scholarly journals STUDIES ON THE MECHANISM OF THE SHWARTZMAN PHENOMENON

1949 ◽  
Vol 89 (5) ◽  
pp. 461-478 ◽  
Author(s):  
Lewis Thomas ◽  
Chandler A. Stetson
Keyword(s):  
Intravenous Injection ◽  
Aerobic Glycolysis ◽  
Normal Skin ◽  
Intradermal Injection ◽  
Anaerobic Glycolysis ◽  
Rabbit Skin ◽  
High Degree ◽  
Shwartzman Phenomenon

Rabbit skin which is prepared for the Shwartzman phenomenon by an intradermal injection of meningococcal toxin exhibits, in vitro, a high degree of aerobic glycolysis. This metabolic abnormality is reflected, in vivo, by a measurable increase in the concentration of lactic acid in the prepared skin. Some increase in anaerobic glycolysis also occurs in prepared skin; this is of less degree than the increase in aerobic glycolysis. The respiratory quotient of prepared skin tends to be somewhat higher than that of normal skin, although the oxygen uptake is not significantly altered. Gross hemorrhagic lesions which resemble the Shwartzman phenomenon are produced by the intradermal injection of papain into rabbits which have received an intravenous injection of meningococcal toxin 1 hour previously. Such hemorrhagic reactions are not observed when papain is injected into normal rabbit skin. Similarly, hemorrhagic lesions are produced by the intradermal injection of cysteine and BAL, following an intravenous injection of meningococcal toxin. An hypothesis to explain the Shwartzman phenomenon, which implicates tissue protease in the damage to the blood vessels of the skin, is proposed.

scholarly journals Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xin Huang ◽  
Yichao Hou ◽  
Xiaoling Weng ◽  
Wenjing Pang ◽  
Lidan Hou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Copper Complex ◽  
Aerobic Glycolysis ◽  
Active Role ◽  
Downstream Effector ◽  
Glycolysis Pathway ◽  
Colorectal Cancer Progression

AbstractExploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.

scholarly journals RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuxia Yan ◽  
Peng Zeng ◽  
Xiuqin Zhou ◽  
Xiaoying Zhao ◽  
Runqiang Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Aerobic Glycolysis ◽  
Histological Grade ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Hnrnp A1

AbstractThe prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

scholarly journals USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Oncogenesis ◽  
2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Ruize Gao ◽  
David Buechel ◽  
Ravi K. R. Kalathur ◽  
Marco F. Morini ◽  
Mairene Coto-Llerena ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptional Activity ◽  
Kinase Inhibitor ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Aberrant Expression ◽  
Key Enzyme ◽  
Hcc Cells

AbstractUnderstanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

scholarly journals Effect of the cholesterol content of small unilamellar liposomes on their stability in vivo and in vitro

1980 ◽  
Vol 186 (2) ◽  
pp. 591-598 ◽  
Author(s):  
Christopher Kirby ◽  
Jacqui Clarke ◽  
Gregory Gregoriadis
Keyword(s):  
Blood Plasma ◽  
Intravenous Injection ◽  
Whole Blood ◽  
Cholesterol Content ◽  
Molar Ratio ◽  
Phosphatidylcholine Liposomes ◽  
Effective Use ◽  
Positively Charged

Small unilamellar neutral, negatively and positively charged liposomes composed of egg phosphatidylcholine, various amounts of cholesterol and, when appropriate, phosphatidic acid or stearylamine and containing 6-carboxyfluorescein were injected into mice, incubated with mouse whole blood, plasma or serum or stored at 4°C. Liposomal stability, i.e. the extent to which 6-carboxyfluorescein is retained by liposomes, was dependent on their cholesterol content. (1) Cholesterol-rich (egg phosphatidylcholine/cholesterol, 7:7 molar ratio) liposomes, regardless of surface charge, remained stable in the blood of intravenously injected animals for up to at least 400min. In addition, stability of cholesterol-rich liposomes was largely maintained in vitro in the presence of whole blood, plasma or serum for at least 90min. (2) Cholesterol-poor (egg phosphatidylcholine/cholesterol, 7:2 molar ratio) or cholesterol-free (egg phosphatidylcholine) liposomes lost very rapidly (at most within 2min) much of their stability after intravenous injection or upon contact with whole blood, plasma or serum. Whole blood and to some extent plasma were less detrimental to stability than was serum. (3) After intraperitoneal injection, neutral cholesterol-rich liposomes survived in the peritoneal cavity to enter the blood circulation in their intact form. Liposomes injected intramuscularly also entered the circulation, although with somewhat diminished stability. (4) Stability of neutral and negatively charged cholesterol-rich liposomes stored at 4°C was maintained for several days, and by 53 days it had declined only moderately. Stored liposomes retained their unilamellar structure and their ability to remain stable in the blood after intravenous injection. (5) Control of liposomal stability by adjusting their cholesterol content may help in the design of liposomes for effective use in biological systems in vivo and in vitro.

