Progress on the relationship of aldehyde dehydrogenase 2 with human diseases and its small-molecule activators / 药学实践杂志

Aldehyde dehydrogenase 2 (ALDH2) is one of important factors against from the damage under oxidative stress in human body. A high proportion of East Asians carry ALDH2 inactive mutation gene. There are many diseases closely related to ALDH2, such as cardiovascular diseases, neurodegenerative diseases and liver diseases. Recent studies also have found that ALDH2 is associated with ferroptosis. Therefore, ALDH2 has becoming a potential target for the treatment of the above related diseases. Several types of small molecule activators with potential value of clinical application have been reported. The research progress on the structure and function of ALDH2 , the relationship with human diseases and its activators were summarized in this paper.

Mechanism of catalpol regulating Th17 cell differentiation by interfering PKM2/LDHA expression / 中国药房

OBJECTIVE To investigate the mechanism of catalpol affecting the differentiation of helper T cell 17 （Th17） by interfering the expressions of pyruvate kinase M2 （PKM2） and lactate dehydrogenase A （LDHA）. METHODS The naive CD4+ T cells were selected from the spleen of C57BL/6 mice， and were differentiated into Th17 cells by adding directional differentiation stimulants for 72 hours. At the same time， the cells were treated with 0 （directed control）， 20， 40 and 80 μg/mL catalpol. The flow cytometry was used to detect the proportion of Th17 cell differentiation in cells； the colorimetric method was adopted to detect the levels of pyruvate and lactate in cell culture supernatant； mRNA expressions of retinoid-related orphan nuclear receptor gamma t （RORγt）， PKM2 and LDHA were detected by qRT-PCR method； Western blot was used to detect the expression levels of PKM2， LDHA， signal transducer and activator of transcription 3 （STAT3）， and phosphorylated STAT3 （p-STAT3） proteins in cells. RESULTS Compared with the directed control group， after 72 hours of treatment with 20， 40， 80 μg/mL catalpol， the differentiation ratio of Th17 cells were decreased by 6.74%， 8.41%， 9.24%， and the levels of pyruvate and lactate in the cell culture supernatant， the mRNA expressions of PKM2， LDHA and RORγt as well as the protein expressions of PKM2 and LDHA and the phosphorylation of STAT3 were significantly reduced （P＜0.05）. CONCLUSIONS Catalpol can reduce the glycolysis level by down-regulating the expressions of PKM2 and LDHA， thereby inhibiting the differentiation of Th17 cells.

Lactate dehydrogenase as a hematopoietic stem cell mobilization biomarker in autologous transplantation

ABSTRACT Introduction: Pre-apheresis peripheral blood CD34+ cell count (PBCD34+) is the most important predictor of good cell mobilization before hematopoietic stem cell transplantation, albeit flow cytometry is not always immediately available. Identification of surrogate markers can be useful. The CD34+ cells proliferate after mobilization, resulting in elevated lactate dehydrogenase (LDH) activity and correlating with the PBCD34+ count. Objective: To determine the LDH cut-off value at which adequate CD34+ cell mobilization is achieved and its diagnostic yield. Materials and methods: A total of 103 patients who received an autologous stem cell transplantation (ASCT) between January 2015 and January 2020 were included. Demographic and laboratory characteristics were obtained, including complete blood count, pre-apheresis PBCD34+ and LDH levels. Receiver operating characteristic (ROC) curves were performed to identify the optimal serum LDH activity cut-off points for ≥ 2 and ≥ 4 × 106 cells/kg post-mobilization CD34+ count and their diagnostic yield. Results: A post-mobilization serum LDH cut-off value of 462 U/L yielded a sensitivity (Se) = 86.8% (positive predictive value [PPV] = 72.7%), a pre- and post-mobilization serum LDH difference cut-off value of 387 U/L, an Se = 45.7% (PPV = 97%) and an LDH ratio of 2.46, with an Se = 47.1% (PPV = 97%) for an optimal mobilization count (CD34+ ≥ 4 × 106). Conclusion: The LDH measurement represents a fast and affordable way to predict PBCD34+ mobilization in cases where flow cytometry is not immediately available. According to the LDH diagnostic yield, it could be used as a surrogate marker in transplant centers, supporting the CD34+ count, which remains the gold standard.

