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Article ; Online: Reply by Authors.

Houston, Charlotte Goldman / Azar, William S / Huang, Sean Shenghsiu / Rubin, Rachel / Dorris, C Scott / Sussman, Rachael D

Urology practice

2024 Volume 11, Issue 2, Page(s) 266

Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ISSN	2352-0787
ISSN (online)	2352-0787
DOI	10.1097/UPJ.0000000000000513.03
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Article ; Online: Urinary 20-HETE

Pamela Houeiss / Rachel Njeim / Hani Tamim / Ahmed F. Hamdy / Tanya S. Azar / William S. Azar / Mohamed Noureldein / Youssef H. Zeidan / Awad Rashid / Sami T. Azar / Assaad A. Eid

Journal of Advanced Research, Vol 44, Iss , Pp 109-

A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease

2023 Volume 117

Abstract: Introduction: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. Objectives: The main objective of this study is ... ...

Abstract	Introduction: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. Objectives: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. Methods: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). Results: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. Conclusion: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.
Keywords	Diabetes ; Biomarkers ; Diabetic Kidney Diseases ; Microvascular Complications ; Macrovascular Complications ; 20-HETE ; Medicine (General) ; R5-920 ; Science (General) ; Q1-390
Subject code	610 ; 616
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Njeim, Rachel / Braych, Kawthar / Ghadieh, Hilda E / Azar, Nadim S / Azar, William S / Dia, Batoul / Leone, Angelo / Cappello, Francesco / Kfoury, Hala / Harb, Frederic / Jurjus, Abdo R / Eid, Assaad A / Ziyadeh, Fuad N

Diabetes

2023 Volume 72, Issue 7, Page(s) 947–957

Abstract: Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against ... ...

Abstract	Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. Article highlights: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.
MeSH term(s)	Rats ; Animals ; Humans ; Diabetic Nephropathies ; Vascular Endothelial Growth Factor A ; Diabetes Mellitus, Type 1 ; Reactive Oxygen Species/metabolism ; Cytochrome P-450 Enzyme System ; Hyperglycemia ; NADPH Oxidase 4/genetics
Chemical Substances	cytochrome P-450 CYP2C subfamily ; Vascular Endothelial Growth Factor A ; Reactive Oxygen Species ; Cytochrome P-450 Enzyme System (9035-51-2) ; Nox4 protein, rat (EC 1.6.3.-) ; NADPH Oxidase 4 (EC 1.6.3.-)
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db22-0636
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Article ; Online: A Cost Savings Analysis of Topical Estrogen Therapy in Urinary Tract Infection Prevention Among Postmenopausal Women.

Houston, Charlotte Goldman / Azar, William S / Huang, Sean Shenghsiu / Rubin, Rachel / Dorris, C Scott / Sussman, Rachael D

Urology practice

2023 Volume 11, Issue 2, Page(s) 257–266

Abstract: Introduction: UTIs are some of the most common infections in geriatric patients, with many women experiencing recurrent infections after menopause. In the US, annual UTI-related costs are $2 billion, with recurrent infections creating a significant ... ...

