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.

Shikonin induces hepatocellular carcinoma cell apoptosis by suppressing PKM2/PHD3/HIF-1α signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the mechanism of shikonin-induced death of human hepatocellular carcinoma SMMC-7721 cells.@*METHODS@#Cultured SMMC-7721 cells and normal hepatocytes (L-02 cells) were treated with 4, 8, or 16 μmol/L shikonin, and the changes in cell viability was assessed using MTT assay. The levels of ATP and lactic acid in the cell cultures were detected using commercial kits. Co-immunoprecipitation and immunofluorescence staining were used to determine the relationship among pyruvate kinase M2 (PKM2), prolyl hydroxylase 3 (PHD3), and hypoxia-inducible factor-1α (HIF-1α). The expressions of PHD3, PKM2, HIF-1α, Bax, cleaved caspase-3, and Bcl-2 in SMMC-7721 cells were detected with Western blotting, and cell apoptosis was analyzed with annexin V-FITC/PI staining. The effects of RNA interference of PKM2 on PHD3 and HIF-1α expressions in SMMC-7721 cells were detected using Western blotting.@*RESULTS@#The IC50 of shikonin against SMMC-7721 and L-02 cells was 8.041 μmol/L and 31.75 μmol/L, respectively. Treatment with shikonin significantly inhibited the protein expressions of PKM2, HIF-1α and PHD3 and nuclear translocation of PKM2 and HIF-1α in SMMC-7721 cells. Coimmunoprecipitation and immunofluorescence staining confirmed that shikonin inhibited the formation of PKM2/PHD3/HIF-1α complex and significantly reduced the contents of lactic acid and ATP in SMMC-7721 cells (P < 0.05). The expressions of PHD3 and HIF-1α decreased significantly after PKM2 knockdown (P < 0.05). Shikonin treatment significantly increased the apoptosis rate, enhanced the expressions of Bax and cleaved caspase-3, and decreased Bcl-2 expression in SMMC-7721 cells (P < 0.05).@*CONCLUSIONS@#Shikonin induces apoptosis of SMMC-7721 cells possibly by inhibiting aerobic glycolysis through the PKM2/PHD3/HIF-1α signaling pathway to cause energy supply dysfunction in the cells.

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.

Expression of serum connective tissue growth factor, glyoxalase Ⅰ, pyruvate kinase M2 in endometrial carcinoma and its relationship with clinicopathological features / 中国医师进修杂志

Objective:To explore the expression of serum connective tissue growth factor (CTGF), glyoxalase Ⅰ (GLO-I) and pyruvate kinase M2 (PKM2) in endometrial cancer and their relationship with clinicopathological characteristics.Methods:A total of 96 endometrial cancer patients in Yuechi County People's Hospital from February 2015 to February 2017 were selected as the research group, 48 patients with endometrial hyperplasia during the same period were selected as the benign control group, and 48 patients with healthy physical examination during the same period were selected as the healthy control group. The serum levels of CTGF, GLO-Ⅰ, and PKM2 in the three groups were analyzed. The correlation between serum levels of CTGF, GLO-Ⅰ and PKM2 in the research group was analyzed, and the relationship between each serum index and clinicopathological characteristics was analyzed.Results:The levels of serum CTGF, GLO-Ⅰ and PKM2 in the research group were higher than those in the benign control group and healthy control group: (184.31 ± 37.14) μg/L vs. (110.45 ± 20.59), (17.28 ± 0.42) μg/L; (95.17 ± 16.56) pmol/L vs. (56.29 ± 10.14), (9.08 ± 0.66) pmol/L; (20.25 ± 6.13) μg/L vs. (13.11 ± 4.58), (9.05 ± 2.74) μg/L; and the levels of serum CTGF, GLO-Ⅰ and PKM2 in the benign control group were higher than those in the healthy control group, there were statistical differences ( P<0.05). The results of Pearson correlation analysis showed that the level of CTGF had positive correlation with GLO-Ⅰ and PKM2 ( r = 0.713, 0.741, P<0.05), and the level of GLO-Ⅰ had positive correlation with PKM2 ( r = 0.823, P<0.05). The results of Spearman correlation analysis showed that the levels of CTGF, GLO-Ⅰ, PKM2 had positive correlation with FIGO stage ( r = 0.609, 0.704, 0.721; P<0.05), myometrial invasion depth ( r = 0.753, 0.695, 0.719; P<0.05), lymph node metastasis ( r = 0.776, 0.744, 0.640; P<0.05); had negative correlation with the degree of differentiation ( r = - 0.711, - 0.720, - 0.668; P<0.05). Conclusions:Serum CTGF, GLO-I, PKM2 expression levels are abnormally elevated in patients with endometrial cancer, which are significantly related to multiple clinicopathological characteristics.

