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Biomolecules Nov 2020Changes in retinal microcirculation are associated with the development of diabetic retinopathy (DR). However, it is unclear whether such changes also develop in...
Changes in retinal microcirculation are associated with the development of diabetic retinopathy (DR). However, it is unclear whether such changes also develop in capillary beds of other non-retinal tissues. Here, we investigated microcirculatory changes involving velocity of rolling neutrophils, adherence of neutrophils, and leukostasis during development of retinal vascular lesions in diabetes in other non-retinal tissues. Intravital microscopy was performed on post-capillary venules of cremaster muscle and ear lobe of mice with severe or moderate diabetes and compared to those of non-diabetic mice. Additionally, number and velocity of rolling leukocytes, number of adherent leukocytes, and areas of leukostasis were quantified, and retinal capillary networks were examined for acellular capillaries (AC) and pericyte loss (PL), two prominent vascular lesions characteristic of DR. The number of adherent neutrophils and areas of leukostasis in the cremaster and ear lobe post-capillary venules of diabetic mice was increased compared to those of non-diabetic mice. Similarly, a significant increase in the number of rolling neutrophils and decrease in their rolling velocities compared to those of non-diabetic control mice were observed and severity of diabetes exacerbated these changes. Understanding diabetes-induced microcirculatory changes in cremaster and ear lobe may provide insight into retinal vascular lesion development in DR.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Leukocytes; Leukostasis; Male; Mice; Mice, Transgenic; Microcirculation; Retina
PubMed: 33233433
DOI: 10.3390/biom10111583 -
Biochimica Et Biophysica Acta.... Dec 2018Glycative stress, caused by the accumulation of cytotoxic and irreversibly-formed sugar-derived advanced glycation end-products (AGEs), contributes to morbidity... (Review)
Review
Glycative stress, caused by the accumulation of cytotoxic and irreversibly-formed sugar-derived advanced glycation end-products (AGEs), contributes to morbidity associated with aging, age-related diseases, and metabolic diseases. In this review, we summarize pathways leading to formation of AGEs, largely from sugars and glycolytic intermediates, and discuss detoxification of AGE precursors, including the glyoxalase system and DJ-1/Park7 deglycase. Disease pathogenesis downstream of AGE accumulation can be cell autonomous due to aggregation of glycated proteins and impaired protein function, which occurs in ocular cataracts. Extracellular AGEs also activate RAGE signaling, leading to oxidative stress, inflammation, and leukostasis in diabetic complications such as diabetic retinopathy. Pharmaceutical agents have been tested in animal models and clinically to diminish glycative burden. We summarize existing strategies and point out several new directions to diminish glycative stress including: plant-derived polyphenols as AGE inhibitors and glyoxalase inducers; improved dietary patterns, particularly Mediterranean and low glycemic diets; and enhancing proteolytic capacities of the ubiquitin-proteasome and autophagy pathways that are involved in cellular clearing of AGEs.
Topics: Animals; Autophagy; Cataract; Diabetic Retinopathy; Drug Discovery; Glycation End Products, Advanced; Humans; Macular Degeneration; Receptor for Advanced Glycation End Products; Ubiquitin
PubMed: 30279139
DOI: 10.1016/j.bbadis.2018.08.036 -
International Journal of Ophthalmology 2019Cystoid macular edema (CME) is the abnormal collection of intraretinal fluid in the macular region, especially in the inner nuclear and outer plexiform layers. CME leads... (Review)
Review
Cystoid macular edema (CME) is the abnormal collection of intraretinal fluid in the macular region, especially in the inner nuclear and outer plexiform layers. CME leads to severe visual impairment in patients with various retinal diseases, such as diabetic retinopathy, retinal vascular occlusion, choroidal neovascularization, and uveitis. Although various retinal conditions lead to CME, a shared pathogenesis of CME is involved in these diseases. Accordingly, the pathogenesis of CME based on vasogenic mechanisms is first discussed in this review, including vascular hyperpermeability, leukostasis, and inflammation. We then describe cytotoxic mechanisms based on retinal Müller cell dysfunction. This comprehensive review will provide an understanding of the pathogenesis of CME for potential therapeutic strategies.
PubMed: 31341814
DOI: 10.18240/ijo.2019.07.23 -
Cureus Jan 2023The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer... (Review)
Review
The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer continues to increase. Internal medicine residents can see patients admitted to the hospital for cancer-related emergencies. Early identification and appropriate management of these emergencies have been shown to improve mortality and morbidity. In this article, we aim to review the recent updates in the management of commonly encountered oncologic emergencies in the practice of internal medicine residents. This review will cover spinal cord compression, superior vena cava syndrome, tumor lysis syndrome, hypercalcemia, pericardial tamponade, hypoglycemia, hyponatremia, bowel obstruction, increased intracranial pressure, leukostasis, hyperviscosity syndrome, neutropenic fever, and hypersensitivity reactions.
PubMed: 36779153
DOI: 10.7759/cureus.33563 -
Journal of Diabetes Oct 2023Diabetic retinopathy (DR) is a significant global public health concern. Alternative, safe, and cost-effective pharmacologic approaches are warranted. We aimed to...
