Delayed Administration of Angiotensin Receptor (AT2R) Agonist C21 Improves Survival and Preserves Sensorimotor Outcomes in Female Diabetic Rats Post-Stroke through Modulation of Microglial Activation

About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals. In the current study, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in diabetic female animals. Young female diabetic rats were subjected to 1 h of middle cerebral artery occlusion (MCAO). Three days post-stroke, rats were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 4 weeks. The impact of C21 on microglial polarization was analyzed by flow cytometry in vivo and in vitro. Compound 21 treatment improved fine motor skills after MCAO through modulation of the microglia/macrophage inflammatory properties. In addition, C21 increased M2 polarization and reduced the M1:M2 ratio in vitro. In conclusion, delayed administration of C21 downregulates post-stroke inflammation in female diabetic animals. C21 may be a useful therapeutic option to lower neuro-inflammation and improve the post-stroke recovery in diabetes.

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The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600585 ◽

2007 ◽

Vol 28 (4) ◽

pp. 812-823 ◽

Cited By ~ 54

Author(s):

Richard Milner ◽

Stephanie Hung ◽

Xiaoyun Wang ◽

Maria Spatz ◽

Gregory J del Zoppo

Keyword(s):

Cerebral Ischemia ◽

Basal Lamina ◽

Focal Cerebral Ischemia ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Receptor Expression ◽

Cerebral Microvessels ◽

The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

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The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

10.2337/figshare.12465515 ◽

2020 ◽

Author(s):

Ada Admin ◽

Ingrid Lovise Augestad ◽

Hiranya Pintana ◽

Martin Larsson ◽

Camilla Krizhanovskii ◽

...

Keyword(s):

Chronic Phase ◽

Clinical Situation ◽

Recovery Phase ◽

Artery Occlusion ◽

Stroke Recovery ◽

Neurological Recovery ◽

Standard Diet ◽

Dipeptidyl Peptidase 4 ◽

Post Stroke ◽

The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride. We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks. We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry. T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery. These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

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Supplemental N-3 Polyunsaturated Fatty Acids Limit A1-Specific Astrocyte Polarization via Attenuating Mitochondrial Dysfunction in Ischemic Stroke in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5524705 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Jun Cao ◽

Lijun Dong ◽

Jialiang Luo ◽

Fanning Zeng ◽

Zexuan Hong ◽

...

Keyword(s):

Fatty Acids ◽

Ischemic Stroke ◽

Polyunsaturated Fatty Acids ◽

Mitochondrial Dysfunction ◽

Artery Occlusion ◽

Mice Model ◽

Neuron Death ◽

The Impact

Ischemic stroke is one of the leading causes of death and disability for adults, which lacks effective treatments. Dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) exerts beneficial effects on ischemic stroke by attenuating neuron death and inflammation induced by microglial activation. However, the impact and mechanism of n-3 PUFAs on astrocyte function during stroke have not yet been well investigated. Our current study found that dietary n-3 PUFAs decreased the infarction volume and improved the neurofunction in the mice model of transient middle cerebral artery occlusion (tMCAO). Notably, n-3 PUFAs reduced the stroke-induced A1 astrocyte polarization both in vivo and in vitro. We have demonstrated that exogenous n-3 PUFAs attenuated mitochondrial oxidative stress and increased the mitophagy of astrocytes in the condition of hypoxia. Furthermore, we provided evidence that treatment with the mitochondrial-derived antioxidant, mito-TEMPO, abrogated the n-3 PUFA-mediated regulation of A1 astrocyte polarization upon hypoxia treatment. Together, this study highlighted that n-3 PUFAs prevent mitochondrial dysfunction, thereby limiting A1-specific astrocyte polarization and subsequently improving the neurological outcomes of mice with ischemic stroke.

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Emodin Ameliorates High Glucose Induced-Podocyte Epithelial-Mesenchymal Transition In-Vitro and In-Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000373963 ◽

2015 ◽

Vol 35 (4) ◽

pp. 1425-1436 ◽

Cited By ~ 23

Author(s):

Tingfang Chen ◽

Li Yang Zheng ◽

Wenzhen Xiao ◽

Dingkun Gui ◽

Xiaoxia Wang ◽

...

Keyword(s):

High Glucose ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Option ◽

Diabetic Rats ◽

Protective Effects ◽

Mesenchymal Transition ◽

Epithelial Marker

Background: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Methods: Conditionally immortalized mouse podocytes were exposed to HG with 30μg /ml of EMO and 1μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg-1· d-1 and QLT0267 at 10 mg· kg-1· w-1 p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. Results: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. Conclusion: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD.

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The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

10.2337/figshare.12465515.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Ingrid Lovise Augestad ◽

Hiranya Pintana ◽

Martin Larsson ◽

Camilla Krizhanovskii ◽

...

