PGC-1α activation ameliorates cancer-induced bone pain via inhibiting apoptosis of GABAergic interneurons.

Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.

Causal pathway from telomere length to occurrence and 28-day mortality of sepsis: an observational and mendelian randomization study.

BACKGROUND: Telomeres are considered to be a physiological marker of aging. Elucidating relationship between telomere length and sepsis is an essential step towards understanding the biological processes involved in sepsis and its salvation. Mendelian randomization studies based on SNPs have given us new insights into genetic susceptibility to disease. OBJECTIVES: To explore the causal pathway from telomere length to occurrence and 28-day mortality of sepsis. METHODS: Leveraging genetic information resource of UK Biobank, we captured three groups of large-scale GWAS data: leukocyte telomere length (LTL), sepsis and all-cause death of 28-day. Study design consisted of three parts: forward analysis, reverse analysis and one-way analysis. Genetic instrumental variables were selected for different analyses under the premise that three MR core assumptions were satisfied. Causality was determined by means of IVW. RESULTS: In forward analysis, we did not observe a significant causal pathway from sepsis to LTL under IVW model: ß (SE) was -0.0051 (0.0075) with a p-value of 0.499. In reverse analysis, based on the IVW model, the OR (95% CI) was 0.89 (0.80-0.99) and the p-values was 0.043; based on the results of leave out method and single SNP analysis, we obtained seven key SNPs. There were results of IVW model in the one-way analysis: ß (SE) was -0.0287(0.1261). CONCLUSIONS: Short LTL increases susceptibility to sepsis, but sepsis does not shorten telomere length. LTL does not affect sepsis 28-day all-cause mortality and does not serve as a causal intermediate in gene regulation during the progression of sepsis to 28-day death.

ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation.

Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these processes is poorly understood. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is activated upon UNC-51-like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients are scarce and promotes lactate production. Lactate connects autophagy and glycolysis through Vps34 lactylation (at lysine-356 and lysine-781), which is mediated by the acyltransferase KAT5/TIP60. Vps34 lactylation enhances the association of Vps34 with Beclin1, Atg14L, and UVRAG, and then increases Vps34 lipid kinase activity. Vps34 lactylation promotes autophagic flux and endolysosomal trafficking. Vps34 lactylation in skeletal muscle during intense exercise maintains muscle cell homeostasis and correlates with cancer progress by inducing cell autophagy. Together, our findings describe autophagy regulation mechanism and then integrate cell autophagy and glycolysis.

Regional block techniques for pain management after video-assisted thoracoscopic surgery: a covariate-adjusted Bayesian network meta-analysis.

Introduction: Nerve block is widely used for pain management after video-assisted thoracoscopic surgery (VATS). Thoracic paravertebral block (TPVB), erector spinae plane block (ESPB), serratus anterior plane block (SAPB), and intercostal nerve block (ICNB) are alternative treatments. Material and methods: Network meta-analysis based on Bayesian analyses was performed to obtain results for direct comparison, indirect comparison, and network comparison, and to make rankings based on probabilities. Covariates were adjusted to determine the effect of the covariates on results of this study. Results: The study identified 61 randomized controlled trials (RCTs) (4468 patients). There were results of probability ranking for the first ("best" treatment): 24 h morphine consumption, TPVB > ESPB > ICNB > SAPB. Covariate adjustment allowed the four treatments to change somewhat in the likelihood of the best choice. Conclusions: TPVB ranks best in our analysis. ESPB is a viable alternative. SAPB and ICNB seem to play a limited role in postoperative pain management.

Near Room-Temperature Synthesis of Vertical Graphene Nanowalls on Dielectrics.

Vertical graphene nanowalls (VGNs) with excellent heat-transfer properties are promising to be applied in the thermal management of electronic devices. However, high growth temperature makes VGNs unable to be directly prepared on semiconductors and polymers, which limits the practical application of VGNs. In this work, the near room-temperature growth of VGNs was realized by utilizing the hot filament chemical vapor deposition method. Catalytic tantalum (Ta) filaments promote the decomposition of acetylene at ∼1600 °C. Density functional theory calculations proved that C2H* was the main active carbon cluster during VGN growth. The restricted diffusion of C2H* clusters induced the vertical growth of graphene nanoflakes on various substrates below 150 °C. The direct growth of VGNs successfully realized the excellent interfacial contact, and the thermal contact resistance could reach 3.39 × 10-9 m2·K·W-1. The temperature of electronic chips had a 6.7 °C reduction by utilizing directly prepared VGNs instead of thermal conductive tape as thermal-interface materials, indicating the great potential of VGNs to be directly prepared on electronic devices for thermal management.

Porous loofah-sponge-like ternary heterojunction g-C3N4/Bi2WO6/MoS2 for highly efficient photocatalytic degradation of sulfamethoxazole under visible-light irradiation.

A novel porous loofah-sponge-like ternary heterojunction g-C3N4/Bi2WO6/MoS2 (CN-BM) was prepared via a facile method. The introduction of binary Bi2WO6/MoS2 into g-C3N4 could be qualified for constructing reasonable heterostructure while regulating photocatalysts morphology. Benefiting from the unique structure, the ternary heterojunction composites not only inhibited the agglomeration but also exhibited the prominent visible-light harvest capacity and abundant active sites, which could accelerate the photogenerated carriers separation and preserve the robust redox ability. The results showed that the optimized sample (CN-BM2) displayed the excellent degradation efficiency of sulfamethoxazole (SMX) under visible-light irradiation (over 99% within 60 min), and the fitted pseudo-first-order kinetic rate constant reached to 0.089 min-1, where it was 3.17 times than that of pure CN. Additionally, the radical scavenger experiments and electron spin resonance experiments indicated that the active species super-oxide radical and hole played a major role in the degradation experiment. The charge transfer mechanism was proposed and the main intermediates indicated that the active radicals attacked on the benzene ring and isoxazole ring in SMX, and further mineralized to inorganic molecules eventually.