scholarly journals Dissemination of Rat Cytomegalovirus through Infected Granulocytes and Monocytes In Vitro and In Vivo

2003 ◽  
Vol 77 (20) ◽  
pp. 11274-11278 ◽  
Author(s):  
B. W. A. van der Strate ◽  
J. L. Hillebrands ◽  
S. S. Lycklama à Nijeholt ◽  
L. Beljaars ◽  
C. A. Bruggeman ◽  
...  
Keyword(s):  
Intravenous Injection ◽  
Systemic Infection ◽  
Insight Into

ABSTRACT The role of leukocytes in the in vivo dissemination of cytomegalovirus was studied in this experiment. Rat cytomegalovirus (RCMV) could be transferred to rat granulocytes and monocytes by cocultivation with RCMV-infected fibroblasts in vitro. Intravenous injection of purified infected granulocytes or monocytes resulted in a systemic infection in rats, indicating that our model is a powerful tool to gain further insight into CMV dissemination and the development of new antivirals.

scholarly journals On the origin of the increased tissue iron content in graded magnesium deficiency states in the rat

1997 ◽  
Vol 77 (3) ◽  
pp. 475-490 ◽  
Author(s):  
Klaus Schumann ◽  
Annette Lebeau ◽  
Ursula Gresser ◽  
Theodor Gunther ◽  
Jürgen Vormann
Keyword(s):  
Haemolytic Anaemia ◽  
Rapid Growth ◽  
Magnesium Deficiency ◽  
Erythropoietic Activity ◽  
Mg Deficiency ◽  
Adequate Diet ◽  
Fe Content ◽  
High Degree

To investigate the mechanism of tissue Fe accumulation in graded Mg deficiency rats were fed on diets of different Mg contents (70, 110, 208, 330, and 850 mg Mg/kg) for 10, 20, and 30 d during rapid growth. There was no significant impact of Mg deficiency or high luminal Mg concentrations on intestinal59Fe transferin vitroorin vivo. Plasma Mg concentrations and body weight started to decrease after 10 d. Significant haemolytic anaemia was observed after 20 d with siderosis in liver and spleen developing in parallel. Anaemia showed no features of Fe deficiency or infiammation. Comparison between the 70 mg Mg/kg group and animals that received the same quantity of a Mg-adequate diet (850 mg Mg/kg) permitted estimation of quantities of Fe liberated by haemolysis and the increased Fe content in liver and spleen. Both variables showed a high degree of correlation, indicating that the excess of liberated haemoglobin Fe was stored in the tissue. The erythropoietic activity was high during rapid growth, i.e. at days 10 and 20 and decreased significantly after 30 d in all except the most Mg-deficient groups. However, haemolytic anaemia developed because even the high erythropoietic activity in the 70 and 110 mg Mg/kg groups was not sutlicient to recycle all haemoglobin Fe liberated by haemolysis. After 30 d of Mg-deficient feeding the erythrocyte Mg content had decreased to 40% of control values. According to the literature Mg-deficient erythrocytes have a decreased survival time which is likely to be the cause of the observed haemolysis.

Developmental regulation of heterochromatin-mediated gene silencing in Drosophila

Development ◽  
1998 ◽  
Vol 125 (12) ◽  
pp. 2223-2234 ◽  
Author(s):  
B.Y. Lu ◽  
J. Ma ◽  
J.C. Eissenberg
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Mitotic Activity ◽  
Larval Stage ◽  
Developmental Regulation ◽  
Promoter Strength ◽  
Lacz Gene ◽  
High Degree

The roles of differentiation, mitotic activity and intrinsic promoter strength in the maintenance of heterochromatic silencing were investigated during development using an inducible lacZ gene as an in vivo probe. Heterochromatic silencing is initiated at the onset of gastrulation, approximately 1 hour after heterochromatin is first visible cytologically. A high degree of silencing is maintained in the mitotically active imaginal cells from mid-embryogenesis until early third instar larval stage, and extensive relaxation of silencing is tightly associated with the onset of differentiation. Relaxation of silencing can be triggered in vitro by ecdysone. In contrast, timing and extent of silencing at both the initiation and relaxation stages are insensitive to changes in cell cycle activity, and intrinsic promoter strength also does not influence the extent of silencing by heterochromatin. These data suggest that the silencing activity of heterochromatin is developmentally programmed.

