-
The American Journal of Pathology Jan 2017Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina.... (Review)
Review
Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy.
Topics: Animals; Diabetic Retinopathy; Humans; Low-Level Light Therapy; Mitochondria; Molecular Targeted Therapy; Oxidative Stress; Retina
PubMed: 27846381
DOI: 10.1016/j.ajpath.2016.08.022 -
Haematologica Jun 2018Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to...
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×10 white blood cells. studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; =0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; =0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; <0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; =0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in -mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with mutation.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Hormonal; Dexamethasone; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukocytosis; Male; Middle Aged; Mutation; Nuclear Proteins; Nucleophosmin; Prognosis; Recurrence; Remission Induction; Treatment Outcome; Young Adult
PubMed: 29519869
DOI: 10.3324/haematol.2017.184267 -
Experimental Eye Research Dec 2022Corneal neovascularization can cause devastating consequences including vision impairment and even blindness. Corneal inflammation is a crucial factor for the induction...
Corneal neovascularization can cause devastating consequences including vision impairment and even blindness. Corneal inflammation is a crucial factor for the induction of corneal neovascularization. Current anti-inflammatory approaches are of limited value with poor therapeutic effects. Therefore, there is an urgent need to develop new therapies that specifically modulate inflammatory pathways and inhibit neovascularization in the cornea. The interaction of chemokines and their receptors plays a key role in regulating leukocyte migration during inflammatory response. CXCR3 is essential for mediating the recruitment of activated T cells and microglia/macrophages, but the role of CXCR3 in the initiation and promotion of corneal neovascularization remains unclear. Here, we showed that the expression of CXCL10 and CXCR3 was significantly increased in the cornea after alkali burn. Compared with WT mice, CXCR3 mice exhibited significantly increased corneal hemangiogenesis and lymphangiogenesis after alkali burn. In addition, exaggerated leukocyte infiltration and leukostasis, and elevated expression of inflammatory cytokines and angiogenic factor were also found in the corneas of CXCR3 mice subjected to alkali burn. With bone marrow (BM) transplantation, we further demonstrated that the deletion of CXCR3 in BM-derived leukocytes plays a key role in the acceleration of alkali burn-induced corneal neovascularization. Taken together, our results suggest that upregulation of CXCR3 does not exhibit its conventional action as a proinflammatory cytokine but instead serves as a self-protective mechanism for the modulation of inflammation and maintenance of corneal avascularity after corneal alkali burn.
Topics: Mice; Animals; Corneal Neovascularization; Burns, Chemical; Alkalies; Eye Burns; Corneal Injuries; Cornea; Inflammation; Cytokines; Disease Models, Animal
PubMed: 36206861
DOI: 10.1016/j.exer.2022.109265 -
The American Journal of Case Reports Jul 2020BACKGROUND Chronic lymphocytic leukemia (CLL) is a mature B cell lymphocytic neoplasm that has an indolent clinical course. Therefore, not all patients with CLL require...
BACKGROUND Chronic lymphocytic leukemia (CLL) is a mature B cell lymphocytic neoplasm that has an indolent clinical course. Therefore, not all patients with CLL require treatment at the time of diagnosis. Hyperleukocytosis (white blood cell count, >100×10⁹/L) is present in a large proportion of patients with CLL. However, symptomatic hyperleukocytosis (leukostasis) is an extremely uncommon presentation of CLL. Leukostasis frequently presents with the clinical manifestation of respiratory, neurological, or renal system problems. This is secondary to the decreased tissue perfusion due to the intravascular accumulation of large aggregates of leukemic cells. Leukostasis is a medical emergency requiring intensive care unit (ICU) admission and its management includes aggressive hydration, prevention and treatment of tumor lysis syndrome, cytoreduction, and leukapheresis. CASE REPORT We report a case of a 77-year-old woman with a long history of untreated CLL who presented with respiratory symptoms with hyperleukocytosis. Her condition rapidly deteriorated, requiring intubation. She required induction chemotherapy with chlorambucil as well as 2 sessions of leukapheresis, to which she responded well. In most reported leukostasis cases in the literature, the white blood cell (WBC) count was >1000×10⁹/L. We present a case of a patient with leukostasis with WBC count 524×10⁹/L who responded to chlorambucil and leukapheresis, with good recovery. CONCLUSIONS Leukostasis, although extremely rare, is a life-threatening complication in patients with CLL. It should be strongly considered in the differential diagnosis of patients with CLL who present with hyperleukocytosis and acute pulmonary symptoms. Clinicians should be aware of this medical emergency, as delayed treatment can increase morbidity and mortality.
Topics: Aged; Antineoplastic Agents, Alkylating; Chlorambucil; Cough; Dyspnea; Female; Humans; Leukapheresis; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocyte Count; Leukostasis
PubMed: 32616708
DOI: 10.12659/AJCR.924798 -
International Journal of Molecular... Jan 2018Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First... (Review)
Review
Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal-regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients.
Topics: Animals; Blood-Retinal Barrier; Diabetic Retinopathy; Humans; Microglia; Retinal Vessels
PubMed: 29301251
DOI: 10.3390/ijms19010110 -
Theranostics 2023Diabetic retinopathy (DR) is associated with retinal neovascularization, hard exudates, inflammation, oxidative stress and cell death, leading to vision loss....
