The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.
Humans ; Neoplasms/metabolism* ; Tumor Microenvironment/immunology* ; Lactic Acid/immunology* ; Warburg Effect, Oncologic ; Animals ; Glycolysis ; Epigenesis, Genetic

Objective:To discuss the effect of Compound Rehmannia Granules on intestinal flora of the pneumonia model rats induced by Streptococcus pneumoniae(Spn)through 16s rRNA sequencing technology,and to clarify its potential mechanism.Methods:A total of 30 rats were randomly divided into control group(normal rats),model group(Spn-induced pneumonia rat models),low dose of Compound Rehmannia Granules group(pneumonia rat models administered 1.75 g·kg-1 Compound Rehmannia Granules by gavage),medium dose of Compound Rehmannia Granules group(pneumonia rat models administered 3.50 g·kg-1 Compound Rehmannia Granules by gavage),and high dose of Compound Rehmannia Granules group(pneumonia rat model administered 7.00 g·kg-1 Compound Rehmannia Granules by gavage),with 6 rats in each group.The wet/dry weight(W/D)ratio of lung tissue and blood gas indexes were measured;HE staining was used to observe the pathomorphology and the degree of lung injury in lung tissue of the rats in various groups were assessed;kit assay was used to detect the bacterial load level and the levels of interleukin(IL)-6,IL-8,and IL-10 in bronchoalveolar lavage fluid(BALF)of the rats in various groups;16s rRNA intestinal flora sequencing analysis was performed.Results:Compared with control group,the arterial partial pressure of carbon dioxide(PaCO2)of the rats in model group was significantly increased(P<0.05),and the arterial partial pressure of oxygen(PaO2)and oxygen saturation(SaO2)were significantly decreased(P<0.05);compared with model group,the PaCO2 of the rats in low,medium,and high doses of Compound Rehmannia Granules groups was significantly decreased(P<0.05),and the PaO? and SaO?were significantly increased(P<0.05),showing a dose-dependent manner.The HE staining results showed no significant injury in lung tissue of the rats in control group;the cells in lung tissue of the rats in model group were arranged disorderly with massive inflammatory cell infiltration,and the alveolar wall capillaries were significantly dilated;compared with model group,the morphological damage of lung tissue of the rats in low,medium,and high doses of Compound Rehmannia Granules groups was improved.Compared with control group,the W/D value and pathological score of lung tissue of the rats in model group were significantly increased(P<0.05);compared with model group,the W/D value and pathological scores of lung tissue of the rats in low,medium,and high doses of Compound Rehmannia Granules groups were significantly decreased(P<0.05),showing a dose-dependent manner.Compared with control group,the bacterial load level in BALF of the rats in model group was significantly increased(P<0.05);compared with model group,the bacterial load level in BALF of the rats in low,medium,and high doses of Compound Rehmannia Granules groups was significantly decreased(P<0.05),showing a dose-dependent manner.Compared with control group,the levels of IL-6 and IL-8 in BALF of the rats in model group were significantly increased(P<0.05),and the IL-10 level was significantly decreased(P<0.05);compared with model group,the levels of IL-6 and IL-8 in BALF of the rats in low,medium,and high doses of Compound Rehmannia Granules groups were significantly decreased(P<0.05),and the IL-10 level was significantly increased(P<0.05),showing a dose-dependent manner.Compared with control group,the microbial abundance indicator(Chao1),microbial diversity and evenness indicator(Shannon),microbial dominance indicator(Simpson),and observed species indicator(observed_species)of the rats in model group were significantly decreased(P<0.05);compared with model group,the Chao1,Shannon,Simpson,and(observed_species)indices of the rats in low,medium,and high doses of Compound Rehmannia Granules groups were significantly increased(P<0.05),showing a dose-dependent manner.Compared with control group,the relative abundance of Bacteroidetes in model group was decreased,the relative abundance of Firmicutes was increased,and the Firmicutes/Bacteroidetes ratio was significantly increased(P<0.05);compared with model group,the relative abundances of Bacteroidetes in low,medium,and high doses of Compound Rehmannia Granules groups were increased,the relative abundance of Firmicutes was decreased,and the Firmicutes/Bacteroidetes ratio was significantly decreased(P<0.05),showing a dose-dependent manner.At the family level,compared with control group,the relative abundances of Corynebacteriaceae,Staphylococcaceae,and Moraxellaceae in model group were significantly increased,while the relative abundances of Lactobacillaceae,Lachnospiraceae,and Akkermansiaceae were significantly decreased;compared with model group,the relative abundances of Corynebacteriaceae,Staphylococcaceae,and Moraxellaceae in low,medium,and high doses of Compound Rehmannia Granules groups were significantly decreased,and the relative abundances of Lactobacillaceae,Lachnospiraceae,and Akkermansiaceae were significantly increased.At the genus level,compared with control group,the relative abundances of Desulfovibrio and Facklamia in model group were significantly increased,and the relative abundances of Bifidobacterium and Ruminococcaceae were significantly decreased;compared with model group,the relative abundances of Desulfovibrio and Facklamia in low,medium,and high doses of Compound Rehmannia Granules groups were significantly decreased,and the relative abundances of Bifidobacterium and Ruminococcaceae were significantly increased.Conclusion:Compound Rehmannia Granules can alleviate inflammation and lung injury in Spn-induced pneumonia rats,which may be related to the increase in the abundance and diversity of intestinal flora.