Abstract	Introduction: UTIs are some of the most common infections in geriatric patients, with many women experiencing recurrent infections after menopause. In the US, annual UTI-related costs are $2 billion, with recurrent infections creating a significant economic burden. Given the data published on topical estrogen in reducing the number of infections for postmenopausal women with recurrent UTI, we sought to evaluate how this would translate to cost savings. Methods: We performed a systematic literature review of UTI reduction secondary to topical estrogen utilization in postmenopausal female patients. The cost per UTI was determined based on published Medicare spending on UTI per beneficiary, weighted on reported likelihood of complicated and resistant infections. For a patient with recurrent infections, topical estrogen therapy reported on average can reduce infections from 5 to 0.5 to 2 times per person per year. Results: At a calculated cost per UTI of $1222, the reduction in UTI spending can range between $3670 and $5499 per beneficiary per year. Per-beneficiary spending on topical estrogen therapies was $1013 on average ($578-$1445) in 2020. After including the cost of the therapy, overall cost savings for topical estrogen therapies were $1226 to $4888 annually per patient. Conclusions: Topical estrogens are a cost-conscious way to improve the burden of UTI on postmenopausal women with the potential for billions of dollars in Medicare savings. System-wide efforts should be made to have these therapies available as prophylaxis for postmenopausal patients and to ensure they are affordable for patients.
MeSH term(s)	Aged ; Humans ; Female ; United States/epidemiology ; Postmenopause ; Reinfection/complications ; Cost Savings ; Medicare ; Urinary Tract Infections/drug therapy ; Estrogens/therapeutic use
Chemical Substances	Estrogens
Language	English
Publishing date	2023-12-28
Publishing country	United States
Document type	Systematic Review ; Journal Article
ISSN	2352-0787
ISSN (online)	2352-0787
DOI	10.1097/UPJ.0000000000000513
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Article ; Online: Urinary 20-HETE: A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease.

Houeiss, Pamela / Njeim, Rachel / Tamim, Hani / Hamdy, Ahmed F / Azar, Tanya S / Azar, William S / Noureldein, Mohamed / Zeidan, Youssef H / Rashid, Awad / Azar, Sami T / Eid, Assaad A

Journal of advanced research

2022 Volume 44, Page(s) 109–117

Abstract	Introduction: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. Objectives: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. Methods: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). Results: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. Conclusion: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.
MeSH term(s)	Humans ; Diabetic Nephropathies/diagnosis ; Diabetic Nephropathies/urine ; Prognosis ; Prospective Studies ; Kidney ; Diabetes Mellitus/metabolism
Chemical Substances	20-hydroxy-5,8,11,14-eicosatetraenoic acid (79551-86-3)
Language	English
Publishing date	2022-04-28
Publishing country	Egypt
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541849-X
ISSN	2090-1224 ; 2090-1224
ISSN (online)	2090-1224
ISSN	2090-1224
DOI	10.1016/j.jare.2022.04.013
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Article ; Online: COVID-19 and diabetes mellitus: how one pandemic worsens the other.

Azar, William S / Njeim, Rachel / Fares, Angie H / Azar, Nadim S / Azar, Sami T / El Sayed, Mazen / Eid, Assaad A

Reviews in endocrine & metabolic disorders

2020 Volume 21, Issue 4, Page(s) 451–463

Abstract: In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone ...

Abstract	In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone to severe symptoms and appear to have a higher mortality rate. In this review, we elucidate suggested mechanisms underlying the increased susceptibility of patients with diabetes to infection with SARS-CoV-2 with a more severe COVID-19 disease. The worsened prognosis of COVID-19 patients with DM can be attributed to a facilitated viral uptake assisted by the host's receptor angiotensin-converting enzyme 2 (ACE2). It can also be associated with a higher basal level of pro-inflammatory cytokines present in patients with diabetes, which enables a hyperinflammatory "cytokine storm" in response to the virus. This review also suggests a link between elevated levels of IL-6 and AMPK/mTOR signaling pathway and their role in exacerbating diabetes-induced complications and insulin resistance. If further studied, these findings could help identify novel therapeutic intervention strategies for patients with diabetes comorbid with COVID-19.
MeSH term(s)	COVID-19 ; Comorbidity ; Coronavirus Infections/epidemiology ; Coronavirus Infections/immunology ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/immunology ; Disease Susceptibility/epidemiology ; Disease Susceptibility/immunology ; Humans ; Pandemics ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/immunology
Keywords	covid19
Language	English
Publishing date	2020-07-26
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2185718-0
ISSN	1573-2606 ; 1389-9155
ISSN (online)	1573-2606
ISSN	1389-9155
DOI	10.1007/s11154-020-09573-6
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Article ; Online: Reducing False-Positives Due to Urinary Stagnation in the Prostatic Urethra on 18F-DCFPyL PSMA PET/CT With MRI.

