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The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao’s research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.

Background Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. Methods Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. Results In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. Conclusions Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by chronic excessive alcohol consumption. In this study, the effect of astaxanthin, a marine bioactive compound, on acetaldehyde-induced cytotoxicity was investigated in SH-SY5Y cells. It was found that astaxanthin protected cells from apoptosis by ameliorating the effect of acetaldehyde on the expression of Bcl-2 family proteins, preventing the reduction of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bak induced by acetaldehyde. Further analyses showed that astaxanthin treatment inhibited acetaldehyde-induced reduction of the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). Astaxanthin treatment also prevented acetaldehyde-induced increase of the level of activated p38 mitogen-activated protein kinase (MAPK) and decrease of the level of activated extracellular signal-regulated kinases (ERKs). Activation of Akt/CREB pathway promotes cell survival and is involved in the upregulation of Bcl-2 gene. P38MAPK plays a critical role in apoptotic events while ERKs mediates the inhibition of apoptosis. Thus, astaxanthin may inhibit acetaldehyde-induced apoptosis through promoting the activation of Akt/CREB and ERKs and blocking the activation of p38MAPK. In addition, astaxanthin treatment suppressed the oxidative stress induced by acetaldehyde and restored the antioxidative capacity of SH-SY5Y cells. Therefore, astaxanthin may protect cells against acetaldehyde-induced cytotoxicity through maintaining redox balance and modulating apoptotic and survival signals. The results suggest that astaxanthin treatment may be beneficial for preventing neurotoxicity associated with acetaldehyde and excessive alcohol consumption.

Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare, severe developmental and epileptic encephalopathies with poor prognosis, and novel drugs are urgently needed to meet clinical needs. CYP46A1 (cholesterol 24-hydroxylase, CH24H) is mainly responsible for the metabolism of cholesterol to 24(S)-hydroxycholesterol in the brain and is implicated in many brain disorders through the mediation of excitatory amino acid transporter 2 (EAAT2) and N-methyl-D-aspartate (NMDA) receptors. Inhibition of CYP46A1 is supposed to provide a novel treatment for disorders associated with neural hyperexcitation, such as epilepsy and epileptic syndromes. Soticlestat, a potent CYP46A1 inhibitor being developed by Takeda, is indicated for LGS and DS but suffers from unsatisfactory in vivo potency in animal models and clinical trials. We designed three series of soticlestat derivatives to explore the structure–activity relationship (SAR) with the aim of finding more potent CYP46A1 inhibitors and understanding the SAR of CYP46A1 inhibitors represented by soticlestat. Eventually, three compounds with a benzenesulfonamide moiety (in subseries C-4) that serves as an isostere of OH in soticlestat were discovered with very potent CYP46A1 inhibitory activities comparable to soticlestat, and an interesting flat SAR profile was observed in some subseries. The findings in the present study provide insight into the SAR of CYP46A1 inhibitors and should be valuable for the future design of novel CYP46A1 inhibitors.

Ten-year measurements of lightning and relative humidity from 2002 - 2011 have been analyzed in the Nanjing city, China. Statistical analysis shows the lightning density is positively correlated to relative humidity during this period. To further investigate the effect of relative humidity on electrification and lightning discharges in thunderstorms, a two-dimensional cumulus model incorporating dynamics, microphysics, and thunderstorm electrification mechanisms is used to present a sensitive study. The results show that the higher relative humidity in surface leads to more cloud droplet and stronger updraft, because of enhanced latent heat releasing from increasing condensation. Greater updraft and cloud water content primarily contribute to stronger ice crystal and graupel particles production with increasing relative humidity. A greater formation of cloud droplet, graupel and ice crystal result in increasing charge separation via non-inductive and inductive mechanism. The total lightning flashes increase as the relative humidity increase from 60 - 90%, and only tests with high relative humidity of 90% can produce negative cloud to ground (CG) flashes and positive CG flashes. In addition, the increase of relative humidity condition generally leads to a quicker and stronger convection, which results in earlier electrification and lightning discharges in thunderstorm.

The synthesis of racemic trans -taxifolin ( trans -(±)-taxifolin) and its derivatives and subsequent chiral separation is the most prevalent chemical method to obtain enantiomerically pure taxifolin and its derivatives. The development of an economical and practical synthetic route to trans -(±)-taxifolin, a key precursor to the enantiomerically pure trans -taxifolin, is therefore of great importance and significance. In this work, we developed a new synthetic method for trans -(±)-taxifolin and its derivatives with 2,4,6-trihydroxyacetophenone as a starting material undergoing hydroxy protection, α-bromination, construction of α,β-epoxy carbonyl products via the Darzens reaction, acid-mediated deprotection, and cyclization to afford the target compounds. This method is highlighted by satisfactory overall yields (20–41%) and proceeds without the use of explosive peroxides (such as H 2 O 2 ), which are commonly employed in methods reported earlier. The avoidance of explosive peroxides in the present method enables safe operation, easy scale-up, and also the synthesis of taxifolin derivatives with oxidant-sensitive groups, largely expanding the substituent scope compared with the previous method.