Objective To observe the clinical efficacy of acupotomy release therapy under the theory of sinew channels in the treatment of femoral head necrosis.Methods A total of 82 patients diagnosed with femoral head necrosis who underwent hip-preserving treatment at Beijing Hepingli Hospital from May 2020 to May 2023 were selected as the study subjects.The patients were randomly divided into an observation group and a control group using a random number table,with 41 patients in each group.The control group received hip joint rehabilitation training combined with sinew channel massage therapy,while the observation group received acupotomy release therapy under the theory of sinew channels in addition to the treatment given to the control group.for 6 months of treatment.Changes in the Visual Analogue Scale(VAS)scores of pain,hip joint range of motion,and Harris scores were observed before and after treatment.Additionally,serum levels of 5-hydroxytryptamine(5-HT),substance P(SP),calcitonin gene-related peptide(CGRP),and neuropeptide Y(NPY)were compared between the two groups before and after treatment.Results(1)After treatment,the VAS scores of both groups were significantly improved(P＜0.05),and the observation group showed significantly better improvement in VAS scores compared to the control group,with a statistically significant difference(P＜0.05).(2)After treatment,the hip joint range of motion improved significantly in both groups(P＜0.05),and the observation group showed significantly better improvement in hip joint range of motion compared to the control group,with a statistically significant difference(P＜0.05).(3)After treatment,the excellent and good rate of hip joint function in the observation group was 95.12%(39/41),while it was 78.05%(32/41)in the control group.The observation group had a significantly higher excellent and good rate of hip joint function compared to the control group,with a statistically significant difference(P＜0.05).(4)After treatment,the levels of 5-HT,SP,CGRP,and NPY improved significantly in both groups(P＜0.05),and the observation group showed significantly better improvement in these levels compared to the control group,with a statistically significant difference(P＜0.05).Conclusion Acupotomy release therapy under the theory of sinew channels in the treatment of femoral head necrosis can significantly alleviate pain symptoms and improve hip joint function in patients.Its analgesic mechanism may be related to the regulation of neurotransmitter levels and the restoration of their balance.

