Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels

In diabetes there is a long latency between onset of hyperglycemia and appearance of structural microangiopathy. Because Ly6Clow patrolling monocytes (PMo) behave as housekeepers of the vasculature, we tested whether PMo protect microvessels against diabetes. We found that, in wild-type mice, diabetes reduced PMo in the general circulation but increased by 4-fold the absolute number of PMo adherent to retinal vessels (leukostasis). Conversely, in diabetic NR4A1-/- mice ─ a model of absence of PMo ─ there was no increase in leukostasis at all; and at 6 months of diabetes the number of retinal acellular capillaries almost doubled when compared to diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculo-protective, and housekeeping activities; as well as profound suppression of genes related to inflammation and apoptosis. Pro-migratory CXCR4 was no longer upregulated at longer duration, when retinal acellular capillaries begin to increase. Thus, after short diabetes duration, PMo are the cells preferentially recruited to the retinal vessels and protect vessels from diabetic damage. These observations support the need for reinterpretation of the functional meaning of leukostasis in diabetes, and document within the natural history of diabetic retinopathy processes of protection-repair that can provide novel paradigms for prevention.

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Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels

10.2337/figshare.12896681 ◽

2020 ◽

Author(s):

Ada Admin ◽

Francesco Tecilazich ◽

Toan A. Phan ◽

Fabio Simeoni ◽

Giulia Maria Scotti ◽

...

Keyword(s):

Gene Expression ◽

Diabetic Retinopathy ◽

General Circulation ◽

Absolute Number ◽

Retinal Vessels ◽

Wild Type ◽

Long Latency ◽

History Of ◽

Acellular Capillaries ◽

Patrolling Monocytes

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Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Cells ◽

10.3390/cells10061379 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1379

Author(s):

Dongjoon Kim ◽

Hiromi Sesaki ◽

Sayon Roy

Keyword(s):

Diabetic Retinopathy ◽

Cell Loss ◽

Vascular Lesions ◽

Protective Effects ◽

Diabetic Mice ◽

Wild Type ◽

Apoptotic Genes ◽

Retinal Vascular Lesions ◽

Acellular Capillaries ◽

Pericyte Loss

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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Faculty Opinions recommendation of GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725374290.793547530 ◽

2018 ◽

Author(s):

Michael Klymkowsky

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transcriptional Response ◽

Wild Type ◽

Reactive Glia

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Cardiac transthyretin wild-type amyloidosis (ATTRwt): a prospective study of 400 patients followed at the Italian referral center

European Heart Journal ◽

10.1093/ehjci/ehaa946.2144 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

P Milani ◽

L Obici ◽

R Mussinelli ◽

M Basset ◽

G Manfrinato ◽

...

Keyword(s):