AIMS
Diabetic retinopathy (DR) is a significant global public health concern. Alternative, safe, and cost-effective pharmacologic approaches are warranted. We aimed to investigate the therapeutic potential of nattokinase (NK) for early DR and the underlying molecular mechanism.
METHODS
A mouse model of diabetes induced by streptozotocin was utilized and NK was administered via intravitreal injection. Microvascular abnormities were evaluated by examining the leakage from blood-retinal barrier dysfunction and loss of pericytes. Retinal neuroinflammation was examined through the assessment of glial activation and leukostasis. The level of high mobility group box 1 (HMGB1) and its downstream signaling molecules was evaluated following NK treatment.
RESULTS
NK administration significantly improved the blood-retinal barrier function and rescued pericyte loss in the diabetic retinas. Additionally, NK treatment inhibited diabetes-induced gliosis and inflammatory response and protected retinal neurons from diabetes-induced injury. NK also improved high glucose-induced dysfunction in cultured human retinal micrangium endothelial cells. Mechanistically, NK regulated diabetes-induced inflammation partially by modulating HMGB1 signaling in the activated microglia.
CONCLUSIONS
This study demonstrated the protective effects of NK against microvascular damages and neuroinflammation in the streptozotocin-induced DR model, suggesting that NK could be a potential pharmaceutical agent for the treatment of DR.
PubMed: 37403338
DOI: 10.1111/1753-0407.13439 -
CA: a Cancer Journal For Clinicians 2011Oncologic emergencies can occur at any time during the course of a malignancy, from the presenting symptom to end-stage disease. Although some of these conditions are... (Review)
Review
Oncologic emergencies can occur at any time during the course of a malignancy, from the presenting symptom to end-stage disease. Although some of these conditions are related to cancer therapy, they are by no means confined to the period of initial diagnosis and active treatment. In the setting of recurrent malignancy, these events can occur years after the surveillance of a cancer patient has been appropriately transferred from a medical oncologist to a primary care provider. As such, awareness of a patient's cancer history and its possible complications forms an important part of any clinician's knowledge base. Prompt identification of and intervention in these emergencies can prolong survival and improve quality of life, even in the setting of terminal illness. This article reviews hypercalcemia, hyponatremia, hypoglycemia, tumor lysis syndrome, cardiac tamponade, superior vena cava syndrome, neutropenic fever, spinal cord compression, increased intracranial pressure, seizures, hyperviscosity syndrome, leukostasis, and airway obstruction in patients with malignancies. Chemotherapeutic emergencies are also addressed.
Topics: Emergencies; Humans; Neoplasms
PubMed: 21858793
DOI: 10.3322/caac.20124 -
VASA. Zeitschrift Fur Gefasskrankheiten Jan 2022Acute lower limb ischemia (ALLI) is a common vascular emergency. However, ALLI presenting as the initial symptom of acute leukemia (AL) is scarce. Here we present a... (Review)
Review
Acute lower limb ischemia (ALLI) is a common vascular emergency. However, ALLI presenting as the initial symptom of acute leukemia (AL) is scarce. Here we present a case of ALLI in the setting of acute myeloid leukemia (AML) while systematically reviewing the current literature to withdraw conclusions about the management, prognosis, and treatment for this atypical presentation of AL. We conducted a systematic electronic research according to Preferred Reporting Items for Systematic Review and Meta-Analysis protocol (PRISMA) for articles published from January 1981 up to January 2021 concerning ALLI in the setting of acute leukemia (AL). Patients' baseline characteristics were recorded and nine outcomes of interest were studied. Twenty-six individuals, 16 males with a mean age of 46.3 years (±20) were included in this review. The diagnosis included 13 AML patients (50%), 11 acute promyelotic leukemia (APL) (42.3%) and two acute lymphoblastic leukemias (ALL) (7.7%). Treatment varied among nine different regimens. Four patients were treated with chemotherapy alone (15.4%), four with thrombectomy alone (15.4%), and 11 with a combination of chemotherapy and thrombectomy (42.3%). Eight major amputations were recorded (30. 8%). Thirty-day mortality was 35.7%. Forty-eight peripheral thrombotic events were recorded with 12 patients suffering recurrent thrombotic events. ALLI as the presenting symptom of AL is a rare condition that carries significant mortality and amputation rates. Timely diagnosis is crucial concerning short-term survival and limb salvage. APL, despite being the rarest form of AL, represented a significant proportion of the patient population in this review. The role of leukostasis in the disease's progression and the efficacy of leukapheresis as a treatment regimen should be further investigated through case-control studies.