METABOLISM OF RAM TESTICULAR SPERMATOZOA IN THE PRESENCE OF TESTOSTERONE AND RELATED STEROIDS

1970 ◽  
Vol 65 (3) ◽  
pp. 565-576 ◽  
Author(s):  
J. K. Voglmayr ◽  
R. N. Murdoch ◽  
I. G. White
Keyword(s):  
Aerobic Glycolysis ◽  
Rete Testis ◽  
Glycolytic Metabolism ◽  
Anaerobic Conditions ◽  
Aerobic Conditions ◽  
Testicular Spermatozoa ◽  
Almost All ◽  
Oxidation Of Glucose

ABSTRACT The effects of testosterone* and related steroids on the oxidative and glycolytic metabolism of freshly collected ram testicular spermatozoa and of spermatozoa stored under air in rete testis fluid for 3 days at 3°C have been studied. When freshly collected testicular spermatozoa were incubated with glucose under aerobic conditions only a small proportion of the utilized glucose could be accounted for as lactate. The addition of a number of steroids, including testosterone, androstanedione, 5β-androstanedione, androsterone, epiandrosterone and 5β-androsterone, greatly increased aerobic glycolysis, the oxidation of the substrate and the proportion of the utilized substrate converted to lactic acid. After 3 days storage at 3°C, testicular spermatozoa respired at a greater rate than spermatozoa freshly collected from the testes. Although the stimulating effect of steroids on aerobic glycolysis increased after storage, they depressed rather than stimulated the oxidation of glucose by stored testicular spermatozoa. With the exception of androstanedione, which slightly stimulated glycolysis, storage of testicular spermatozoa for 3 days in the presence of steroids did not significantly influence their subsequent metabolism when washed free of the steroids. Both freshly collected and stored ram testicular spermatozoa displayed a marked Pasteur effect, and utilized more glucose and produced more lactate under anaerobic than under aerobic conditions. In the absence of oxygen the steroids did not stimulate glycolysis to any extent. However, epiandrosterone depressed the glycolysis of freshly collected spermatozoa under anaerobic conditions and after storage, 5β-androsterone had a similar effect. Androstanedione, 5β-androstanedione, epiandrosterone and 5β-androsterone were the most effective steroids in altering the metabolism of testicular spermatozoa and, under almost all conditions of incubation, depressed the synthesis of amino acids from glucose. The results suggest that the effects of testosterone and related steroids in vitro may depend on the age of the spermatozoa after their release from the Sertoli cells; the steroid effects may have important consequences in vivo in relation to sperm maturation.

scholarly journals Differential inhibition of polymorphonuclear leukocyte recruitmentin vivoby dextran sulphate and fucoidan

1996 ◽  
Vol 5 (5) ◽  
pp. 346-357 ◽  
Author(s):  
N. Van Osselaer ◽  
M. Rampart ◽  
A. G. Herman
Keyword(s):  
Polymorphonuclear Leukocyte ◽  
Intradermal Injection ◽  
Initial Contact ◽  
Dextran Sulphate ◽  
Differential Inhibition ◽  
Rabbit Skin ◽  
Sulphated Polysaccharides ◽  
Independent Mechanism ◽  
Plasma Leakage

The selectin-mediated rolling of leukocytes along the endothelial cells is a prerequisite step followed by firm adhesion and extravasation into the inflamed tissue. This initial contact can be suppressed by sulphated polysaccharides. We have studied the effect of sulphated polysaccharides on the ultimate polymorphonuclear leukocyte (PMN) recruitment and plasma leakage in rabbit skin in response to intradermal injection of various inflammatory mediators. PMN infiltration evoked by various PMN chemoattractants (FMLP, C5a desArg, LTB4and IL-8) was significantly inhibited after intravenous injection of dextran sulphate (25 mg/kg), heparin (2 × 90 mg/kg) or fucoidan (1 mg/kg). PMN-dependent plasma leakage was equally well reduced by the different sulphated polymers. Vascular permeability induced by histamine or thrombin acting via a PMN-independent mechanism was not reduced. Fucoidan was the only polysaccharide able to suppress IL-1-induced PMN infiltration for 60–70%. Local administration of dextran sulphate had no effect on PMN-dependent plasma leakage. Differential inhibition of PMN recruitment was determined after injection of dextran sulphate or fucoidan depending on the type of insult. Therefore, these results suggest that different adhesion pathways are utilized during PMN recruitmentin vivoin response to chemoattractants and IL-1.

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