CORRELATION OF SERUM FERRITIN AND LDH ON CRITICALLY ILL PATIENTS OF COVID-19 DISEASE DURING 1ST AND 2ND WAVE OF COVID 19 PANDEMIC IN TERTIARY CARE HOSPITAL, INDIA

In both the earlier waves of COVID-19 variants, severe and fatal respiratory disease like acute respiratory distress syndrome (ARDS) became more fatal in population with comorbid conditions. Therefore, early identi?cation of severe COVID-19 is very important for individual's precise management, including antiviral, oxygen support and intensive care unit (ICU) management. First case of COVID-19 got reported in the medical record of India on 30th January 2020 in a student who had returned from Wuhan, China. In 2020 and 2021 it was found that individuals with increased serum ferritin and LDH level landed up with severe and very severe COVID-19 if not treated timely and correctly. So correlation between S. Ferritin and LDH in 1st and 2nd wave was required to evaluate the condition of patients who remained admitted in critical care unit with or without comorbid conditions. This is hospital based cross- sectional observational study on 50-50 (total-100) critically ill patients admitted during 2020 and 2021 respectively. We found that In 2020 during the 1st wave serum LDH and serum Ferritin levels were signi?cantly high with the mean value of 481.65 U/L and 532.56 ng/ml respectively and in 2021 during 2nd wave serum LDH and serum Ferritin levels were again signi?cantly high with the mean value of 488.43 U/L and 667.27 ng/ml respectively. In 2020 patients with comorbid conditions showed S. LDH and Ferritin mean value of 543.47 U/L and 582.63 ng/ml respectively and in 2021 during 2nd wave it showed S.LDH and Ferritin levels mean value of 672.72 U/L and 727.38 ng/ml respectively. Both in?ammatory markers were signi?cantly more increased in the critically ill patients who presented with co-morbidities. This study will provide improved con?dence to health workers working in remote areas and COVID-19 hospitals in predicting transfer of COVID-19 patients to tertiary care hospitals for critical care management at the earliest.

Ventajas de la secuenciación de próxima generación sobre la hibridación fluorescente in situ para detectar la codeleción 1p/19q en oligodendrogliomas / Advantages of next generation sequencing over fluorescent in situ hybridization to detect 1p/19q codeletion in oligodendroglioma / Vantagens do sequenciamento de próxima geração sobre a hibridização fluorescente in situ para detectar codeleção 1p/19q em oligodendrogliomas

El perfil molecular de los gliomas permite garantizar la precisión del diagnóstico, informar el pronóstico e identificar opciones de tratamiento. Esta revisión tiene como objetivo exponer que con la secuenciación de próxima generación (NSG) el diagnóstico de los pacientes con oligodendrogliomas puede ser más exacto. Además, con un dispositivo de diagnóstico in vitro, basado en la NSG (F1CDx), en el que se utilizan los bloques de parafina de gliomas para analizar hasta 395 genes relacionados con cáncer (incluido IDH 1 y 2), se puede también informar la pérdida de la totalidad del brazo corto del cromosoma 1 y del brazo largo del cromosoma 19 (codeleción 1p/19q), a diferencia de la hibridación fluorescente in situ (FISH) que detecta desde la más mínima deleción, lo cual los hace sensibles pero no específicos ya que el FISH es incapaz de distinguir entre la pérdida de la totalidad del brazo del cromosoma y una deleción focal. Esta distinción es importante ya que la sobrevida es inferior en tumores con deleción parcial en rela­ción con los oligodendrogliomas, que tienen por definición la pérdida total de ambos cromosomas. Se hace también alusión a otras plataformas genómicas como GlioSeq y GLIO-DNA panel, que pueden cumplir la misma función. En conclusión, la F1CDx puede determinar con precisión 1p/19q con una concordancia del 96.7% frente a FISH. Los casos en que el FISH dio positivo y no concordaban con F1CDx, era porque no se trataba de oligodendrogliomas. F1CDx también analiza todos los genes que permiten la aproximación más exacta al diagnóstico de oligodendroglioma.