Topics: Acute Disease; Amputation, Surgical; Humans; Ischemia; Leukemia, Myeloid, Acute; Limb Salvage; Male; Middle Aged; Risk Factors; Time Factors; Treatment Outcome
PubMed: 34794339
DOI: 10.1024/0301-1526/a000977 -
British Journal of Pharmacology Jan 2012Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and remains a major cause of preventable blindness among adults at working... (Review)
Review
Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and remains a major cause of preventable blindness among adults at working age. DR involves an abnormal pathology of major retinal cells, including retinal pigment epithelium, microaneurysms, inter-retinal oedema, haemorrhage, exudates (hard exudates) and intraocular neovascularization. The biochemical mechanisms associated with hyperglycaemic-induced DR are through multifactorial processes. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in the pathogenesis of DR by inhibiting diabetes-induced retinal leukostasis and leakage. Despite DR causing eventual blindness, only a few visual or ophthalmic symptoms are observed until visual loss develops. Therefore, early medical interventions and prevention are the current management strategies. Laser photocoagulation therapy is the most common treatment. However, this therapy may cause retinal damage and scarring. Herbal and traditional natural medicines may provide an alternative to prevent or delay the progression of DR. This review provides an analysis of the therapeutic potential of herbal and traditional natural medicines or their active components for the slowdown of progression of DR and their possible mechanism through the PPAR-γ pathway.
Topics: Biological Products; Diabetic Retinopathy; Humans; PPAR gamma; Plants, Medicinal; Retina
PubMed: 21480863
DOI: 10.1111/j.1476-5381.2011.01411.x -
Clinical Ophthalmology (Auckland, N.Z.) 2019The aim of this article is to provide an overview of characteristics and principles of use of dexamethasone implant in patients with diabetic macular edema (DME). The... (Review)
Review
The aim of this article is to provide an overview of characteristics and principles of use of dexamethasone implant in patients with diabetic macular edema (DME). The condensed information about patient selection, dosing, and postinjection management is provided to make the clinician's decisions easier in real-life practice. DME is a common complication of diabetes and the leading cause of visual loss in the working-age population. Inflammation plays an important role in the pathogenesis of DME. The breakdown of the blood-retinal barrier involves the expression of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF). Steroids have proved to be effective in the treatment of DME by blocking the production of VEGF and other inflammatory cytokines, by inhibiting leukostasis, and by enhancing the barrier function of vascular endothelial cell tight junctions. Dexamethasone intravitreal implant has demonstrated efficacy in the treatment of DME resistant to anti-VEGF therapy and in vitrectomized eyes. Data from clinical trials suggest that dexamethasone implant can be considered as first-line treatment in pseudophakic eyes. Dexamethasone implant is also the first-line therapy in patients not suited for anti-VEGF therapy, pregnant women, and patients unable to return for frequent monitoring. It has been shown that the maximum effect of dexamethasone implant on visual gain and retinal thickness occurs approximately 2 months after injection. Various treatment regimens are used in real-life situations, and reported reinjection intervals were usually <6 months. The number of retreatments needed decreased over time. Treatment algorithms should be personalized. Postinjection management and follow-up should consider potential adverse events such as intraocular pressure elevation and cataract.
PubMed: 31190726
DOI: 10.2147/OPTH.S206769 -
Experimental Eye Research Jan 2020Diabetic retinopathy (DR) is triggered by retinal cell damage stimulated by the diabetic milieu, including increased levels of intraocular free fatty acids. Free fatty...
Diabetic retinopathy (DR) is triggered by retinal cell damage stimulated by the diabetic milieu, including increased levels of intraocular free fatty acids. Free fatty acids may serve as an initiator of inflammatory cytokine release from Müller cells, and the resulting cytokines are potent stimulators of retinal endothelial pathology, such as leukostasis, vascular permeability, and basement membrane thickening. Our previous studies have elucidated a role for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in promoting several steps in the pathologic cascade in DR, including angiogenesis and expression of inflammatory mediators. Furthermore, PPARβ/δ is a known target of lipid signaling, suggesting a potential role for this transcription factor in fatty acid-induced retinal inflammation. Therefore, we hypothesized that PPARβ/δ stimulates both the induction of inflammatory mediators by Müller cells as well the paracrine induction of leukostasis in endothelial cells (EC) by Müller cell inflammatory products. To test this, we used the PPARβ/δ inhibitor, GSK0660, in primary human Müller cells (HMC), human retinal microvascular endothelial cells (HRMEC) and mouse retina. We found that palmitic acid (PA) activation of PPARβ/δ in HMC leads to the production of pro-angiogenic and/or inflammatory cytokines that may constitute DR-relevant upstream paracrine inflammatory signals to EC and other retinal cells. Downstream, EC transduce these signals and increase their synthesis and release of chemokines such as CCL8 and CXCL10 that regulate leukostasis and other cellular events related to vascular inflammation in DR. Our results indicate that PPARβ/δ inhibition mitigates these upstream (MC) as well as downstream (EC) inflammatory signaling events elicited by metabolic stimuli and inflammatory cytokines. Therefore, our data suggest that PPARβ/δ inhibition is a potential therapeutic strategy against early DR pathology.
Topics: Adult; Animals; Cells, Cultured; Cytokines; Endothelial Cells; Ependymoglial Cells; Humans; Inflammation; Leukostasis; Male; Mice; Mice, Inbred C57BL; PPAR delta; PPAR-beta; Palmitic Acids; Real-Time Polymerase Chain Reaction; Retina; Retinitis; Sulfones; Thiophenes
PubMed: 31758977
DOI: 10.1016/j.exer.2019.107885