scholarly journals Restoring glucose uptake rescues neutrophil dysfunction and protects against systemic fungal infection in mouse models of kidney disease

2020 ◽  
Vol 12 (548) ◽  
pp. eaay5691 ◽  
Author(s):  
Chetan V. Jawale ◽  
Kritika Ramani ◽  
De-dong Li ◽  
Bianca M. Coleman ◽  
Rohan S. Oberoi ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Fungal Infection ◽  
Glucose Uptake ◽  
Clinical Problem ◽  
Antifungal Drugs ◽  
Ros Generation ◽  
Systemic Fungal Infection ◽  
Disseminated Candidiasis ◽  
Underlying Basis ◽  
Neutrophil Dysfunction

Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia; disseminated candidiasis fatality is twice as common in patients with uremia as those with normal kidney function. Many antifungal drugs are nephrotoxic, making treatment of these patients particularly challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here, we show in multiple models that uremic mice exhibit an increased susceptibility to systemic fungal infection. Uremia inhibits Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of GSK3β, resulting in reduced ROS generation and hence impaired killing of C. albicans in mice. Consequently, pharmacological inhibition of GSK3β restored glucose uptake and rescued ROS production and candidacidal function of neutrophils in uremic mice. Similarly, neutrophils isolated from patients with kidney disease and undergoing hemodialysis showed similar defect in the fungal killing activity, a phenotype rescued in the presence of a GSK3β inhibitor. These findings reveal a mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of disseminated candidiasis.

scholarly journals Amphotericin B, the Wonder of Today’s Pharmacology Science: Persisting Usage for More Than Seven Decades

2020 ◽  
Author(s):  
Falah Hasan Obayes AL-Khikani
Keyword(s):  
Adverse Effects ◽  
Fungal Infection ◽  
Amphotericin B ◽  
Antimicrobial Agents ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Antifungal Drugs ◽  
Systemic Fungal Infection

Background: Despite several available topical and systemic antifungal drugs for the treatment of fungal infections, Amphotericin B (AmB) is still one of the most common first-line choices in treating systemic fungal infection for more than seven decades after its discovery.  Objectives: Amphotericin B which belongs to the polyene group has a wide spectrum of in vitro and in vivo antifungal activity. Its mechanism of antifungal action is characterized by creating a pore in the fungal plasma membrane leading to cell death. Methods: In addition to the old formula of deoxycholate-Amphotericin B (D-AmB), three lipid formulas have been developed to reduce the adverse effects of conventional AmB (D-AmB) in the human body and increase its therapeutic efficacy. All of the known available formulas of AmB are administrated via intravenous injection to treat severe systemic fungal infections, while the development of the topical formula of AmB is still under preliminary research. Numerous pharmaceutical formulas of systemic and topical applications with clinical uses of AmB in just humans, not in vitro or animals model, against various fungal infections are discussed in this review. Topical AmB formulas are a promising way to develop effective management and to reduce the adverse effects of intravenous formulas of AmB without laboratory monitoring. Results: The wonderful pharmacological properties of AmB with its prolonged use for about seven decades may help researchers to apply its unique features on other various antimicrobial agents by more understanding about the AmB mechanisms of actions. Conclusion: Amphotericin B is widely used intravenously for the treatment of systemic fungal infection, while the topical formula of AmB is still under experimental study. 

Osteopontin is dispensable for protection against high load systemic fungal infection

2008 ◽  
Vol 8 (10) ◽  
pp. 1441-1448 ◽  
Author(s):  
Ikuko Sato ◽  
Nobuchika Yamamoto ◽  
Susan R. Rittling ◽  
David T. Denhardt ◽  
Motohiro Hino ◽  
...  
Keyword(s):  
Fungal Infection ◽  
High Load ◽  
Systemic Fungal Infection

scholarly journals Diabetes potentiates ROS production in granulocytes from patients with chronic kidney disease

2021 ◽  
Vol 9 (1) ◽  
pp. 9-14
Author(s):  
Jose Augusto Nogueira-Machado ◽  
Gabriela Rossi Ferreira ◽  
Caroline Maria Oliveira Volpe ◽  
Pedro Henrique Villar-Delfino ◽  
Fabiana Rocha Silva
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nadph Oxidase ◽  
Ros Generation ◽  
Ros Production ◽  
Clinical Prognosis ◽  
Before And After ◽  
Healthy Control ◽  
Toll Receptor