Molecular profiling of gliomas helps ensure diagnostic accuracy, inform prognosis, and identify treatment options. This review aims to show that with next generation sequencing (NGS) the diagnosis of patients with oligodendrogliomas can be more accurate. In addition, with an in vitro diagnostic device, based on NSG (F1CDx), in which glioma paraffin blocks are used to analyze up to 395 cancer-related genes (including IDH 1 and 2), it is also possible to report the loss of the entire short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q codeletion), unlike fluorescence in situ hybridization (FISH) that detects even the slightest deletion, making them sensitive but not specific, as FISH is unable to distinguish between the loss of the entire arm of the chromosome and a focal deletion. This distinction is important since survival is lower in tumors with partial deletion compared to oligodendrogliomas, which by definition have the total loss of both chromosomes. Reference is also made to other genomic platforms such as GlioSeq and GLIO-DNA panel, which can fulfill the same function. In conclusion, the F1CDx can accurately determine 1p/19q with a concordance of 96.7% against FISH. The cases in which the FISH was positive and did not agree with F1CDx, it was because they were not oligodendrogliomas. F1CDx also analyzes all the genes that allow the most accurate approach to the diagnosis of oligodendroglioma.

O perfil molecular de gliomas ajuda a garantir a precisão do diagnóstico, informar o prognóstico e identificar as opções de tratamento. Esta revisão tem como objetivo mostrar que com o sequenciamento de próxima geração (NSG) o diagnóstico de pacientes com oligodendrogliomas pode ser mais preciso. Além disso, com um dispositivo de diagnóstico in vitro baseado em NSG (F1CDx), no qual blocos de parafina de glioma são usados para analisar até 395 genes relacionados ao câncer (incluindo IDH 1 e 2), também é possível relatar a perda do todo o braço curto do cromossomo 1 e o braço longo do cromossomo 19 (codeleção 1p/19q), ao contrário da hibridização fluorescente in situ(FISH) que detecta desde a menor deleção, o que os torna sensíveis, mas não específicos, pois o FISH é incapaz de distinguir entre a perda de todo o braço do cromossomo e uma deleção focal. Essa distinção é importante, pois a sobrevida é menor nos tumores com deleção parcial em relação aos oligodendrogliomas, que por definição apresentam a perda total de ambos os cromossomos. Também é feita referência a outras plataformas genômicas, como GlioSeq e painel GLIO-DNA, que podem cumprir a mesma função. Em conclusão, o F1CDx pode determinar com precisão 1p/19q com uma concordância de 96,7% versus FISH. Os casos em que FISH foi positivo e não concordaram com F1CDx, foi porque não eram oligodendrogliomas. O F1CDx também analisa todos os genes que permitem a abordagem mais precisa para o diagnóstico de oligodendroglioma.

Expression of acetaldehyde dehydrogenase 2 in endometrial carcinoma and its correlation with clinical characteristics of patients / 中国医师杂志

Objective:To detect the expression of acetaldehyde dehydrogenase (ALDH) 2 and microRNA (miR)-135b-3p in endometrial cancer (EC) tissues, and to explore their correlation with clinical characteristics.Methods:94 endometrial cancer tissue specimens (EC group) and 60 normal endometrial specimens (control group) were selected from Northwest Women′s and Children′s Hospital from February 2019 to February 2022. Real time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression changes of ALDH2 mRNA and miR-135b-3p in endometrial tissue of two groups, and immunohistochemistry was used to detect the positive expression rate of ALDH2 protein. The relationship between the expression levels of ALDH2 and miR-135b-3p and the clinicopathological characteristics was analyzed.Results:The expression of ALDH2 mRNA in the EC group (0.67±0.15) was lower than that in the control group (1.05±0.12), and the expression level of miR-135b-3p (1.52±0.26) was higher than that in the control group (1.01±0.06). The positive expression rate of ALDH2 in cancer tissue of EC group was 30.85%(29/94), which was lower than 51.67%(31/60) in normal endometrial tissue of the control group ( P<0.05). The expression levels of ALDH2 mRNA and miR-135b-3p in EC patients were related to International Federation of Obstetrics and Gynecology (FIGO) stage, lymph node metastasis, differentiation and myometrium invasion (all P<0.05), but not to age, pathological type, menopause, HPV infection, menarche age, parity, tumor length and BMI (all P>0.05). Conclusions:In EC tissues, the expression of ALDH2 is down-regulated and the expression of miR-135b-3p is up-regulated, which may be involved in the occurrence and development of EC.