Objective: To explore the relationship between the ratio of dietary vitamin A (VitA) to body weight and hypertension among children, so as to provide a reference for blood pressure control through dietary nutritional interventions and childhood hypertension prevention. Methods: Utilizing the baseline survey and followup sample data from the Healthy Children Cohort established in urban and rural areas of Chongqing from 2014 to 2019, structured quantitative dietary questionnaire and selfdesigned questionnaire were used to investigate the information of dietary intake and socioeconomic characteristics of 15 279 children, as well as blood pressure, height, weight measurement. The ratio of dietary VitA to body weight was divided into four groups based on quartiles [≤P25(Q1), >P25~P50(Q2), >P50~P75(Q3), >P75(Q4)]. Generalized linear regression models and Logistic regression models were used to analyze the correlation between ratio of dietary VitA to body weight with blood pressure levels and prevalence of hypertension. Results: The results of the 2014 baseline survey indicated that, after adjusting for confounding factors such as demographic indicators and nutritional intake, significant differences were observed in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) among different groups categorized by the ratio of dietary VitA to body weight (F=157.57, 44.71, 95.92, P<0.01). The baseline ratio of dietary VitA to body weight in children exhibited a negative correlation with DBP, SBP and MAP at baseline and in 2019[baseline: β(95%CI)=-0.65(-0.89--0.42), -0.22(-0.42--0.01), -0.36(-0.56--0.16); 2019: β(95%CI)=-0.77(-1.34--0.19), -0.62(-1.21--0.02), -0.77(-1.34--0.19), P＜0.05]. Compared to Q1 group, the risk of hypertension decreased among children in Q4 at baseline and followup in 2019 [OR(95%CI)=0.63(0.49-0.81), 0.18(0.08-0.42), P<0.01]. Conclusions The ratio of dietary VitA to body weight is significantly negatively correlated with blood pressure levels among children, and dietary VitA deficiency is an independent risk factor for hypertension among children. Measures should be taken to actively adjust childrens dietary nutrition and reduce the risk of childhood hypertension.

Objective To observe the effect of Qixian Tongluo Formula on contralateral corticospinal tract(CST)remodeling and motor functional recovery in rats with cerebral infarction,and to explore its potential molecular mechanism from the perspective of regulating factors related to never remodeling.Methods The rat middle cerebral artery occlusion(MCAO)model was established by silk thread ligation.Fifty model rats were randomly divided into model group,citicoline group(0.054 g·kg-1),Qixian Tongluo Formula low-,medium-and high-dose(7.83,15.66,31.32 g·kg-1)groups,and sham operation group,with 10 rats in each group.The intervention administration was started on the 3rd day after operation once a day for 26 consecutive days.On the 3rd,14th and 28th day after operation,the gross motor function was evaluated by Longa score,and the fine motor function was evaluated by beam-walking test(BWT)score.The contralateral motor cortex was injected with the nerve tracer biotin dextran amine(BDA)on the 14 th day after operation to anterogradely trace the CST.On the 28th day after operation,the expression of axonal growth associated protein-43(GAP-43)and BDA positive fibers in the contralateral motor cortex and cervical spinal cord were detected by immunohistochemistry.The co-localization areas of BDA positive fibers and presynaptic marker protein vesicular glutamate transporter 1(VGLUT1)in the cervical spinal cord gray matter were detected by immunofluorescence.The expressions of brain-derived neurotrophic factor(BDNF),glial cell-derived neurotrophic factor(GDNF),nerve growth factor(NGF)and nerve remodeling-associated inhibitory factor[Nogo-A,oligodendrocyte myelin glycoprotein(OMgp)and myelin-associated glycoprotein(MAG)]in the contralateral motor cortex were detected by Western Blot.Pearson correlation analysis was used to analyze the correlation between Longa score or BWT score and BDA/VGLUT1 co-localization area,respectively.Results Compared with the sham operation group,rats in the model group had obvious symptoms of motor function deficits,and the Longa scores were significantly increased(P＜0.01)and the BWT scores were significantly decreased(P＜0.05,P＜0.01)at each time point.The expression of GAP-43 in the contralateral motor cortex and cervical spinal cord was up-regulated(P＜0.05),the number of edge-crossing fibers from the posterior funiculus in cervical cord was increased(P＜0.05),the co-localization area of BDA/VGLUT1 in the gray matter of the cervical spinal cord was increased(P＜0.05),the expressions of BDNF,GDNF and NGF in the contralateral motor cortex were up-regulated(P＜0.05),while the expressions of Nogo-A,OMgp and MAG were down-regulated(P＜0.05).Compared with the model group,the Longa scores in each administration group on the 14th and 28th day after MCAO operation were significantly decreased(P＜0.01),the BWT scores were significantly increased(P＜0.01),the expression of GAP-43 in the contralateral motor cortex and cervical spinal cord was significantly up-regulated(P＜0.01).The number of edge-crossing fibers from the posterior funiculus in cervical cord was significantly increased(P＜0.01),the co-localization area of BDA/VGLUT1 in the gray matter of the cervical spinal cord was significantly increased(P＜0.01).The expressions of BDNF,GDNF and NGF in the contralateral motor cortex were significantly up-regulated(P＜0.01,P＜0.05),while the expressions of Nogo-A,OMgp and MAG were significantly down-regulated(P＜0.05),and the most significant effect was observed in the high dose group.The Longa score was negatively correlated with the co-localization area of BDA/VGLUT1(r=-0.89,P＜0.01),and the BWT score was positively correlated with the co-localization area of BDA/VGLUT1(r=0.84,P＜0.01).Conclusion Qixian Tongluo Formula can improve motor function through promoting contralateral CST remodeling in MCAO rats after cerebral infarction,and the molecular mechanism may be related to the regulation of the expression of nerve remodeling-associated factor in the contralateral motor cortex.