Macrophages hold a critical position in maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated β-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-β release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p/TBP promotes β-TrCP/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.

The effect of aerosols on lightning has been noted in many studies, but much less is known about the long-term impacts in air-polluted urban areas of China. In this paper, 9-year data sets of cloud-to-ground (CG) lightning, aerosol optical depth (AOD), convective available potential energy (CAPE), and surface relative humidity (SRH) from ground-based observation and model reanalysis are analyzed over three air-polluted urban areas of China. Decreasing trends are found in the interannual variations of CG lightning density (unit: flashes km−2day−1) and total AOD over the three study regions during the study period. An apparent enhancement in CG lightning density is found under conditions with high AOD on the seasonal cycles over the three study regions. The joint effects of total AOD and thermodynamic factors (CAPE and SRH) on CG lightning density and the percentage of positive CG flashes (+CG flashes/total CG flashes × 100; PPCG; unit: %) are further analyzed. Results show that CG lighting density is higher under conditions with high total AOD, while PPCG is lower under conditions with low total AOD. CG lightning density is more sensitive to CAPE under conditions with high total AOD.

IntroductionCommercial automatic planning modules are currently limited to single, conventional disease types, which severely restricts their utility when dealing with unconventional plans. Given that such unconventional plans are actually the norm in most hospitals, there is an urgent need for an automatic planning algorithm that can be applied to a wide range of clinical situations. To address this issue, we developed an algorithm capable of automatically cropping target areas and setting optimization conditions for multiple diseases, known as the Auto Crop and Optimization Setup Algorithm (ACOSA). This paper presents the principles of ACOSA and conducts a preliminary comparative evaluation of its performance against existing solutions.MethodsThe development of ACOSA utilized the Eclipse Script Application Programming Interface (ESAPI) scripting language provided by Eclipse. Based on the input prescriptions, the algorithm simulates the operations of a physicist, automatically crops the target areas, and sets appropriate optimization parameters. Retrospectively, 20 cases of glioma and head and neck cancers were selected. Without considering organ-at-risk dose limits, dose calculations were performed using both ACOSA and Eclipse's built-in AutoCrop, and a dosimetric comparison was conducted.ResultsIn terms of target volume homogeneity index ( ) and D98, the AutoCrop group demonstrated slight superiority over the ACOSA group. However, the ACOSA group exhibited superior performance in conformity index ( ), gradient index ( ), , and particularly in parameters reflecting the rate of low-dose fall-off outside the target volume, including , , and , when compared to the AutoCrop group.ConclusionsACOSA can be reliably applied in clinical settings and demonstrates superiority over the AutoCrop module of the Eclipse planning system.

Background Mitochondrial dynamics play a critical role in the proper functioning of both the innate and adaptive immune systems. Coiled-coil domain-containing 58 (CCDC58), a mitochondrial-related gene, has been implicated in various diseases, including cancer and infections. However, its predictive value in immune cell infiltration in hepatocellular carcinoma (HCC) remains unexplored. Methods In this study, RNA-seq data from The Cancer Genome Atlas and multiple online datasets were analyzed to explore the correlation between CCDC58 and clinicopathological features, prognosis, related signaling pathways and immune cell infiltration in HCC. Furthermore, primary T cells were isolated and cell experiments such as cytotoxic assays and transwell assays were conducted to verify pivotal conclusions. Results We found that CCDC58 expression levels were significantly increased in HCC tissues. High CCDC58 expression in HCC tissues was significantly correlated with the patients’ TNM stage, histologic grade, AFP level, tumor status, and poor clinical outcomes. Furthermore, the high expression of CCDC58 conferred a decreased immune activated phenotype and poor immune cell infiltration, and was strongly associated with expression of immune cell exhaustion markers in HCC. After the knockdown of CCDC58 in HCC cell lines, we observed that cytotoxicity of primary T cells increased via decreasing PD-1 expression on T cells and migration ability of primary T cell enhanced. Conclusion Our study indicated that CCDC58 might serve as a potential predictive biomarker of immune cell infiltration in HCC and is correlated with poor prognosis in HCC patients.