Clinical efficacy of ateplase combined with heparin in the treatment of acute moderate- and high-risk pulmonary thromboembolism and its effects on arterial blood gas analysis and myocardial enzyme level / 中国基层医药

Objective:To investigate the clinical efficacy of alteplase combined with heparin in the treatment of acute moderate- and high-risk pulmonary thromboembolism and its effects on arterial blood gas analysis and myocardial enzyme level.Methods:Seventy-eight patients with acute moderate- and high-risk pulmonary thromboembolism who received treatment in Dongyang People's Hospital from January 2015 to January 2022 were retrospectively included in this study. They were divided into observation ( n = 39) and control ( n = 39) groups according to different treatment methods. The control group was treated with heparin, while the observation group was treated with alteplase based on heparin. All patients were treated for 7 days. Clinical efficacy as well as arterial blood gas analysis, myocardial enzymes, pulmonary artery pressure, and tricuspid annular plane systolic excursion pre- and post-treatment were compared between the two groups. Results:The total response rate in the observation group was significantly higher than that in the control group (94.87% vs. 76.92%, χ2 = 5.18, P < 0.05). After treatment, the partial pressure of carbon dioxide in the observation group was significantly lower than that in the control group [(36.24 ± 5.12) mmHg vs. (44.25 ± 3.78) mmHg, 1 mmHg = 0.133 kPa, t = 7.86, P < 0.05]. After treatment, the partial pressure of oxygen in the observation group was significantly higher than that in the control group [(78.82 ± 5.1) mmHg vs. (71.23 ± 4.89) mmHg, t = 6.66, P < 0.05]. After treatment, lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme in the observation group were (107.42 ± 15.45) U/L, (37.21 ± 10.84) U/L, and (12.28 ± 3.54) U/L, respectively, which were significantly lower than (189.94 ± 21.20) U/L, (65.42 ± 6.57) U/L, and (19.29 ± 3.08) U/L in the control group ( t = 19.64, 13.89, 9.33, all P < 0.001). After treatment, the pulmonary arterial pressure in the observation group was significantly lower than that in the control group [(32.24 ± 3.86) mmHg vs. (37.79 ± 5.17) mmHg, t = 5.37, P < 0.001]. Tricuspid annular plane systolic excursion in the observation group was significantly higher than that in the control group [(14.07 ± 1.27) mm vs. (12.63 ± 1.16) mm, t = 5.22, P < 0.001]. Conclusion:Ateplase combined with heparin has an obvious effect on acute moderate- and high-risk pulmonary thromboembolism. It can improve arterial blood gas analysis and reduce myocardial enzyme levels.

Inhibitory Effect of Sophora alopecuroides Total Alkaloids and Two Monomer Alkaloids on PC12 Cell Activity / 中国实验方剂学杂志

