PaCO2 increased from 36 (36 - 37) to 42 (41-43) mmHg (p = 0.0020), there was a significant increase in ΔPOCC [from 5.6 (4.7-8.0) to 11.1 (8.5-13.1) cm H2O, p = 0.0020] and PMI [from 3.0 ± 1.4 to 6.5 ± 2.1 cm H2O, p < 0.0001]. Meanwhile, increased inspiratory effort determined by elevated PaCO2 levels led to enhancement of tidal volume from 4.1 ± 1.2 mL/kg to 5.3 ± 1.5 mL/kg (p = 0.0003) and respiratory rate from 13 ± 2 to 15 ± 2 bpm (p = 0.0266). In addition, the increase in PaCO2 was linearly correlated with changes in ΔPOCC and PMI (R2 = 0.7293, p = 0.0003 and R2 = 0.4105, p = 0.0460, respectively). CONCLUSIONS: In patients with COVID-19 undergoing PSV with ECMO, an increase of PaCO2 could increase the inspiratory effort.

Efficacy and Safety of Nerve Block for Postoperative Analgesia in Patients Undergoing Breast Cosmetic Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: To evaluate the postoperative analgesic efficacy and safety of nerve block (NB) in patients undergoing breast surgery for cosmetic purposes. METHODS: PubMed, Web of Science, Embase and Cochrane Libraries were searched from inception to September 2022, to identify all eligible randomized controlled trials (RCTs). Continuous data are presented as mean difference (MD) with 95% confidence intervals (CI), whereas dichotomous data are provided as odds ratios (OR) with 95% CI. This meta-analysis was performed in RevMan 5.4. RESULTS: A total of 10 RCTs with 565 patients were meta-analyzed. Compared to the control group, the pain score of the NB group was significantly lower at postoperative 2, 3-4, 6-8, 12-16 and 24 h. Opioid consumption in the first postoperative 24 h was significantly lower in the NB group (MD = - 9.02, 95% CI - 14.29 to - 3.75, P < 0.05), I2 = 95%). In addition, the NB group showed a prolonged time to first postoperative analgesic requirement (MD = 43.15, 95% CI 4.74-81.56, P < 0.05, I2 = 96%), decreased incidence of additional postoperative analgesia (OR 0.14, 95% CI 0.07-0.28, P < 0.05, I2 = 0%) and reduced incidence of postoperative nausea or vomiting (OR 0.33; 95% CI 0.22-0.48; P < 0.05; I2 = 0%). There was no significant difference in operation duration between the two groups. CONCLUSIONS: Nerve block is an effective and safe option for postoperative analgesia after breast cosmetic surgery. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Risk factors for bronchopulmonary dysplasia in twin preterm infants: a multicenter study]. / åŒèƒŽæ—©äº§å„¿æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯å±é™©å› ç´ åˆ†æžï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.

Genetic variations in ZmSAUR15 contribute to the formation of immature embryo-derived embryonic calluses in maize.

The ability of immature maize (Zea mays) embryos to form embryonic calluses (ECs) is highly genotype dependent, which limits transgenic breeding development in maize. Here, we report the association map-based cloning of ZmSAUR15 using an association panel (AP) consisting of 309 inbred lines with diverse formation abilities for ECs. We demonstrated that ZmSAUR15, which encodes a small auxin-upregulated RNA, acts as a negative effector in maize EC induction. Polymorphisms in the ZmSAUR15 promoter that influence the expression of ZmSAUR15 transcripts modulate the EC induction capacity in maize. ZmSAUR15 is involved in indole-3-acetic acid biosynthesis and cell division in immature embryo-derived callus. The ability of immature embryos to induce EC formation can be improved by the knockout of ZmSAUR15, which consequently increases the callus regeneration efficiency. Our study provides new insights into overcoming the genotypic limitations associated with EC formation and improving genetic transformation in maize.

Electrospun Cellulose Nanocrystals Reinforced Flexible Sensing Paper for Triboelectric Energy Harvesting and Dynamic Self-Powered Tactile Perception.