Natural History ◽

Median Survival ◽

Troponin I ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Wild Type ◽

Staging Systems ◽

Significant Difference ◽

History Of

Abstract Background Cardiac wild type transthyretin (ATTRwt) amyloidosis, formerly known as senile systemic amyloidosis, is an increasingly recognized, progressive, and fatal cardiomyopathy. Two biomarkers staging systems were proposed based on NT-proBNP (in both cases) and troponin or estimated glomerular filtration rate, that are able to predict survival in this population. The availability of novel effective treatments requires large studies to describe the natural history of the disease in different populations. Objective To describe the natural history of the disease in a large, prospective, national series. Methods Starting in 2007, we protocolized data collection in all the patients diagnosed at our center (n=400 up to 7/2019). Results The referrals to our center increased over time: 5 cases (1%) between 2007–2009, 33 (9%) in 2010–2012, 90 (22%) in 2013–2015 and 272 (68%) in 2016–2019. Median age was 76 years [interquartile range (IQR): 71–80 years] and 372 patients (93%) were males. One hundred and seventy-three (43%) had atrial fibrillation, 63 (15%) had a history of ischemic cardiomyopathy and 64 (15%) underwent pacemaker or ICD implantation. NYHA class was I in 58 subjects (16%), II in 225 (63%) and III in 74 (21%). Median NT-proBNP was 3064 ng/L (IQR: 1817–5579 ng/L), troponin I 0.096 ng/mL (IQR: 0.063–0.158 ng/mL), eGFR 62 mL/min (IQR: 50–78 mL/min). Median IVS was 17 mm (IQR: 15–19 mm), PW 16 mm (IQR: 14–18 mm) and EF 53% (IQR: 45–57%). One-hundred and forty-eight subjects (37%) had a concomitant monoclonal component in serum and/or urine and/or an abnormal free light chain ratio. In these patients, the diagnosis was confirmed by immunoelectron microscopy or mass spectrometry. In 252 (63%) the diagnosis was based on bone scintigraphy. DNA analysis for amyloidogenic mutations in transthyretin and apolipoprotein A-I genes was negative in all subjects. The median survival of the whole cohort was 59 months. The Mayo Clinic staging based on NT-proBNP (cutoff: 3000 ng/L) and troponin I (cutoff: 0.1 ng/mL) discriminated 3 different groups [stage I: 131 (35%), stage II: 123 (32%) and stage III: 127 (33%)] with different survival between stage I and II (median 86 vs. 81 months, P=0.04) and between stage II and III (median 81 vs. 62 months, P<0.001). The UK staging system (NT-proBNP 3000 ng/L and eGFR 45 mL/min), discriminated three groups [stage I: 170 (45%), stage II: 165 (43%) and stage III: 45 (12%)] with a significant difference in survival: between stage I and stage II (86 vs. 52 months, P<0.001) and between stage II and stage III (median survival 52 vs. 33 months, P=0.045). Conclusions This is one of the largest series of patients with cardiac ATTRwt reported so far. Referrals and diagnoses increased exponentially in recent years, One-third of patients has a concomitant monoclonal gammopathy and needed tissue typing. Both the current staging systems offered good discrimination of staging and were validated in our independent cohort. Funding Acknowledgement Type of funding source: None

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The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

Cell Death and Disease ◽

10.1038/s41419-021-03948-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ian Edward Gentle ◽

Isabel Moelter ◽

Mohamed Tarek Badr ◽

Konstanze Döhner ◽

Michael Lübbert ◽

...

Keyword(s):

Gene Expression ◽

Cell Culture ◽

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activity ◽

Target Gene ◽

Wild Type ◽

Elevated Expression ◽

Factor C ◽

Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

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Association between self-care agency and depression and anxiety in patients with diabetic retinopathy

BMC Ophthalmology ◽

10.1186/s12886-021-01883-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bo Zhang ◽

Qin Wang ◽

Xuancan Zhang ◽

Li Jiang ◽

Lezhi Li ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Rural Areas ◽

Self Care ◽

Depression Scale ◽

Anxiety Symptoms ◽

Depression And Anxiety ◽

Clinical Factors ◽

Cross Sectional ◽

History Of ◽

Care Agency

Abstract Background This study aimed at investigating: 1) the relationship between self-care agency and depression and anxiety; 2) the sociodemographic and clinical factors associated with depression and anxiety in patients with diabetic retinopathy (DR) in China. Methods A cross-sectional study was conducted. One-hundred and five patients with DR were recruited. Self-care agency was assessed by the exercise of self-care agency (ESCA) scale. Depression and anxiety were assessed by the hospital anxiety and depression scale (HADS-D and HADS-A). Pearson or Spearman correlations were performed to assess the association between self-care agency and depression and anxiety. Stepwise multivariate linear regression analyses were conducted to assess the contribution of the sociodemographic and clinical factors to depression and anxiety. Results Thirty-six (34.3%) and 43 (41.1%) patients exhibited depressive and anxiety symptoms, respectively. Only 24 (22.9%) patients showed a high self-care agency. The ESCA total and subscale scores were negatively correlated depressive symptoms (P < 0.05). Self-care skills were negatively correlated with anxiety symptoms (P < 0.05). ESCA total score, rural residence, history of hypertension and visual acuity were associated with depression; self-care skills and diastolic blood pressure were associated with anxiety. Conclusions Self-care agency negatively correlates with depression and anxiety in patients with DR. Special attention should be paid to patients living in rural areas and/or those having a history of hypertension when assessing depression and anxiety in patients with DR. Future studies are needed to clarify the causal relationship between self-care agency and depression and anxiety.