ObjectiveTo compare the effects of total alkaloids， matrine， and sophoridine extracted from Sophora alopecuroides on the activity of pheochromocytoma cells （PC12 cells）. MethodThe effect of S. alopecuroides total alkaloids， matrine， and sophoridine at concentrations of 2， 1， 0.5， 0.25， 0.125， and 0.062 5 g·L-1 on the proliferation of PC12 cells was evaluated using the 3-（4，5-dimethylthiazol-2-yl）-2，5-diphenyl tetrazolium bromide （MTT） assay. The lactate dehydrogenase （LDH） leakage rate was measured by enzyme-linked immunosorbent assay （ELISA）. Flow cytometry was used to assess cell apoptosis rate， cell cycle distribution， and intracellular Ca2+ levels. Real-time quantitative polymerase chain reaction （Real-time PCR） was performed to determine the mRNA transcription levels of B-cell lymphoma-2 （Bcl-2） and Bcl-2-associated X protein （Bax）. Protein expression levels of apoptosis-related proteins Caspase-3， Caspase-8， Bcl-2， and Bax were detected by Western blot. ResultCompared to the control group， S. alopecuroides total alkaloids， matrine， and sophoridine inhibited the proliferation of PC12 cells， increased LDH leakage rate， enhanced intracellular Ca2+ fluorescence intensity， and induced cell apoptosis in concentration-dependent manner （P<0.05， P<0.01）. Among them， S. alopecuroides total alkaloids had the strongest inhibitory effect on cell proliferation and induction of apoptosis in PC12 cells （P<0.01）. After treatment with S. alopecuroides total alkaloids， matrine， and sophoridine， the cell cycle progression of PC12 cells was arrested at G1/G0 in the S. alopecuroides total alkaloids group， and at G1/S in the matrine and sophoridine groups. The expression levels of Bax mRNA were significantly increased （P<0.05， P<0.01）， while the expression levels of Bcl-2 mRNA were significantly decreased （P<0.05， P<0.01）. All treatments significantly downregulated the expression of the anti-apoptotic protein Bcl-2 （P<0.05， P<0.01） and upregulated the expression of the pro-apoptotic proteins Bax， Caspase-3， and Caspase-8 （P<0.05， P<0.01）， with the most significant protein expression changes observed in the S. alopecuroides total alkaloids group. ConclusionAmong the S. alopecuroides total alkaloids， matrine， and sophoridine， S. alopecuroides total alkaloids exhibit the strongest inhibitory effect on the activity of PC12 cells， and its mechanism of action may be related to the inhibition of anti-apoptotic protein expression， upregulation of pro-apoptotic protein expression， and activation of the mitochondrial Caspase-8 apoptotic pathway.

Baicalin inhibits PDK1 to mediate glucose metabolism reprogramming and intervene rheumatoid arthritis synovial inflammation / 药学学报

This study started from the effect of baicalin (BC), the main active component of the labiaceae plant Scutellaria baicalensis, on collagen-induced arthritis (CIA) in rats, to explore the mechanism of glucose metabolism reprogramming in fibroblast like synoviocytes (FLSs), a key effector cell of synovial inflammation in rheumatoid arthritis (RA). First of all, CIA rats and tumor necrosis factor-α (TNF-α)-induced RASFs in vitro and in vivo models were established, the arthritis index (AI) score and histopathological changes of CIA rats after BC administration were observed, and the levels of inflammatory factors in serum and cell supernatant were quantified by ELISA, immunocytochemistry and Western blot were used to detect the expression of G-protein-coupled receptor 81 (GPR81) and pyruvate dehydrogenase kinase 1 (PDK1) proteins. In addition, the kit was used to measure the levels of key products and enzyme activities in glucose metabolism reprogramming. The results showed that BC (50, 100 and 200 mg·kg-1) could alleviate the symptoms of arthritis in CIA rats in a dose-dependent manner, inhibit synovial hyperplasia, alleviate the infiltration of inflammatory cells, down-regulate the levels of pro-inflammatory factors TNF-α and interleukin (IL)-1β, and up-regulate the levels of anti-inflammatory factor IL-10 in CIA rats. At the same time, the secretion levels of lactate, pyruvate, acetyl-CoA, citrate and the activity of lactate dehydrogenase B (LDH-B) were decreased, and the expressions of GRP81 and PDK1 were down-regulated, suggesting that BC mediated the reprogramming process of glucose metabolism. However, when GPR81 inhibitor 3-OBA inhibited lactate uptake, the activity of LDH-B was significantly increased, suggesting that BC inhibited the expression of PDK1, a key enzyme in the reprogramming metabolism from glycolysis to oxidative phosphorylation. All animal experiments in this study were conducted in accordance with the ethical standards of the Laboratory Animal Care Center of Anhui University of Chinese Medicine (approval number: AHUCM-rats-2021049). These studies revealed that baicalin mediated metabolic reprogramming of RASFs from glycolysis to oxidative phosphorylation by inhibiting PDK1 protein expression, and alleviated joint inflammation in CIA rats.