The technical synergy between flexible sensing paper and triboelectric nanogenerator (TENG) in the next stage of artificial intelligence Internet of Things engineering makes the development of intelligent sensing paper with triboelectric function very attractive. Therefore, it is extremely urgent to explore functional papers that are more suitable for triboelectric sensing. Here, a cellulose nanocrystals (CNCs) reinforced PVDF hybrid paper (CPHP) is developed by electrospinning technology. Benefitting from the unique effects of CNCs, CPHP forms a solid cross-linked network among fibers and obtains a high-strength (25 MPa) paper-like state and high surface roughness. Meanwhile, CNCs also improve the triboelectrification effect of CPHP by assisting the PVDF matrix to form more electroactive phases (96% share) and a higher relative permittivity (17.9). The CPHP-based TENG with single electrode configuration demonstrates good output performance (open-circuit voltage of 116 V, short-circuit current of 2.2 µA and power density of 91 mW m-2 ) and ultrahigh pressure-sensitivity response (3.95 mV Pa-1 ), which endows CPHP with reliable power supply and sensing capability. More importantly, the CPHP-based flexible self-powered tactile sensor with TENG array exhibits multifunctional applications in imitation Morse code compilation, tactile track recognition, and game character control, showing great prospects in the intelligent inductive device and human-machine interaction.

Constructing CoO/Mo2 C Heterostructures with Interfacial Electron Redistribution Induced by Work Functions for Boosting Overall Water Splitting.

Space charge transfer of heterostructures driven by the work-function-induced built-in field can regulate the electronic structure of catalysts and boost the catalytic activity. Herein, an epitaxial heterojunction catalyst of CoO/Mo2 C with interfacial electron redistribution induced by work functions (WFs) is constructed for overall water splitting via a novel top-down strategy. Theoretical simulations and experimental results unveil that the WFs-induced built-in field facilitates the electron transfer from CoO to Mo2 C through the formed "Co─C─Mo" bond at the interface of CoO/Mo2 C, achieving interfacial electron redistribution, further optimizing the Gibbs free energy of primitive reaction step and then accelerating kinetics of hydrogen evolution reaction (HER). As expected, the CoO/Mo2 C with interfacial effects exhibits excellent HER catalytic activity with only needing the overpotential of 107 mV to achieve 10 mA cm-2 and stability for a 60-h continuous catalyzing. Besides, the assembled CoO/Mo2 C behaves the outstanding performance toward overall water splitting (1.58 V for 10 mA cm-2 ). This work provides a novel possibility of designing materials based on interfacial effects arising from the built-in field for application in other fields.

The Nanoscale Wetting Parameter and Its Role in Interfacial Phenomena: Phase Transitions in Nanopores.

Through analysis of the statistical mechanical equations for a thin adsorbed film (gas, liquid, or solid) on a solid substrate or confined within a pore, it is possible to express the equilibrium thermodynamic properties of the film as a function of just two dimensionless parameters: a nanoscale wetting parameter, αw, and pore width, H*. The wetting parameter, αw, is defined in terms of molecular parameters for the adsorbed film and substrate and so is applicable at the nanoscale and for films of any phase. The main assumptions in the treatment are that (a) the substrate structure is not significantly affected by the adsorbed layer and (b) the diameter of the adsorbate molecules is not very small compared to the spacing of atoms in the solid substrate. We show that different surface geometries of the substrate (e.g., slit, cylindrical, and spherical pores) and various models of wall heterogeneity can be accounted for through a well-defined correction to the wetting parameter; no new dimensionless variables are introduced. Experimental measurements are reported for contact angles for various liquids on several planar substrates and are shown to be closely correlated with the nanoscale wetting parameter. We apply this approach to phase separation in nanopores of various geometries. Molecular simulation results for the phase diagram in confinement, obtained by the flat histogram Monte Carlo method, are reported and are shown to be closely similar to experimental results for capillary condensation, melting, and the triple point. The value of the wetting parameter, αw, is shown to determine the qualitative behavior (e.g., increase vs decrease in the melting temperature, capillary condensation vs evaporation), whereas the pore width determines the magnitude of the confinement effect. The triple point temperature and pressure for the confined phase are always lower than those for the bulk phase for all cases studied.

Enhanced Visible-Photocatalytic Activities in Strong Acids and Strong Alkalis of Flexible Iron-SrTiO3 Nanofibrous Membranes.

Traditional SrTiO3 (STO) materials have high brittleness and poor deformation resistance. In this work, macroscopically flexible iron-doped SrTiO3 (SFTO) nanofibrous membranes were prepared by electrospinning and calcination, which can be easily isolated and can maintain integrity to recycle as photocatalysts. Moreover, the SFTO nanofibrous membranes showed enhanced photocatalytic performance under strong acids (pH = 2) and strong alkalis (pH = 12). The SFTO nanofibrous membranes increased the catalytic rate of Congo red (CR) dye by about 10 times in visible light. The mechanism of photocatalytic activity enhancement was discussed by the combined effects of hydroxyl radicals and superoxide radicals. The successful preparation of SFTO nanofibrous membranes has offered a simple and economical approach to photocatalysis as well as environmental remediation.