Prenatal diagnosis of pyruvate dehydrogenase E1-α deficiency: a case report / 中华围产医学杂志

This article reported a case of pyruvate dehydrogenase E1-α deficiency suggested by abnormal brain development during prenatal ultrasound imaging. Prenatal ultrasound revealed a mild enlargement of bilateral cerebral ventricles and the possibility of intracranial hemorrhage in the fetus at 25 +1 weeks of gestation. MRI showed the fetus with absent corpus callosum, enlarged bilateral cerebral ventricles and paraventricular cysts. After genetic counseling and careful consideration, the couple opted for pregnancy termination. To clarify the cause of the disease, whole-exome sequencing was performed on the fetal skin to detect possible variants, and which revealed a frameshift mutation c.924_930dup(p.R311Gfs*5) in exon 10 of the PDHA1 gene. Sanger sequencing confirmed the mutation was a de novo pathogenic variant, indicating that the fetus was affected by pyruvate dehydrogenase E1-α deficiency.

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.

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.

Effect of PKM2 on Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Myeloma Bone Disease / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression of pyruvate kinase M2 (PKM2) in bone marrow mesenchymal stem cells (BMSCs) in myeloma bone disease (MBD) and its effect on osteogenic and adipogenic differentiation of BMSCs.@*METHODS@#BMSCs were isolated from bone marrow of five patients with multiple myeloma (MM) (MM group) and five with iron deficiency anemia (control group) for culture and identification. The expression of PKM2 protein were compared between the two groups. The differences between osteogenic and adipogenic differentiation of BMSCs were assessed by using alkaline phosphatase (ALP) and oil red O staining, and detecting marker genes of osteogenesis and adipogenesis. The effect of MM cell line (RPMI-8226) and BMSCs co-culture on the expression of PKM2 was explored. Functional analysis was performed to investigate the correlations of PKM2 expression of MM-derived BMSCs with osteogenic and adipogenic differentiation by employing PKM2 activator and inhibitor. The role of orlistat was explored in regulating PKM2 expression, osteogenic and adipogenic differentiation of MM-derived BMSCs.@*RESULTS@#Compared with control, MM-originated BMSCs possessed the ability of increased adipogenic and decreased osteogenic differentiation, and higher level of PKM2 protein. Co-culture of MM cells with BMSCs markedly up-regulated the expression of PKM2 of BMSCs. Up-regulation of PKM2 expression could promote adipogenic differentiation and inhibit osteogenic differentiation of MM-derived BMSCs, while down-regulation of PKM2 showed opposite effect. Orlistat significantly promoted osteogenic differentiation in MM-derived BMSCs via inhibiting the expression of PKM2.@*CONCLUSION@#The overexpression of PKM2 can induce the inhibition of osteogenic differentiation of BMSCs in MBD. Orlistat can promote the osteogenic differentiation of BMSCs via inhibiting the expression of PKM2, indicating a potential novel agent of anti-MBD therapy.

Dichloroacetic acid and rapamycin synergistically inhibit tumor progression / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+‍) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.