Research progress on T cell glycolytic metabolism in oral lichen planus / 口腔疾病防治

@#Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. The pathogenesis of OLP is still unclear. Immune abnormalities mediated by T cells and related cytokines play a crucial role in the pathogenesis of OLP. In recent years, glycolytic metabolism-related transporters, enzymes and regulators, such as glucose transporter-1 (Glut1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), mammalian target of rapamycin (mTOR) and hypoxia inducible factor-1α (HIF-1a), have attracted an increasing amount of attention in OLP by regulating the proliferation and differentiation of T cells and the secretion of inflammatory factors. It has been shown that 2-deoxy-D-glucose (2-DG) or rapamycin (RAPA) inhibits the glycolytic metabolism of T cells and then inhibits OLP. This article reviews the research progress of glycolytic metabolism-related transporters, enzymes and regulatory factors in OLP in recent years.

Advances in research on mechanism of lactate dehydrogenase B in tumors / 中国药科大学学报

@#Increased glycolysis is a major feature of metabolic reprogramming in cancer.Glycolysis provides not only energy for cancer cells but also necessary precursors for biosynthesis, which is important for promoting tumor growth.Cancer cells meet their own needs by regulating glycolytic enzymes, which play an active role in promoting cancer survival, metastasis, and invasion.Lactate dehydrogenase (LDH), as a key enzyme in glycolysis, consists of two subunits: lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB).LDHA is known to play a key role in aerobic glycolysis and has been extensively studied, whereas less has been done on LDHB.However, at present, more and more reports have revealed the important effects of LDHB on the progression of various cancers.A large number of studies have shown that LDHB is abnormally expressed in a variety of cancers, which is related to the malignant progression of tumors.The article reviews the research progress of LDHB in recent ten years, including its regulatory mechanism in tumor, its relationship with cancer development and its role as a biomarker in clinical diagnosis of cancer, which provides some insight for further investigation of the mechanism of LDHB in cancer research.

Research progress on cold ischemia injury of steatotic donor livers / 器官移植

Liver transplantation is a vital treatment for end-stage liver disease. However, the shortage of donor livers has limited the development of liver transplantation. How to expand the source of donor livers has become a challenge in the academic community. In recent years, the proportion of donors with non-alcoholic fatty liver disease (NAFLD) has been increased. Rational use of steatotic donor livers is a feasible approach to expand the donor pool. Cold ischemia injury during donor liver preservation before liver transplantation increases the risk of postoperative organ dysfunction. Therefore, it is of significance to unravel the mechanism and intervention measures of cold ischemia injury of steatotic donor livers. Cold ischemia injury of steatotic donor livers is characterized as the damage of mitochondria, lysosomes and endoplasmic reticulum at the organelle level, and up-regulated expression of adenosine monphosphate activated protein kinase (AMPK), aldehyde dehydrogenase 2 (ALDH2) and heme oxygenase (HO)-1 at the protein level. In this article, the research progresses on cold ischemia injury of steatotic donor livers and relevant intervention measures were reviewed.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

Clinical analysis of severe hyperbilirubinemia caused by hemolytic disease of the newborn and G6PD deficiency / 中国新生儿科杂志

Objective:To study the clinical characteristics and differences of severe hyperbilirubinemia caused by hemolytic disease of the newborn (HDN) and glucose-6-phosphate dehydrogenase (G6PD) deficiency.Methods:From January 2014 to December 2021, newborns (gestational age ≥ 35 weeks and postnatal age ≤ 28 d) admitted to the Department of Neonatology of Hunan Children's Hospital with severe hyperbilirubinemia caused by HDN or G6PD deficiency were retrospectively analyzed. According to the etiology of hyperbilirubinemia, they were assigned into HDN group and G6PD deficiency group. The general conditions, clinical manifestations, laboratory results, treatment and prognosis of the two groups were compared using SPSS 26.0 software.Results:A total of 532 cases were in the HDN group and 413 cases in the G6PD deficiency group. The HDN group reached peak hyperbilirubinemia earlier than the G6PD deficiency group [3(2,5) d vs. 6(4,8)d, P<0.05]. The HDN group had lower peak value of total serum bilirubin [379.5(345.6,426.7) μmol/L vs. 486.4 (413.5,577.4) μmol/L] and lower incidence of anemia [37.4% (199/532) vs. 55.0% (227/413)]than the G6PD deficiency group.The incidence of anemia with elevated reticulocyte percent(Ret%) in the HDN group was higher than the G6PD deficiency group[66.3%(132/199) vs. 5.7%(13/227), P<0.05]. Compared with the G6PD deficiency group, the incidences of exchange transfusion and repeated (≥2 times) exchange transfusion, acute bilirubin encephalopathy(ABE) and the mortality rate after withdrawal of treatment in the HDN group were significantly lower ( P<0.05). Conclusions:Neonatal severe hyperbilirubinemia caused by HDN has early onset. G6PD deficiency caused hyperbilirubinemia has higher incidences of anemia, more severe jaundice and ABE, without increased Ret%.