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Association of changes of retinal vessels diameter with ocular blood flow in eyes with diabetic retinopathy

Scientific Reports ◽

10.1038/s41598-021-84067-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoshitaka Ueno ◽

Takeshi Iwase ◽

Kensuke Goto ◽

Ryo Tomita ◽

Eimei Ra ◽

...

Keyword(s):

Blood Flow ◽

Diabetic Retinopathy ◽

Adaptive Optics ◽

Laser Speckle ◽

The Other ◽

Systemic Hypertension ◽

Laser Speckle Flowgraphy ◽

Retinal Vessels ◽

External Diameter ◽

The Mean

AbstractWe investigated morphological changes of retinal arteries to determine their association with the blood flow and systemic variables in type 2 diabetes patients. The patients included 47 non-diabetic retinopathy eyes, 36 mild or moderate nonproliferative diabetic retinopathy (M-NPDR) eyes, 22 severe NPDR (S-NPDR) eyes, 32 PDR eyes, and 24 normal eyes as controls. The mean wall to lumen ratio (WLR) measured by adaptive optics camera was significantly higher in the PDR groups than in all of the other groups (all P < 0.001). However, the external diameter of the retinal vessels was not significantly different among the groups. The mean blur rate (MBR)-vessel determined by laser speckle flowgraphy was significantly lower in the PDR group than in the other groups (P < 0.001). The WLR was correlated with MBR-vessel (r = − 0.337, P < 0.001), duration of disease (r = 0.191, P = 0.042), stage of DM (r = 0.643, P < 0.001), systolic blood pressure (r = 0.166, P < 0.037), and presence of systemic hypertension (r = 0.443, P < 0.001). Multiple regression analysis demonstrated that MBR-vessel (β = − 0.389, P < 0.001), presence of systemic hypertension (β = 0.334, P = 0.001), and LDL (β = 0.199, P = 0.045) were independent factors significantly associated with the WLR. The increased retinal vessel wall thickness led to a narrowing of lumen diameter and a decrease in the blood flow in the PDR group.

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Effects of the domestic thyroid stimulating hormone receptor (TSHR) variant on the hypothalamic-pituitary-thyroid axis and behavior in chicken

Genetics ◽

10.1093/genetics/iyaa050 ◽

2021 ◽

Vol 217 (1) ◽

Author(s):

Amir Fallahshahroudi ◽

Martin Johnsson ◽

Enrico Sorato ◽

S J Kumari A Ubhayasekera ◽

Jonas Bergquist ◽

...

Keyword(s):

Gene Expression ◽

Hormone Receptor ◽

Thyroid Stimulating Hormone ◽

Phenotypic Traits ◽

Wild Type ◽

Data Set ◽

Red Junglefowl ◽

Pituitary Thyroid Axis ◽

And Behavior ◽

Stimulating Hormone

Abstract Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it’s function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.

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The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone

Scientific Reports ◽

10.1038/s41598-021-89608-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anastasia Ricci ◽

Sara Orazi ◽

Federica Biancucci ◽

Mauro Magnani ◽

Michele Menotta

Keyword(s):

Gene Expression ◽

Cell Cycle Progression ◽

Regulation Of Gene Expression ◽

Lamin A ◽

Wild Type ◽

Cycle Progression ◽

C Dynamics ◽

E2f Transcription Factor ◽

Transcription Factor 1

AbstractAtaxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.

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