Phosphorylated PKM2 regulates endothelium-dependent vasodilation in diabetes / 中南大学学报(医学版)

OBJECTIVES@#Endothelium-dependent vasodilation dysfunction is the pathological basis of diabetic macroangiopathy. The utilization and adaptation of endothelial cells to high glucose determine the functional status of endothelial cells. Glycolysis pathway is the major energy source for endothelial cells. Abnormal glycolysis plays an important role in endothelium-dependent vasodilation dysfunction induced by high glucose. Pyruvate kinase isozyme type M2 (PKM2) is one of key enzymes in glycolysis pathway, phosphorylation of PKM2 can reduce the activity of pyruvate kinase and affect the glycolysis process of glucose. TEPP-46 can stabilize PKM2 in its tetramer form, reducing its dimer formation and phosphorylation. Using TEPP-46 as a tool drug to inhibit PKM2 phosphorylation, this study aims to explore the impact and potential mechanism of phosphorylated PKM2 (p-PKM2) on endothelial dependent vasodilation function in high glucose, and to provide a theoretical basis for finding new intervention targets for diabetic macroangiopathy.@*METHODS@#The mice were divided into 3 groups: a wild-type (WT) group (a control group, C57BL/6 mice) and a db/db group (a diabetic group, db/db mice), which were treated with the sodium carboxymethyl cellulose solution (solvent) by gavage once a day, and a TEPP-46 group (a treatment group, db/db mice+TEPP-46), which was gavaged with TEPP-46 (30 mg/kg) and sodium carboxymethyl cellulose solution once a day. After 12 weeks of treatment, the levels of p-PKM2 and PKM2 protein in thoracic aortas, plasma nitric oxide (NO) level and endothelium-dependent vasodilation function of thoracic aortas were detected. High glucose (30 mmol/L) with or without TEPP-46 (10 μmol/L), mannitol incubating human umbilical vein endothelial cells (HUVECs) for 72 hours, respectively. The level of NO in supernatant, the content of NO in cells, and the levels of p-PKM2 and PKM2 protein were detected. Finally, the effect of TEPP-46 on endothelial nitric oxide synthase (eNOS) phosphorylation was detected at the cellular and animal levels.@*RESULTS@#Compared with the control group, the levels of p-PKM2 in thoracic aortas of the diabetic group increased (P<0.05). The responsiveness of thoracic aortas in the diabetic group to acetylcholine (ACh) was 47% lower than that in the control group (P<0.05), and that in TEPP-46 treatment group was 28% higher than that in the diabetic group (P<0.05), while there was no statistically significant difference in the responsiveness of thoracic aortas to sodium nitroprusside (SNP). Compared with the control group, the plasma NO level of mice decreased in the diabetic group, while compared with the diabetic group, the phosphorylation of PKM2 in thoracic aortas decreased and the plasma NO level increased in the TEPP-46 group (both P<0.05). High glucose instead of mannitol induced the increase of PKM2 phosphorylation in HUVECs and reduced the level of NO in supernatant (both P<0.05). HUVECs incubated with TEPP-46 and high glucose reversed the reduction of NO production and secretion induced by high glucose while inhibiting PKM2 phosphorylation (both P<0.05). At the cellular and animal levels, TEPP-46 reversed the decrease of eNOS (ser1177) phosphorylation induced by high glucose (both P<0.05).@*CONCLUSIONS@#p-PKM2 may be involved in the process of endothelium-dependent vasodilation dysfunction in Type 2 diabetes by inhibiting p-eNOS (ser1177)/NO pathway.

Effect of Liangfang Wenjing Decoction on expression of key glycolytic enzymes in uterus and ovaries of rats with coagulating cold and blood stasis syndrome / 中国中药杂志