Keyword(s):

Chronic Phase ◽

Clinical Situation ◽

Recovery Phase ◽

Artery Occlusion ◽

Stroke Recovery ◽

Neurological Recovery ◽

Standard Diet ◽

Dipeptidyl Peptidase 4 ◽

Post Stroke ◽

The Impact

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Racial Disparities in Stroke Recovery Persistence in the Post-Acute Stroke Recovery Phase: Evidence from the Health and Retirement Study

Ethnicity & Disease ◽

10.18865/ed.30.2.339 ◽

2020 ◽

Vol 30 (2) ◽

pp. 339-348

Author(s):

Joy N. J. Buie ◽

Yujing Zhao ◽

Suzanne Burns ◽

Gayenell Magwood ◽

Robert Adams ◽

...

Keyword(s):

Racial Differences ◽

Motor Skills ◽

Stroke Recovery ◽

Fine Motor ◽

Stroke Survivors ◽

Factors Associated ◽

Post Stroke ◽

Stroke Disability ◽

The Impact

Background and Purpose: Blacks have a higher burden of post-stroke disability. Factors associated with racial differences in long-term post-stroke disability are not well-understood. Our aim was to assess the long-term racial differences in risk factors associated with stroke recovery.Methods: We examined Health and Retirement Study (HRS) longitudinal interview data collected from adults living with stroke who were aged >50 years during 2000- 2014. Analysis of 1,002 first-time, non- Hispanic, Black (210) or White (792) stroke survivors with data on activities of daily living (ADL), fine motor skills (FMS) and gross motor skills (GMS) was conducted. Ordinal regression analysis was used to assess the impact of sex, race, household residents, household income, comorbidities, and the time since having a stroke on functional outcomes.Results: Black stroke survivors were younger compared with Whites (69 ± 10.4 vs 75 ± 11.9). The majority (~65%) of Black stroke survivors were female compared with about 54% White female stroke survivors (P=.007). Black stroke survivors had more household residents (P<.001) and comorbidities (P<.001). Aging, being female, being Black and a longer time since stroke were associated with a higher odds of having increased difficulty in ADL, FMS and/or GMS. Comorbidities were associated with increased difficulty with GMS. Black race increased the impact of comorbidities on ADL and FMS in comparison with Whites.Conclusion: Our data suggest that the effects of aging, sex and unique factors associated with race should be taken into consideration for future studies of post-stroke recovery and therapy.Ethn Dis. 2020;30(2):339-348; doi:10.18865/ ed.30.2.339

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Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling

Cellular Oncology ◽

10.1007/s13402-020-00559-9 ◽

2020 ◽

Author(s):

Ioannis Pozios ◽

Nina N. Seel ◽

Nina A. Hering ◽

Lisa Hartmann ◽

Verena Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Therapeutic Option ◽

Tumor Xenograft ◽

Ductal Adenocarcinoma ◽

Stat3 Signaling ◽

Stat3 Phosphorylation ◽

The Impact

Abstract Purpose Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. Methods Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. Results Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. Conclusions Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype.

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LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2 / HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats

10.21203/rs.3.rs-78864/v1 ◽

2020 ◽

Author(s):

Daoyong Li ◽

Chao Wu ◽

He Tian ◽

Liang Mao ◽

Zhanshan Gao ◽

...

Keyword(s):

Wound Healing ◽

Effective Treatment ◽

Diabetic Rats ◽

In Vitro Experiments ◽

Endothelial Cell Function ◽

Promote Wound Healing ◽

The Impact ◽

Wound Tissue

Abstract Background:Impaired wound healing is one of the important complications of diabetes. However, the specific pathogenesis is still unclear, and there is no effective treatment. Macrophages pretreated with chemical or biological factors may increase the biological activity of macrophage-derived exosomes, which is expected to become a new effective treatment method. The purpose of this study was to investigate whether the exosomes secreted by macrophages pretreated with lipopolysaccharide (LPS) have better anti-inflammatory and angiogenic abilities in the treatment of diabetic wound healing and their underlying molecular mechanisms.Methods:In this study, macroscopical, biochemical, histological, immunofluorescence and molecular biology methods were used to evaluate the potential protective mechanism and effect of lipopolysaccharide stimulated macrophage exosomes (LPS-Exos) on wound healing in streptozotocin induced hyperglycemia rats.In the in vivo experiment, the percentages of wound closure and contraction were compared and analyzed on the 7th, 14th, and 21st day after treatment by grouping treatments with different concentrations of LPS-Exos.At the same time, hematoxylin and eosin staining (HE), Masson staining, immunofluorescence staining and Western blotting (WB) were used for histological analysis of the wound tissue on the 14th day after injury to evaluate the impact of different treatment methods on wound healing.In in vitro experiments, the ability of endothelial cells related to proliferation, migration, tube formation and the expression of vascular endothelial growth factor (VEGF) were tested.At the same time, in vivo and in vitro experiments, the effect of Nrf2/HO-1 signaling pathway on LPS-Exos in inhibiting inflammation and promoting angiogenesis was evaluated by using exosome-specific inhibitors.Results:LPS-Exos reduced the content of ROS and MDA in the wound tissue of hyperglycemic rats, increased the activity of SOD and the production of GSH-Px, activated the Nrf2/HO-1 pathway, inhibited the expression of inflammation-related proteins, and promoted blood vessels generate. The group given exosome inhibitors reversed this phenomenon.Conclusions: LPS-Exos may activate the Nrf2/HO-1 defense pathway, improve endothelial cell function, inhibit oxidative damage and inflammation, and promote wound healing in diabetic rats, thereby having the potential to treat diabetic skin defects.