Diabetic retinopathy (DR) is associated with retinal neovascularization, hard exudates, inflammation, oxidative stress and cell death, leading to vision loss. Anti-vascular endothelial growth factor (Anti-VEGF) therapy through repeated intravitreal injections is an established treatment for reducing VEGF levels in the retina for inhibiting neovascularization and leakage of hard exudates to prevent vision loss. Although anti-VEGF therapy has several clinical benefits, its monthly injection potentially causes devastating ocular complications, including trauma, intraocular hemorrhage, retinal detachment, endophthalmitis, etc. As mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) demonstrated safety in clinical studies, we have tested the efficacy of MSC-derived small EVs (MSC-sEVs) loaded anti-VEGF drug bevacizumab in a rat model of DR. The study identified a clinically significant finding that sEV loaded with bevacizumab reduces the frequency of intravitreal injection required for treating diabetic retinopathy. The sustained effect is observed from the reduced levels of VEGF, exudates and leukostasis for more than two months following intravitreal injection of sEV loaded with bevacizumab, while bevacizumab alone could maintain reduced levels for about one month. Furthermore, retinal cell death was consistently lower in this period than only bevacizumab. This study provided significant evidence for the prolonged benefits of sEVs as a drug delivery system. Also, EV-mediated drug delivery systems could be considered for clinical application of retinal diseases as they maintain vitreous clarity in the light path due to their composition being similar to cells.
Topics: Animals; Rats; Bevacizumab; Intravitreal Injections; Diabetic Retinopathy; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Extracellular Vesicles; Diabetes Mellitus
PubMed: 37153730
DOI: 10.7150/thno.78426 -
Regulation by reversible S-glutathionylation: molecular targets implicated in inflammatory diseases.Molecules and Cells May 2008S-glutathionylation is a reversible post-translational modification that continues to gain eminence as a redox regulatory mechanism of protein activity and associated... (Review)
Review
S-glutathionylation is a reversible post-translational modification that continues to gain eminence as a redox regulatory mechanism of protein activity and associated cellular functions. Many diverse cellular proteins such as transcription factors, adhesion molecules, enzymes, and cytokines are reported to undergo glutathionylation, although the functional impact has been less well characterized. De-glutathionylation is catalyzed specifically and efficiently by glutaredoxin (GRx, aka thioltransferase), and facile reversibility is critical in determining the physiological relevance of glutathionylation as a means of protein regulation. Thus, studies with cohesive themes addressing both the glutathionylation of proteins and the corresponding impact of GRx are especially useful in advancing understanding. Reactive oxygen species (ROS) and redox regulation are well accepted as playing a role in inflammatory processes, such as leukostasis and the destruction of foreign particles by macrophages. We discuss in this review the current implications of GRx and/or glutathionylation in the inflammatory response and in diseases associated with chronic inflammation, namely diabetes, atherosclerosis, inflammatory lung disease, cancer, and Alzheimer's disease, and in viral infections.
Topics: Cytokines; Glutaredoxins; Glutathione; Humans; Inflammation; Inflammation Mediators; Macrophages; Monocytes; Protein Processing, Post-Translational; Reactive Oxygen Species; Virus Diseases
PubMed: 18483468
DOI: No ID Found -
Autopsy & Case Reports 2023Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with...
Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with maturation arrest and no significant myeloblasts. We describe an autopsy case of this rare entity in a 62-year-old man with co-morbidities. He underwent a bone marrow (BM) examination for pancytopenia during the first outpatient department visit, which revealed an increased number of erythroid precursors with dysmegakaryopoiesis suggesting the possibility of Myelodysplastic syndromes (MDS). Thereafter, his cytopenia got worsened, warranting blood and platelet transfusions. Four weeks later on the second BM examination, AEL was diagnosed based on morphology and immunophenotyping. Targeted resequencing for myeloid mutations revealed TP53 and DNMT3A mutations. He was initially managed along febrile neutropenia with the stepwise escalation of antibiotics. He developed hypoxia attributed to anemic heart failure. Subsequently, he had hypotension and respiratory fatigue pre-terminally and succumbed to his Illness. A complete autopsy showed infiltration of various organs by AEL and leukostasis. Besides, there was extramedullary hematopoiesis, arterionephrosclerosis, diabetic nephropathy (ISN-RPS class II), mixed dust pneumoconiosis, and pulmonary arteriopathy. The histomorphology of AEL was challenging, and the differential diagnoses were many. Thus, this case highlights the autopsy pathology of AEL, an uncommon entity with a strict definition, and its relevant differentials.
PubMed: 37287566
DOI: 10.4322/acr.2023.429 -
Experimental Diabetes Research 2007Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy.... (Review)
Review
Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-kappaB, increased production of nitric oxide, prostaglandin E2, IL-1beta, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.
Topics: Animals; Antioxidants; Capillaries; Capillary Permeability; Caspase 1; Cell Adhesion; Cytokines; Diabetic Retinopathy; Disease Models, Animal; Glycation End Products, Advanced; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Leukocytes; NF-kappa B; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Retinal Vessels; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A
PubMed: 18274606
DOI: 10.1155/2007/95103 -
International Journal of Molecular... Jun 2020We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and...
Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model.
We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8-18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood-retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1b, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.
Topics: Animals; Blood-Retinal Barrier; Capillary Permeability; Carrier Proteins; Caspase 1; Cell Adhesion Molecules; Coculture Techniques; Diet, High-Fat; Disease Models, Animal; Endothelial Cells; Female; Gene Deletion; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-1beta; Leukostasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Retina; Thioredoxins
PubMed: 32492941
DOI: 10.3390/ijms21113983