Melatonin restores endoplasmic reticulum homeostasis to protect injured neurons in a rat model of chronic cervical cord compression.

Cervical spondylotic myelopathy (CSM) refers to a chronic injury of the cervical cord caused by cervical intervertebral disc degeneration. Endoplasmic reticulum (ER) homeostasis is essential to counteract neuronal apoptosis. ER stress, an integral part of ER homeostasis, was observed in a rat model of chronic cervical cord compression in our previous study. However, the correlation between ER homeostasis and CSM remains unknown. The antioxidant melatonin is known to exert therapeutic effects in acute spinal cord injury, but the specific effects and their potential mechanisms in the pathological processes of CSM require further exploration. The present study hypothesized that ER homeostasis is essential for neuronal apoptosis in the CSM and that melatonin maintains this homeostasis. The results showed that ER stress led to neuronal apoptosis in rats with chronic cervical cord compression. Conversely, melatonin attenuates protein kinase R-like ER kinase-eukaryotic initiation factor 2α-C/EBP-homologous protein, inositol-requiring enzyme 1, and transcription factor 6 signaling pathways to release ER stress and prevents Bax translocation to the mitochondrion, thereby promoting motor recovery and protecting neurons in vivo. It also rescued primary rat cortical neurons from ER stress-induced glutamate toxicity in vitro. Moreover, melatonin remodels the ER morphology and restores homeostasis via ER-phagy in injured neurons. FAM134B, CCPG1, RTN3, and Sec. 62 are four known ER-phagy receptors. In this study, Sec. 62 was identified as a key melatonin factor in promoting ER-phagy and restoring ER homeostasis in damaged neurons in vivo and in vitro. In conclusion, melatonin suppresses neuronal apoptosis by reducing ER stress and promoting ER-phagy to restore ER morphology and homeostasis. The current results suggested that melatonin is a promising treatment for CSM owing to its restorative effect on ER homeostasis; however, well-designed randomized controlled trials must be carried out to further investigate its clinical effects.

Shikonin inhibits neuronal apoptosis via regulating endoplasmic reticulum stress in the rat model of double-level chronic cervical cord compression.

Cervical spondylotic myelopathy (CSM) is a clinically symptomatic entity arising from the spinal cord compression by degenerative diseases. Although endoplasmic reticulum (ER) stress has been commonly observed in several neurodegenerative diseases, the relationship between ER stress and CSM remains unknown. Shikonin is known to protect PC12 by inhibiting apoptosis in vitro. This study hypothesised that ER stress was vital in neuronal apoptosis in CSM. Shikonin might inhibit such responses by regulating ER stress through the protein kinase-like ER kinase-eukaryotic translation initiation factor 2 α-subunit-C/EBP homologous protein (PERK-eIF2α-CHOP) signalling pathway. Thus, the aim of this study was evaluating the neuroprotective effect of shikonin in rats with double-level chronic cervical cord compression, as well as primary rat cortical neurons with glutamate-induced neurotoxicity. The result showed that ER stress-related upregulation of PERK-eIF2α-CHOP resulted in rat neuronal apoptosis after chronic cervical cord compression; then, shikonin promoted motor recovery and inhibited neuronal apoptosis by attenuating PERK-eIF2α-CHOP and prevented Bax translocation from cytoplasm to mitochondrion induced by CHOP of neurons in rats with chronic compression. Also, it was found that shikonin could protect rat primary cortical neuron against glutamate toxicity by regulating ER stress through the PERK-eIF2α-CHOP pathway in vitro. In conclusion, shikonin might inhibit neuronal apoptosis by regulating ER stress through attenuating the activation of PERK-eIF2α-CHOP.

Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.

Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase delta (DGKdelta) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKdelta protein and DGK kinase activity were restored upon correction of glycemia. DGKdelta haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions, was impaired in DGKdelta haploinsufficient mice. We reveal a previously unrecognized role for DGKdelta in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKdelta deficiency causes peripheral insulin resistance and metabolic inflexibility. These defects in glucose and energy homeostasis contribute to mild obesity later in life.