Expression and Significance of Lactate Dehydrogenase A in Renal Cell Carcinoma / 中山大学学报(医学科学版)

ObjectiveTo analyze the expression of Lactate dehydrogenase A（LDHA） in both renal cell carcinoma （RCC） tissue and RCC cell lines， and to investigate the impact of LDHA expression on the progression of RCC. MethodsFrom June 2018 to June 2022， totally 52 cases of RCC tissue samples and 49 cases of para-cancerous tissue samples were collected through surgical procedures from our hospital. LDHA expression was detected using immunohistochemistry （IHC）. The expression levels of LDHA in vitro were also detected in the normal human proximal tubule epithelial cell line HK-2 and renal cell carcinoma cell lines A498， Caki-2， ACHN， and 786-O by using qRT-PCR and Western blot. A recombinant plasmid carrying LDHA-shRNA was constructed and then transfected into 786-O cells to down-regulate the expression of LDHA. Tumor proliferative capacity was monitored using CCK-8 assay， clonal formation assay and EdU assessments. Additionally， cell glycolytic activity was assessed through glucose uptake assay， lactate secretion assay， and ECAR analysis. ResultsIHC analysis revealed significantly higher expression of LDHA in RCC tissue compared to adjacent tissues（P<0.05）. Furthermore， RCC tissues with higher TNM stage exhibited greater expression of LDHA than those with lower TNM stage （P<0.05）. The results of qRT-PCR and Western blot demonstrated that the expression of LDHA in each RCC cell line was significantly higher than that in HK-2（P<0.05）. After blocking the expression of LDHA in 786-O， there was a significant down-regulation of cell proliferation and glycolysis capacity （P<0.05）. ConclusionsThe expression of LDHA in RCC tissue and RCC cell lines is significantly overexpressed compared with normal one， particularly in those with higher TNM stage. Knockdown of the expression of LDHA significantly suppresses cell proliferation and aerobic glycolysis capacity in 786-O.

Aldehyde dehydrogenase 2 rs671 genetic polymorphisms are associated with chemotherapy-induced nausea and vomiting / 南方医科大学学报

OBJECTIVE@#To investigate the correlation between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and chemotherapy-induced nausea and vomiting (CINV).@*METHODS@#A total of 90 Chinese patients with malignant tumors receiving chemotherapy for the first time were recruited in this study. The occurrence of CINV was observed within 120 h after treatment with docetaxel and cis-platinum chemotherapy (DP regimen). The data of the patients (including age, gender, tumor stage, habitual alcohol consumption, motion sickness, morning sickness, and average sleep time prior to chemotherapy) were collected through a questionnaire. ALDH2 rs671 polymorphisms of the patients were analyzed using a multiple single nucleotide polymorphism genotyping, and the Hardy-Weinberg equation was used for genetic linkage analysis. The correlations between the factors including ALDH2 rs671 polymorphisms and the occurrence of CINV were analyzed.@*RESULTS@#The incidence of CINV was 48.9% among the patients receiving their first chemotherapy with DP regimen. Univariate analysis indicated that the genetic polymorphisms of ALDH2 rs671 were significantly correlated with the occurrence of CINV (P < 0.05). Multivariate logistic analysis indicated that ALDH2 rs671 mutation (OR: 3.019, 95% CI: 1.056-8.628, P < 0.05) and average sleep time prior to chemotherapy no longer than 6 h (OR: 2.807, 95% CI: 1.033-7.628, P < 0.05) were risk factors for CINV in patients with malignant tumors receiving the first chemotherapy with DP regimen.@*CONCLUSION@#ALDH2 gene mutation at rs671 is a risk factor contributing to the occurrence of CINV, and understanding of the underlying mechanism may help to more effectively control the occurrence of CINV.

EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis / 南方医科大学学报

OBJECTIVE@#To explore the driving gene of hepatocellular carcinoma (HCC) occurrence and progression and its potential as new therapeutic target of HCC.@*METHODS@#The transcriptome and genomic data of 858 HCC tissues and 493 adjacent tissues were obtained from TCGA, GEO, and ICGC databases. Gene Set Enrichment Analysis (GSEA) identified EHHADH (encoding enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase) as the hub gene in the significantly enriched differential pathways in HCC. The downregulation of EHHADH expression at the transcriptome level was found to correlate with TP53 mutation based on analysis of the TCGA- HCC dataset, and the mechanism by which TP53 mutation caused EHHADH downregulation was explored through correlation analysis. Analysis of the data from the Metascape database suggested that EHHADH was strongly correlated with the ferroptosis signaling pathway in HCC progression, and to verify this result, immunohistochemical staining was used to examine EHHADH expression in 30 HCC tissues and paired adjacent tissues.@*RESULTS@#All the 3 HCC datasets showed signficnatly lowered EHHADH expression in HCC tissues as compared with the adjacent tissues (P < 0.05) with a close correlation with the degree of hepatocyte de-differentiation (P < 0.01). The somatic landscape of HCC cohort in TCGA dataset showed that HCC patients had the highest genomic TP53 mutation rate. The transcriptomic level of PPARGC1A, the upstream gene of EHHADH, was significantly downregulated in HCC patients with TP53 mutation as compared with those without the mutation (P < 0.05), and was significantly correlated with EHHADH expression level. GO and KEGG enrichment analyses showed that EHHADH expression was significantly correlated with abnormal fatty acid metabolism in HCC. The immunohistochemical results showd that the expression level of EHHADH in HCC tissues was down-regulated, and its expression level was related to the degree of hepatocytes de-differentiation and the process of ferroptosis.@*CONCLUSION@#TP53 mutations may induce abnormal expression of PPARGC1A to cause downregulation of EHHADH expression in HCC. The low expression of EHHADH is closely associated with aggravation of de-differentiation and ferroptosis escape in HCC tissues, suggesting the potential of EHHADH as a therapeutic target for HCC.

Predictive value of serum lactate dehydrogenase on prognosis of patients with paraquat poisoning / 中华劳动卫生职业病杂志

Objective: To investigate the predictive value of serum lactate dehydrogenase (LDH) in the prognosis of patients with paraquat (PQ) poisoning, and to provide evidence for early prognosis assessment. Methods: In February 2022, 50 patients with PQ poisoning who completed serum LDH detection admitted to the Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University from January 2012 to December 2021 were selected as the observation group, and 50 healthy physical examination personnel were randomly selected as the control group. Patients with PQ poisoning were divided into survival group and death group according to the prognosis, and the differences of blood routine routine, liver and kidney function and other indicators in the first admission between the two groups were compared. Multivariate logisitic regression model was established, ROC curve was drawn, and the influencing factors of prognosis of patients with PQ poisoning were analyzed. Results: Compared with the control group, the white blood cell count (WBC), total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, glucose (GLU) and creatinine (Cr) in observation group were significantly increased, while albumin (ALB) and total cholesterol (TC) were significantly decreased (P<0.05). Univariate analysis showed that WBC, elevated LDH (>247 U/L), TBil, ALT, AST and Cr were significantly different between PQ poisoning survival group and death group (P<0.05). Multivariate logisitic regression analysis showed that elevated serum LDH was an independent risk factor for the prognosis of PQ poisoning patients (OR=9.95, 95%CI: 1.34-73.82, P=0.025). The area under the ROC curve of LDH was 0.811 (95%CI: 0.692-0.930). When the cut-off value was 340 U/L, the sensitivity was 0.889 and the specificity was 0.719. Log-rank test showed that there was a statistically significant difference in survival rate between the normal LDH group and the elevated LDH group (P=0.001) . Conclusion: Serum LDH has a good predictive value in evaluating the prognosis of patients with PQ poisoning. Elevated LDH is a risk factor for poor prognosis of patients with PQ poisoning.