P2X7 Receptor: Warburg effect revisited

Ability to adapt to conditions of limited nutrient supply is a key feature of all cells. This may require a complex re-organization of metabolic pathways to balance energy generation and production of biosynthetic intermediates. Several fast-growing cells overexpress the P2X7 receptor (P2X7R) for extracellular ATP. A peculiar feature of this receptor is that it allows growth in the absence of serum. We show here that transfection of P2X7R allows proliferation of HEK293 (HEK293-P2X7) cells not only in the absence of serum but also in low (4 mM) glucose and strongly increases lactate output compared to mock-transfected cells (HEK293-mock). In HEK293-P2X7 lactate output is further stimulated upon addition of exogenous ATP or of the mitochondrial uncoupler FCCP. In another tumour cell line constitutively expressing the P2X7R, the human neuroblastoma cell line ACN, lactate output is also dependent on P2X7R function. P2X7R-expressing cells up-regulate a) the glucose transporter Glut-1, b) the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (G3PDH), c) pyruvate kinase M2 (PK-M2) and d) pyruvate dehydrogenase kinase 1 (PDHK1), e) increase phosphorylated Akt/PKB (ph- Akt/PKB) and f) the level of intracellular glycogen stores. In HEK293-P2X7 cells glucose deprivation strongly increases lactate production, expression of glycolytic enzymes and ph-Akt/PKB level. These data show that the P2X7R has an intrinsic ability to reprogram cell metabolism to meet the needs imposed by adverse environmental conditions

Serum uric acid as a marker of microvascular damage in systemic sclerosis patients

Background: Microvascular damage of skin and internal organs is a hallmark of systemic sclerosis (SSc). Serum uric acid (UA) represents a marker of inflammation and endothelial dysfunction. The aims of this study were to evaluate the correlation between serum UA and intrarenal arterial stiffness evaluated by Doppler ultrasound in SSc patients with normal renal function. We also evaluated the correlation between serum UA and other clinical variables of the disease. Methods: Forty-five SSc patients underwent clinical assessment, Doppler ultrasound of intrarenal arteries with evaluation of resistive index (RI), pulsatile index (PI), and systolic/diastolic ratio (S/D), echocardiography with systolic pulmonary artery pressure (PAPs), baseline pulmonary function tests, and nailfold videocapillaroscopy (NVC). In all patients serum UA was measured. Results: The serum UA showed a significant positive correlation with sCr (r = 0.33, p < 0.0001) and PAPs (r = 0.38, p < 0.01) > and negative correlation with CKD-EPI (r = -0.35, p < 0.01). The mean value of serum UA increased with severity of NVC damage. Using this cut-off value of 4.7 mg/dl, the mean value of Doppler indices of intrarenal stiffness is significantly different (p < 0.05) in SSc patients with low normal or high normal serum UA. Conclusions: Serum UA concentration is higher in patients with high microvascular damage than in patients with low microvascular damage. These preliminary data must be confirmed in large prospective studies

P2X7 Receptor Function in Bone-Related Cancer

Modulation of tumor microenvironment by different mediators is central in determining neoplastic formation and progression. Among these molecules extracellular ATP is emerging as a good candidate in promoting cell growth, neovascularization, tumor-host interactions, and metastatization. This paper summarizes recent findings on expression and function of P2X7 receptor for extracellular ATP in primary and metastatic bone cancers. Search of mRNA expression microchip databases and literature analysis demonstrate a high expression of P2X7 in primary bone tumors as well as in other malignancies such as multiple myeloma, neuroblastoma, breast, and prostate cancer. Evidence that P2X7 triggers NFATc1, PI3K/Akt, ROCK, and VEGF pathways in osteoblasts promoting either primary tumor development or osteoblastic lesions is also reported. Moreover, P2X7 receptor is involved in osteoclast differentiation, RANKL expression, matrix metalloproteases and cathepsin secretion thus promoting bone resorption and osteolytic lesions. Taken together these data point to a pivotal role for the P2X7 receptor in bone cancer biology

Left ventricular mass and intrarenal arterial stiffness as early diagnostic markers in cardiorenal syndrome type 5 due to systemic sclerosis

Background: Cardiorenal syndrome type 5 (CRS-5) includes a group of conditions characterized by a simultaneous involvement of the heart and kidney in the course of a systemic disease. Systemic sclerosis (SSc) is frequently involved in the etiology of acute and chronic CRS-5 among connective tissue diseases. In SSc patients, left ventricular mass (LVM) can be used as a marker of nutritional status and fibrosis, while altered intrarenal hemodynamic parameters are suggestive of early kidney involvement. Methods: Forty-two consecutive patients with a diagnosis of SSc without cardiac and/or renal impairment were enrolled to assess whether cardiac muscle mass can be related to arterial stiffness. Thirty subjects matched for age and sex were also enrolled as healthy controls (HC). All patients performed echocardiography and renal ultrasound. Results: Doppler indices of intrarenal stiffness and echocardiographic indices of LVM were significantly increased in SSc patients compared to HC. A positive correlation exists between LVM/body surface area and pulsatile index (p < 0.05, r = 0.36), resistive index (p < 0.05, r = 0.33) and systolic/diastolic ratio (p < 0.05, r = 0.38). Doppler indices of intrarenal stiffness and LVM indices were significantly higher in SSc patients with digital ulcers than in SSc patients without a digital ulcer history. Conclusions: SSc is characterized by the presence of microvascular and multiorgan injury. An early cardiac and renal impairment is very common. LVM and intrarenal arterial stiffness can be considered as early markers of CRS onset. The clinical use of these markers permits a prompt identification of organ damage. An early diagnosis allows the appropriate setting of pharmacological management, by slowing disease progression

Role of Management Strategies in Reducing Mortality From Invasive Fungal Disease in Children With Cancer or Receiving Hemopoietic Stem Cell Transplant

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