This study aimed to investigate the relationship between coagulating cold and blood stasis syndrome and glycolysis, and observe the intervention effect of Liangfang Wenjing Decoction(LFWJD) on the expression of key glycolytic enzymes in the uterus and ovaries of rats with coagulating cold and blood stasis. The rat model of coagulating cold and blood stasis syndrome was established by ice-water bath. After modeling, the quantitative scoring of symptoms were performed, and according to the scoring results, the rats were randomly divided into a model group and LFWJD low-, medium-and high-dose groups(4.7, 9.4, 18.8 g·kg~(-1)·d~(-1)), with 10 in each group. Another 10 rats were selected as the blank group. After 4 weeks of continuous administration by gavage, the quantitative scoring of symptoms was repeated. Laser speckle flowgraphy was used to detect the changes of microcirculation in the ears and uterus of rats in each group. Hematoxylin-eosin(HE) staining was used to observe the pathological morphology of uterus and ovaries of rats in each group. The mRNA and protein expressions of pyruvate dehydrogenase kinase 1(PDK1), hexokinase 2(HK2) and lactate dehydrogenase A(LDHA) in the uterus and ovaries of rats were examined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. The rats in the model group showed signs of coagulating cold and blood stasis syndrome, such as curl-up, less movement, thickened veins under the tongue, and reduced blood perfusion in the microcirculation of the ears and uterus, and HE staining revealed a thinning of the endometrium with disorganized arrangement of epithelial cells and a decrease in the number of ovarian follicles. Compared with the model group, the treatment groups had alleviated coagulating cold and blood stasis, which was manifested as red tongue, reduced nail swelling, no blood stasis at the tail end as well as increased blood perfusion of the microcirculation in the ears and uterus(P<0.05 or P<0.01). Among the groups, the LFWJD medium-and high-dose groups had the most significant improvement in coagulating cold and blood stasis, with neatly arranged columnar epithelial cells in uterus, and the number of ovarian follicles was higher than that in the model group, especially mature follicles. The mRNA and protein expressions of PDK1, HK2, LDHA in uterus and ovaries were up-regulated in the model group(P<0.05 or P<0.01), while down-regulated in LFWJD medium-and high-dose groups(P<0.05 or P<0.01). The LFWJD low-dose group presented a decrease in the mRNA expressions of PDK1, HK2 and LDHA in uterus and ovaries as well as in the protein expressions of HK2 and LDHA in uterus and HK2 and PDK1 in ovaries(P<0.05 or P<0.01). The therapeutic mechanism of LFWJD against coagulating cold and blood stasis syndrome is related to the down-regulation of key glycolytic enzymes PDK1, HK2 and LDHA, and the inhibition of glycolytic activities in uterus and ovaries.

Research progress of pyruvate kinase type M2 in hepatocellular carcinoma / 中华肝脏病杂志

Primary hepatocellular carcinoma is one of the most common high-grade malignant tumors in the world. Its incidence ranks fifth among malignant tumors in China, and various therapeutic measures have poor curative effect. Pyruvate kinase type M2 is a key enzyme in the glycolytic pathway, and its abnormal expression in liver cancer is closely related to the proliferation, metastasis, diagnosis, treatment, prognosis, as well as drug and radiation resistance. Therefore, multi-pathway targeted regulation of pyruvate kinase type M2 use is expected to become a new direction for the treatment of primary liver cancer.

Genetic diagnosis of MN and ABO hemolytic disease of the newborn complicated with pyruvate kinase deficiency: a case report and literature review / 中国输血杂志

【Objective】 To investigate the clinical and genetic characteristics of hemolytic disease of the newborn(HDN) induced by anti-M complicated with pyruvate kinase deficiency (PKD) disease. 【Methods】 The clinical data of a pregnant woman with unexplained adverse pregnancy outcome in the third trimester were retrospectively analyzed, and neonate anemia status and blood transfusion were followed up. With informed consent, peripheral blood of the neonate and her parents were collected for serological tests and disease-related gene target sequence capture and sequencing. The clinical and genetic characteristics of HDN induced by anti-M or PKD were reviewed. 【Results】 The neonate presented severe anemia, hepatosplenomegalism, hyperbilirubinemia at birth, and was confirmed MN combined with ABO neonatal hemolysis by serological tests. The neonate recovered by receiving blood exchange and phototherapy treatments, but he needed to receive blood transfusion each month because of hemolytic anemia. Genetic analysis showed that the neonate had compound heterozygous mutations (c. 1096C>T; c. 941T>C) of PKLR gene inherited from her parents. 【Conclusion】 The clinical manifestations of PKD are similar to that of HDN caused by anti-M in the early stage of the disease. Clinicians should exclude the metabolic diseases of red blood cells when diagnosing severe HDN caused by anti-M.