Background: Type 2 diabetes (DM2) and chronic kidney disease (CKD) are inflammatory pathologies. Diabetes is characterized by hyperglycemia and CKD by the gradual and irreversible loss of kidney function. Both diseases develop oxidative stress, and reactive oxygen species (ROS) play a pivotal role in the pathogenesis. This study aimed to determine ROS production by granulocytes from renal patients (CKD) with or without diabetes. Methods: Granulocytes from patients with DM2, CKD, CKD-DM2, and healthy controls were purified using the Ficoll-Hypaque gradient method. Granulocyte ROS generation in the absence or the presence of PDB (an activator of NADPH-oxidase) or Concanavalin A (Toll- receptor 3,9 activator) was evaluated in a luminol-dependent chemiluminescence method. The cell-free DNA in the serum of DM2, CKD, and CKD-DM2 patients was measured by the fluorescence method before and after hemodialysis. Results: Our results show a significant increase in ROS production by granulocytes from patients with CKD, DM2, and CKD-DM2 compared to healthy control (p<0.05). CKD-DM2 group produced the most significant ROS levels with or without NADPH-oxidase activation. ROS production showed a significant increase in the presence of ConA. In contrast, mitochondrial (internal) ROS showed a different ROS response. DNA extrusion was higher in the CKD-DM2 group after hemodialysis suggesting cell death. Conclusion: The results demonstrated that CKD-DM2 patients produced high ROS generation levels and increased DNA extrusion after hemodialysis. It may suggest that CKD-DM2 disease is more severe and has a worse clinical prognosis.

scholarly journals Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

2018 ◽  
Vol 51 (3) ◽  
pp. 1287-1300 ◽  
Author(s):  
Manel Vera ◽  
Sergi Torramade-Moix ◽  
Susana Martin-Rodriguez ◽  
Aleix Cases ◽  
Josep M. Cruzado ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Glutathione Peroxidase ◽  
Antioxidant Properties ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Anti Inflammatory

Background/Aims: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. Methods: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. Results: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. Conclusion: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.

scholarly journals Itraconazole Oral Solution for Primary Prophylaxis of Fungal Infections in Patients with Hematological Malignancy and Profound Neutropenia: a Randomized, Double-Blind, Double-Placebo, Multicenter Trial Comparing Itraconazole and Amphotericin B

2000 ◽  
Vol 44 (7) ◽  
pp. 1887-1893 ◽  
Author(s):  
J. L. Harousseau ◽  
A. W. Dekker ◽  
A. Stamatoullas-Bastard ◽  
A. Fassas ◽  
W. Linkesch ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Hematological Malignancy ◽  
Fungal Infections ◽  
Treated Group ◽  
Multicenter Trial ◽  
Oral Solution ◽  
Double Blind ◽  
Systemic Fungal Infection

ABSTRACT Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 × 109 neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%];P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.

Cytosine-arabinoside-induced colitis and peritonitis: nonoperative management.

1985 ◽  
Vol 3 (5) ◽  
pp. 607-612 ◽  
Author(s):  
H Johnson ◽  
T J Smith ◽  
J Desforges
Keyword(s):  
Side Effects ◽  
Fungal Infection ◽  
Conservative Management ◽  
Cytosine Arabinoside ◽  
Patient Population ◽  
Nonoperative Management ◽  
Clinical Monitoring ◽  
Systemic Fungal Infection ◽  
Gastrointestinal Side Effects

Cytosine arabinoside is known to cause severe gastrointestinal side effects in an already very ill patient population. Three cases are reviewed in which apparent surgical peritonitis was managed conservatively, with very careful clinical monitoring. Two of the patients recovered completely, and one died of systemic fungal infection. No patient had a surgically remediable condition, and all were extremely poor surgical risks. A review of our experience and the literature leads us to recommend careful conservative management in patients receiving cytosine arabinoside who appear to have a "surgical abdomen," but in whom a definitive surgical diagnosis cannot be made.

scholarly journals Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection

2018 ◽  
Vol 27 (5) ◽  
pp. 988-1006.e7 ◽  
Author(s):  
Timothy M. Tucey ◽  
Jiyoti Verma ◽  
Paul F. Harrison ◽  
Sarah L. Snelgrove ◽  
Tricia L. Lo ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Cell Viability ◽  
Glucose Homeostasis ◽  
Immune Cell ◽  
Systemic Fungal Infection

scholarly journals Resveratrol metabolites ameliorate insulin resistance in HepG2 hepatocytes by modulating IRS-1/AMPK

RSC Advances ◽  
2018 ◽  
Vol 8 (63) ◽  
pp. 36034-36042 ◽  
Author(s):  
Wendi Teng ◽  
Wenjing Yin ◽  
Liang Zhao ◽  
Changwei Ma ◽  
Jiaqiang Huang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Hepg2 Cell ◽  
Glycogen Synthesis ◽  
Ros Generation ◽  
Ampk Signaling ◽  
Ameliorate Insulin Resistance

RSV metabolites R3G and R4G protected HepG2 cell from insulin resistance by improving glucose uptake and glycogen synthesis, along with inhibiting ROS generation and modulating the RS-1/AMPK signaling pathway.

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