Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

The mechanism of improved intracellular organic selenium and glutathione contents in selenium-enriched Candida utilis by acid stress.

Batch culture of Candida utilis CCTCC M 209298 for the preparation of selenium (Se)-enriched yeast was carried out under different pH conditions, and maximal intracellular organic Se and glutathione (GSH) contents were obtained in a moderate acid stress environment (pH 3.5). In order to elucidate the physiological mechanism of improved performance of Se-enriched yeast by acid stress, assays of the key enzymes involved in GSH biosynthesis and determinations of energy supply and regeneration were performed. The results indicated that moderate acid stress increased the activity of γ-glutamylcysteine synthetase and the ratios of NADH/NAD+ and ATP/ADP, although no significant changes in intracellular pH were observed. In addition, the molecular mechanism of moderate acid stress favoring the improvement of Se-yeast performance was revealed by comparing whole transcriptomes of yeast cells cultured at pH 3.5 and 5.5. Comparative analysis of RNA-Seq data indicated that 882 genes were significantly up-regulated by moderate acid stress. Functional annotation of the up-regulated genes based on gene ontology and the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway showed that these genes are involved in ATP synthesis and sulfur metabolism, including the biosynthesis of methionine, cysteine, and GSH in yeast cells. Increased intracellular ATP supply and more amounts of sulfur-containing substances in turn contributed to Na2SeO3 assimilation and biotransformation, which ultimately improved the performance of the Se-enriched C. utilis.

Myotomy of Distal Esophagus Influences Proximal Esophageal Contraction and Upper Esophageal Sphincter Relaxation in Patients with Achalasia After Peroral Endoscopic Myotomy

BACKGROUND/AIMS: The motility change after peroral endoscopic myotomy (POEM) in achalasia is currently focused on lower esophageal sphincter (LES). This study aims to investigate the correlation of motility response between distal and proximal esophagus after POEM. METHODS: A total of 32 achalasia patients who received POEM and high-resolution manometry (HRM) were included for analysis. Eckardt score was used to assess symptom improvement. HRM was applied for studying motility. Main parameters analyzed were (1) LES: resting pressure (restP), 4-second integrated relaxation pressure; (2) esophageal body (EB): contractile integral of distal segment with myotomy (CI-DM) and proximal segment without myotomy (CI-PNM); and (3) upper esophageal sphincter (UES): relaxation pressure (UES-RP). RESULTS: There were 6 type I, 17 type II, and 9 type III achalasia patients included for analysis. (1) Eckardt score, LES tone, CI-DM, CI-PNM and UES-RP were reduced remarkably after POEM (P < 0.001). (2) no significant correlation was noted between LES tone and contractile intergral of EB. (3) a positive linear correlation of CI-DM and CI-PNM changes was detected (P < 0.001). (4) the change of UES-RP was positively correlated with the change of contractile integral of EB (P < 0.001). CONCLUSIONS: Myotomy of the distal esophagus would attenuate proximal EB contraction and assist UES relaxation in achalasia patients after POEM.

Identification of plants in Mussaenda L. based on DNA barcoding / 中草药

This study aims at developing fast and accurate species identification methods for the plants of Mussaenda L. In the present study, DNA barcoding analysis was carried out on 89 individuals representing 20 species of Mussaenda in order to evaluate the performance of the four candidate barcoding loci (matK, rbcL, trnH-psbA, and ITS) and ITS2 region. Based on sequence similarity and Neighbor-joining (NJ) tree reconstruction, we detected inter-and intra-specific genetic distances using Kimura 2-parameter (K2P). Inter-specific genetic distance of species in Mussaenda was significantly higher than intra-specific genetic distance. The region of ITS2 showed the highest discrimination power among the independent sequences. Comparably high species discrimination power was also revealed by the matK and ITS data set. The candidate barcode of rbcL displayed the lowest identification rate among the others. However, each individual candidate barcode demonstrated significantly lower discrimination power than the barcode of combined data set. Comparable discrimination power was revealed between the two barcodes of combined sequences matK + rbcL + ITS and matK + rbcL + trnH-psbA + ITS, which showed the values around 77% and 75% based on sequence similarity and NJ tree method. Totally 15 species were identified based on NJ analysis of matK + rbcL + ITS. Consequently, the combined sequence of matK + rbcL + ITS provides an effective and fast tool for the identification and authentication of medicinal plant species in the genus Mussaenda L.

Effect of Modified Baizhu Powder on Gastrointestinal Functions in Mouse Models with Stomach-cold Functional Dyspepsia / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the effect of modified Baizhu (Rhizoma Atractylodis Macrocephalae) powder on the gastrointestinal function in mouse models with stomach-cold functional dyspepsia. Meanwhile,the mouse models were administered with Shihu (dendrobium), a traditional Chinese drug with cold nature and flavour, to explore the way via which it exert its effect on specific symptoms. Methods: Mouse models with stomach-cold functional dyspepsia were established by ice water and ice NaOH. The effects of modified Baizhu powder and dendrobium on mice were observed in terms of water intake, weight change,small intestine propulsion rate, intestinal absorption function, and effects on ghrelin and motilin.</p><p><b>RESULTS</b>The modified Baizhu powder effectively increased food intake, water intake, body weight (P<0.05) and swimming time (P<0.01), increased the small intestine propulsion rate and serum D-xylose content (P<0.05), and up-regulated ghrelin (P<0.05). Also, it showed a trend to down-regulate the motilin, although the change was not statistically significant (P>0.05). In contrast,the use of Shihu aggravated symptoms in the mouse models. Conclusion: The changes in ghrelin and motilin levels may be the neuro-endocrine mechanisms via which the modified Baizhu powder and Shihu exert their effects on mouse models.</p>

The antioxidant effects of garlic saponins protect PC12 cells from hypoxia-induced damage.