Objective To identify the pathogenic bacteria such as Staphylococcus aureus and Enterococcus faecalis in bloodstream infec-tions with high confidence based on three deep learning models such as GoogleNet,ResNet101,and Vgg19,compare the performance and classification ability of these models,and explore the feasibility of applying the deep learning models for the rapid identification of pathogenic bacteria in bloodstream infections.Methods The preprocessed Gram-stained bacterial images,including 1 682 images for Staphylococcus aureus and 1 723 for Enterococcus faecalis,and 688 blank control microscopic images were input into three models for training and validation,respectively.Among them,1 344 images for Staphylococcus aureus,1 376 for Enterococcus faecalis,and 544 blank control images were used for training,and the remaining images were used for validation.The model with the best performance was identified according to the classification parameters between the models.Results The ResNet101 model had the lowest cross-en-tropy loss value(0.008 710 3),the largest Epoch value(93),and the highest accuracy rate(99％)for identifying the three types of validation set images.The cross-entropy loss value,Epoch value,and accuracy rate of the GoogleNet model were 0.063 89,86 and 98.6％,respectively,for identifying the three types of validation set images.Those of the Vgg19 model were 0.035 682,86 and 97.7％,respectively.Conclusion The ResNet101 model has the best performance in the classification of three kinds of images.The deep learning model may accurately,reliably and rapidly identify the Gram-stained images of pathogenic bacteria such as Staphylococcus aureus and Enterococcus faecalis in bloodstream infections.