Gelikman, David G / Mena, Esther / Lindenberg, Liza / Azar, William S / Rathi, Nityam / Yilmaz, Enis C / Harmon, Stephanie A / Schuppe, Kyle C / Hsueh, Jessica Y / Huth, Hannah / Wood, Bradford J / Gurram, Sandeep / Choyke, Peter L / Pinto, Peter A / Turkbey, Baris

Clinical nuclear medicine

2024

Abstract: Purpose: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation ...

Abstract	Purpose: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra. Patients and methods: Eighty-five patients who underwent both 18F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored. Results: Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively (P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls. Conclusions: Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer.
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	197628-x
ISSN	1536-0229 ; 0363-9762
ISSN (online)	1536-0229
ISSN	0363-9762
DOI	10.1097/RLU.0000000000005220
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Article ; Online: Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy.

Abou Daher, Alaa / Alkhansa, Sahar / Azar, William S / Rafeh, Rim / Ghadieh, Hilda E / Eid, Assaad A

Antioxidants & redox signaling

2022 Volume 37, Issue 10-12, Page(s) 802–819

Abstract: ... Significance: ... Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic ...

Abstract	*Significance:* Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. *Recent Advances:* Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. *Critical Issues:* A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. *Future Directions:* Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.
MeSH term(s)	Autophagy ; Diabetic Nephropathies/metabolism ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2021.0217
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Article: SGLT2 Inhibitor-Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism.

Dia, Batoul / Alkhansa, Sahar / Njeim, Rachel / Al Moussawi, Sarah / Farhat, Theresa / Haddad, Antony / Riachi, Mansour E / Nawfal, Rashad / Azar, William S / Eid, Assaad A

Pharmaceutics

2023 Volume 15, Issue 3

Abstract: Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic ... ...

Abstract	Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.
Language	English
Publishing date	2023-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15030965
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Article ; Online: NETosis contributes to the pathogenesis of diabetes and its complications.

Njeim, Rachel / Azar, William S / Fares, Angie H / Azar, Sami T / Kfoury Kassouf, Hala / Eid, Assaad A

Journal of molecular endocrinology

2020 Volume 65, Issue 4, Page(s) R65–R76

Abstract: NETosis, a novel form of neutrophil-related cell death, acts as a major regulator of diabetes and diabetes-associated complications. In this review, we show that the extrusion of neutrophil extracellular traps, termed NETs, plays an important role in the ...

Abstract	NETosis, a novel form of neutrophil-related cell death, acts as a major regulator of diabetes and diabetes-associated complications. In this review, we show that the extrusion of neutrophil extracellular traps, termed NETs, plays an important role in the pathogenesis of type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and diabetes-induced complications. In T1DM, β-cell death induces the sequestration of neutrophils in the pancreas and seems to be correlated with increased NETosis. In T2DM patients, products of NETs release are significantly elevated. Increased levels of dsDNA are correlated with the presence of cardiovascular disease and diabetic kidney disease, further supporting the role of NETosis in the pathogenesis of other diabetes-induced complications such as impaired wound healing and diabetic retinopathy. NETosis is induced by high glucose through incompletely understood mechanisms, but it also appears to be elevated in patients with diabetes who have tightly controlled glucose levels. We hypothesize that hyperglycemia worsens the already elevated baseline of NETosis in diabetic patients to further increase its detrimental effects.
MeSH term(s)	Animals ; Biomarkers ; Diabetes Complications/etiology ; Diabetes Complications/metabolism ; Diabetes Mellitus/etiology ; Diabetes Mellitus/metabolism ; Disease Susceptibility ; Extracellular Traps/genetics ; Extracellular Traps/immunology ; Extracellular Traps/metabolism ; Humans ; NADPH Oxidases/genetics ; NADPH Oxidases/metabolism ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/pathology
Chemical Substances	Biomarkers ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2020-10-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1530/JME-20-0128
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