Hypoxia frequently occurs under several different cellular circumstances. Excess reactive oxygen species that are induced by hypoxia may result in cell injury and dysfunction. Recently, garlic has been found to possess some biological and pharmacological activities. The present study examined the effects of garlic saponins (GSP) on the survival of differentiated PC12 (dPC12) cells and the oxidative-antioxidant system. dPC12 cells were exposed to 2 % O2 in order to establish a neuronal insult model. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay and lactate dehydrogenase (LDH) release assay. The expression of selected genes (catalase (CAT), p65 and neuron-specific class III ß-tubulin) was evaluated by real-time PCR and immunoblot assays. CAT activity, malondialdehyde (MDA) and 8-hydroxy-deoxyguanosine (8-OH-dG) concentrations were also determined. The data showed that hypoxia dramatically damaged dPC12 cells, while treatment with approximately 5 × 10- 2-10 ng/ml GSP improved cell viability, decreased LDH leakage and caused the cells to maintain neuronal-like characteristics in hypoxia. The production of MDA and 8-OH-dG was attenuated by GSP. CAT activity in dPC12 cells pretreated with GSP was higher than that of the hypoxic control. Moreover, GSP up-regulated CAT expression and decreased the total protein expression as well as the nuclear expression of p65 in hypoxic cells. These data indicate that GSP has antioxidant properties that can protect dPC12 cells from hypoxia-induced damage, which may be related to the up-regulation of CAT expression and activity as well as a decrease in the expression and nucleus distribution of p65 through effects on redox-sensitive signalling pathways.

[QTL analysis of low-temperature-sensitive pollen sterility in Indica-japonica hybrid rice (Oryza sativa L.)].

There existed a number of biological constraints in exploiting the heterosis of indica-japonica hybrid rice. The low-temperature-sensitive sterility (LTSS) of indica-japonica hybrid has become one of the major problems in indica-japonica hybrid rice breeding after the solution of poor fertility of the hybrids by the finding of wide-compatibility gene. Previous studies revealed that the LTSS might be caused by low-temperature-sensitive pollen sterility (LTSPS). However, the genetic basis of LTSPS remained unclear. To explore the genetic basis of LTSPS in indica-japonica hybrid rice, an F2 genetic population derived from 3037 (indica) and 02428 (japonica) was developed. At the booting stage, pollen fertility of F2 population together with parents were surveyed after the treatment with low temperature daily average of 21-23 degrees C. The linkage map was constructed containing 108 SSR markers distributed throughout the whole 12 chromosomes with average marker interval of 16.26 cM. Using software MapMaker/QTL, two putative QTLs, namely qLTSPS2 and qLTSPS5 on chromosomes 2 and 5 were detected by interval mapping, which could explain the phenotypic variation 15.6% and 11.9% respectively. The additive effects were 0.021 and 0.045, dominant effects were -0.246 and -0.215, and the degrees of dominance were 11.7 and 4.8, respectively for the two QTLs. Therefore, the mode of gene action in response to low-temperature stress was overdominance and LTSPS was mainly the result of interaction between the indica and japonica alleles within each locus. In addition, two-way ANOVA showed that the two QTLs acted essentially independent of each other in conditioning LTSPS.

Effect of scalp acupuncture on glucose metabolism in brain of patients with depression / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effect of scalp acupuncture (SA) on the glucose metabolism in different regions of brain in patients with depression by positron emission computed tomography (PET).</p><p><b>METHODS</b>Twelve depressive patients were treated by scalp acupuncture on middle line of vertex (MS5), middle line of forehead (MS1) and bilateral lateral line 1 of forehead (MS2), once a day for six days per week, and received PET detection on different region of brain before and after 6 weeks acupuncture treatment. Semiquantitative analysis was used to compare the average values of radioactive count gotten from various brain regions before and after treatment, which could reflect the condition of glucose metabolism at the brain region detected.</p><p><b>RESULTS</b>SA could increase the glucose metabolism at bilateral frontal lobes, bilateral parietal lobes, right occipital lobe, right caudate nucleus, right cingulated gyrus and left cerebellum and decrease that at right temporal lobe and bilateral thalamus.</p><p><b>CONCLUSION</b>SA on MS5, MS1 and MS2 in depressive patients could influence the glucose metabolism in various brain regions. It primarily illustrated that the mechanism of SA in treating depression is related with its regulation on cortex-limbic circuitry dysfunction and increase the glucose metabolism in various brain regions.</p>