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The Influence of Sulindac on Experimental Streptozotocin-Induced Diabetic Neuropathy

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100041160 ◽

1994 ◽

Vol 21 (3) ◽

pp. 194-202 ◽

Cited By ~ 26

Author(s):

Douglas W. Zochodne ◽

Lam T. Ho

Keyword(s):

Dorsal Root Ganglion ◽

Diabetic Neuropathy ◽

Oxygen Tension ◽

Dorsal Root ◽

Low Dose ◽

Diabetic Rats ◽

Sensory Fibers ◽

The Impact

Abstract:We studied the influence of sulindac, a nonsteroidal anti-inflammatory agent on experimental streptozotocin-induced diabetic neuropathy. Untreated diabetic rats were compared with nondiabetic rats, diabetic rats treated with low dose insulin and diabetic rats given sulindac (6.0 mg/kg by gavage 5 of 7 days weekly). Neuropathy was assessed by following serialin vivomotor and sensory caudal conduction, resistance to ischemic conduction failure, andin vitroconduction in sural myelinated and unmyelinated sensory fibers. The impact of low dose insulin and sulindac treatment on the microenvironment of the L4 dorsal root ganglion and sciatic endoneurium was asssessed by measuring local perfusion and oxygen tension after 16 weeks of diabetes. Sulindac normalized conduction velocity in caudal sensory fibers, sural myelinated fibers and sural unmyelinated fibers, and reduced the number of diabetic cataracts. Sulindac also normalized a deficit in dorsal root ganglion blood flow and a reduction in sciatic endoneurial oxygen tension in diabetic rats. Low dose insulin improved neuropathy as well but the pattern of benefits was less robust than that of sulindac. Sulindac may be a candidate for a clinical trial in human diabetic polyneuropathy.

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Pharmacological features of osthole

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0010.3824 ◽

2017 ◽

Vol 71 (1) ◽

pp. 0-0 ◽

Cited By ~ 11

Author(s):

Agata Jarząb ◽

Aneta Grabarska ◽

Krystyna Skalicka-Woźniak ◽

Andrzej Stepulak

Keyword(s):

Tumor Cells ◽

Therapeutic Option ◽

Inhibitory Effect ◽

Experimental Models ◽

Naturally Occurring ◽

Anti Cancer ◽

Anti Inflammatory ◽

The Impact

Coumarins are a group of naturally occurring compounds common in the plant world. These substances and their derivatives exhibit a broad range of biological activities.One of the naturally occurring coumarins is osthole, which can most frequently be found in plants of the Apiaceae family. Cnidium monnieri (L.) Cusson ex Juss. Angelica pubescens Maxim. and Peucedanum ostruthium (L.). It has anti-proliferative, anti-inflammatory, anti-convulsant, and antiallergic properties; apart from that, inhibition of platelet aggregation has also been proved. The impact of osthole on bone metabolism has been demonstrated; also its hepatoprotective and neuroprotective properties have been confirmed. The inhibitory effect of this metokcompound on the development of neurodegenerative diseases has been proved in experimental models. Anticancer features of osthole have been also demonstrated both in vitro on different cell lines, and in vivo using animals xenografts. Osthole inhibited proliferation, motility and invasiveness of tumor cells, which may be associated with the induction of apoptosis and cell cycle slowdown. The exact molecular mechanism of osthole anti-cancer mode of action has not been fully elucidated. A synergistic effect of osthole with other anti-tumor substances has been also reported. Modification of its chemical structure led to the synthesis of many derivatives with significant anticancer effects.To sum up, osthole is an interesting therapeutic option, due to both its direct effect on tumor cells, as well as its neuroprotective or anti-inflammatory properties. Thus, there is a chance to use osthole or its synthetic derivatives in the treatment of cancer.

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