Role of M2 isoform of pyruvate kinase in diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Diabetic retinopathy(DR), one of the most common diabetes-specific microvascular complications, is classically described by intraretinal microvascular abnormalities and neovascularization. It is the main reason why visual impairment and blindness in people aged 20-65 years worldwide. Glycolysis can provide energy by converting glucose into pyruvate. Endothelial cells mainly utilize glycolysis to produce ATP to maintain the function, including forming tight junctions and barrier functions. Pyruvate kinase(PK)M2(M2 isoform of pyruvate kinase)is a key enzyme of glycolysis and is widely expressed in most tissues. As major cellular components in the retina, endothelial cells and photoreceptor cells play a crucial role in the occurrence and development of DR. Studies have shown that PKM2 takes part in the development of DR by regulating the function of endothelial cells and photoreceptors in metabolic and non-metabolic ways. Therefore, this article overviews the role of PKM2 in DR from the direction of endothelial cells and photoreceptor cells and provides new insight into the diagnosis and treatment of DR.

Effect of Anti-Oxidative of Ethyl Pyruvate and Taurine on the Red Blood Cell Storage at 4 ℃ / 中国实验血液学杂志

OBJECTIVE@#To investigate the anti-oxidative effect of ethyl pyruvate (EP) and taurine (TAU) on the quality of red blood cells stored at 4±2 ℃, hemolysis, energy metabolism and lipid peroxidation of the red blood cells in the preservation solution were studied at different intervals.@*METHODS@#At 4±2 ℃, the deleukocyte red blood cells were stored in the citrate-phosphate-dextrosesaline-adenine-1 (CPDA-1) preservation (control group), preservation solution with EP (EP-AS), and TAU (TAU-AS) for long-term preservation. The enzyme-linked immunoassay and automatic blood cell analyzer were used to detect hemolysis and erythrocyte parameters. Adenine nucleoside triphosphate (ATP), glycerol 2,3-diphosphate (2,3-DPG) and malondialdehyde (MDA) kits were used to test the ATP, 2,3-DPG and MDA concentration.@*RESULTS@#During the preservation, the rate of red blood cell hemolysis in EP-AS and TAU-AS groups were significantly lower than that in CPDA-1 group (P<0.01). The MCV of EP-AS group was increased with the preservation time (r=0.71), while the MCV of the TAU-AS group was significantly lower than that in the other two groups (P<0.05). The concentration of ATP and MDA in EP-AS and TAU-AS groups were significantly higher than that in CPDA-1 group at the 14th day (P<0.01). The concentrations of 2,3-DPG in the EP-AS and TAU-AS groups were significantly higher than that in the CPDA-1 group from the 7th day (P<0.01).@*CONCLUSION@#EP and TAU can significantly reduce the red blood cell hemolysis rate, inhibit the lipid peroxidation level of red blood cells, and improve the energy metabolism of red blood cells during storage. The mechanism of EP and TAU may be related to their antioxidation and membrane protection effect, so as to improve the red blood cell quality and extend the preservation time.

Progress in studies on production of chemicals from xylose by Saccharomyces cerevisiae / 生物工程学报

Effective utilization of xylose is a basis for economic production of biofuels or chemicals from lignocellulose biomass. Over the past 30 years, through metabolic engineering, evolutionary engineering and other strategies, the metabolic capacity of xylose of the traditional ethanol-producing microorganism Saccharomyces cerevisiae has been significantly improved. In recent years, the reported results showed that the transcriptome and metabolome profiles between xylose and glucose metabolism existed significant difference in recombinant yeast strains. Compared with glucose, the overall process of xylose metabolism exhibits Crabtree-negative characteristics, including the limited glycolytic pathway activity, which reduces the metabolic flux of pyruvate to ethanol, and the enhanced cytosolic acetyl-CoA synthesis and respiratory energy metabolism. These traits are helpful to achieve efficient synthesis of downstream products using pyruvate or acetyl-CoA as precursors. This review provides a detailed overview on the modification and optimization of xylose metabolic pathways in S. cerevisiae, the characteristics of xylose metabolism, and the construction of cell factories for production of chemicals using xylose as a carbon source. Meanwhile, the existed difficulties and challenges, and future studies on biosynthesis of bulk chemicals using xylose as an important carbon source are proposed.