Hepatocellular carcinoma(HCC),one of the most prevalent malignant tumors causing the highest mortality globally,imposes an especially heavy burden of disease in China.Individuals living in high-altitude areas have a lower incidence of and mortality resulting from HCC compared with those in low-altitude regions do,potentially due to adaptive evolution in responses to hypoxic stress.Notably,high-altitude hypoxic stress is associated with the development and progression of HCC.Hypoxic stress may be involved in the development and progression of HCC by modulating the senescence,apoptosis,metabolism,tumor microenvironment,and tumor immunity of HCC cells.Additionally,the latest clinical findings indicate that high-altitude hypoxic environment has a significant impact on liver regeneration after HCC resection surgery.However,there is still a debate going on regarding whether high-altitude hypoxic stress promotes or inhibits the progression of HCC.This review covers three main aspects,the impact of adaptive evolution to high-altitude hypoxic stress on the development and progression of HCC in long-term residents of high-altitude areas,the effects of high-altitude hypoxic stress on the senescence,apoptosis,metabolism,tumor microenvironment,tumor metabolism,and tumor immunity of HCC cells,and the effect of high-altitude hypoxic stress on liver regeneration after HCC resection.We discussed the effect of changes in oxygen concentrations,cellular context,and tissue microenvironment on HCC development and progression.Moreover,we highlighted the potential for using research findings on mechanisms underlying high-altitude hypoxic stress to optimize HCC treatment strategies.

Six new ent-abietane diterpenoids, abientaphlogatones A-F (1-6), along with two undescribed ent-abietane diterpenoid glucosides, abientaphlogasides A-B (7-8) and four known analogs were isolated from the aerial parts ofPhlogacanthus curviflorus (P. curviflorus). The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD) spectra, and quantum chemical calculations. Notably, compounds 5 and 6 represented the first reported instances of ent-norabietane diterpenoids from the genus Phlogacanthus. In the β-hematin formation inhibition assay, compounds 2, 4, 7-10, and 12 displayed antimalarial activity, with IC₅₀ values of 12.97-65.01 μmol·L^-1. Furthermore, compounds 4, 5, 8, and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H₂O₂ and MPP⁺.
Abietanes/pharmacology* ; Antimalarials ; Hydrogen Peroxide ; Biological Assay ; Plant Components, Aerial

Abstract OBJECTIVE To optimize the extraction process of Guiqi Yiyuan decoction and establish its quality control method. METHODS L9(34) orthogonal test was used to optimize the extraction process of Guiqi Yiyuan decoction by using index as comprehensive evaluation of the extraction rate, total polysaccharide content and n-butanol extract content. Thin layer chromatography(TLC) was used to identify Astragali Radix, Angelicae Sinensis Radix, Lycii Fructus and Ginseng Radix et Rhizoma in the decoction. The content of glucoside of calycosin as the main active ingredient of Astragali Radix was determined by HPLC. The differences in relative density, insoluble matter and loading amount were checked according to the Chinese Pharmacopoeia 2020 edition, and the quality control method was established. RESULTS The optimum process was 12 times water, 4 h extraction time and 2 times extraction. TLC identification results showed that the chromatograms had clear spots, good separation and strong specificity. The linear range of calycosin glucoside was 0.089 6-1.344 0 µg(r2=0.999 4), the average recovery was 99.51%, RSD was 2.59%(n=9). The relative density of decoction was 1.39, and the difference of insoluble matter and loading amount was in accordance with the provisions of Chinese Pharmacopoeia 2020 edition. CONCLUSION The optimized water extraction process is scientific and reasonable, and the quality standard is effective and controllable, which can be used for the quality control of Guiqi Yiyuan decoction.

Objective:To explore the construction of evaluation criteria for long-term care ability of the elderly suitable for China's national conditions.Methods:The evaluation criteria were initially established through literature research and field semi-structured interviews. Through the Delphi method, 15 experts were consulted and the evaluation criteria for the long-term care ability of the elderly were finally established.Results:The effective rate of the two rounds of expert consultation questionnaires was 100%, and the expert authority coefficients were 0.91 and 0.92 respectively. The evaluation criteria for long-term care ability of the elderly were established, including two first-level indicators of self-care ability and disease severity, four second-level indicators of abilities of daily living, mental state and social participation, perception and communication, and disease severity, as well as 39 third-level indicators including recumbent status, cognitive function, level of consciousness, illness and so on.Conclusions:The evaluation criteria for long-term care ability of the elderly are scientific and reliable, which can provide a reference for the classification of long-term care services for the disabled elderly in China.