Research of progress of pyruvate dehydrogenase complex in sepsis metabolism / 中华危重病急救医学

Sepsis is a critical illness with high morbidity and mortality. Anaerobic glycolysis plays an important role in the pathogenesis of sepsis. Pyruvate dehydrogenase complex (PDHC) serves as a key regulator during sepsis. With PDHC dephosphorylation and deacetylation, PDHC activity is upregulated, allowing pyruvate translocate to mitochondria in aerobic condition, preceding the production of acetyl-CoA to accelerate aerobic oxidation. Activation of PDHC improves the prognosis of sepsis through regulating the balance of lactate, release of inflammatory factors and energy metabolism. A variety of remedies can improve the prognosis of patients with sepsis by up-regulating the activity of PDHC, including dichloroacetate (DCA), vitamin B1, milrinone, tumor necrosis factor binding protein, and ciprofloxacin.This article reviews the role and the regulatory mechanism of PDHC and signal pathway in the sepsis metabolism, in order to innovate treatment for sepsis and multiple organ dysfunction.

Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

Abstract Inborn errors of metabolism are predominantly autosomal-recessive disorders, but several follow an X-linked pattern of inheritance. They are called X-linked recessive, if the female carriers are asymptomatic, and are called X-linked dominant disorders, if almost all females are affected. Conditions, in which some females have symptoms while others are asymptomatic lifelong are simply referred to as X-linked. The aim of this review is to point out the variability in clinical manifestation of affected females in some X-linked metabolic disorders and to discuss on the basis of these examples possible mechanisms that may explain the broad phenotypic spectrum, such as the type of the underlying mutation, the issue of autonomous versus non-autonomous gene expression and the degree of skewing of X-inactivation. The use of the terms "X-linked dominant" and "X-linked recessive" will be discussed.

Research progress on pyruvate dehydrogenase kinase inhibitors / 药学学报

Tumor cells can metabolize glucose through glycolysis to intermediates for biomacromolecule synthesis by inhibiting the activity of the pyruvate dehydrogenase complex (PDC) in mitochondria. In this process, pyruvate dehydrogenase kinases (PDKs) play a key role. The inhibition of the activity of PDKs can effectively block this metabolic pathway, activate mitochondrial oxidative metabolism, and induce tumor cell apoptosis. PDK inhibitors have become a research hotspot in medicinal chemistry, and novel structures targeting classical binding sites have been synthesized. In this paper, recent research progress on PDK inhibitors is reviewed to provide information on these latest entities and to explore their clinical applicability.

Roles of PTBP1 in alternative splicing, glycolysis, and oncogensis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and is expressed in almost all cell types in humans, unlike the other proteins of the PTBP family. PTBP1 mediates several cellular processes in certain types of cells, including the growth and differentiation of neuronal cells and activation of immune cells. Its function is regulated by various molecules, including microRNAs (miRNAs), long non-coding RNAs (IncRNAs), and RNA-binding proteins. PTBP1 plays roles in various diseases, particularly in some cancers, including colorectal cancer, renal cell cancer, breast cancer, and glioma. In cancers, it acts mainly as a regulator of glycolysis, apoptosis, proliferation, tumorigenesis, invasion, and migration. The role of PTBP1 in cancer has become a popular research topic in recent years, and this research has contributed greatly to the formulation of a useful therapeutic strategy for cancer. In this review, we summarize recent findings related to PTBP1 and discuss how it regulates the development of cancer cells.