This article is available online at http://www.jlr.org Diabetic retinopathy (DR) remains a leading cause of vision loss in working-age adults. Early disease is characterized by vascular abnormalities, including pericyte loss, basement membrane thickening, microaneurysm formation, and capillary leakage ( 1, 2 ). Pericytes are critical to vascular integrity ( 3 ), and their loss is considered an initiating event in DR.Dyslipidemia has been implicated in DR, and associations between plasma lipoprotein profi les and disease severity have been observed in large cohort studies ( 4-6 ), but were not of suffi cient strength to defi ne risk for individuals. The term "dyslipidemia" may include qualitative as well as quantitative alterations in plasma lipoproteins. The qualitative abnormalities include modifi cation by oxidation, but oxidized LDL (ox-LDL) constitutes only a small fraction of total plasma LDL, ranging from 0.001% in healthy people to 5% in the presence of cardiovascular

Diabetic nephropathy is characterized by progressive mesangial expansion. Although we have reported that circulating oxidized LDL-containing immune complexes (oxLDL-ICs) are associated with abnormal levels of albuminuria, the underlying mechanisms have not been investigated. In this study, we have studied the effect of oxLDL-ICs on collagen IV expression by mesangial cells. We found that oxLDL-ICs markedly stimulated collagen IV expression in a concentration- and time-dependent fashion while oxLDL only had moderate effect. We also found that oxLDL-ICs stimulated collagen IV expression by engaging Fc gamma receptor (FcγR) I and III, but not FcγRII, and that p38 MAPK, JNK and PKC pathways were involved in collagen IV expression. Furthermore, we found that oxLDL-ICs stimulated FcγRI expression, suggesting a positive feedback mechanism involved in oxLDL-IC-stimulated collagen IV expression. Taken together, this study showed that oxLDL-ICs stimulated collagen IV in mesangial cells via FcγRI and FcγRIII, and the expression of FcγRI was increased by oxLDL-ICs.

We recently reported that IGF-II binding to the IGF-II/mannose-6-phosphate (M6P) receptor activates the ERK1/2 cascade by triggering sphingosine kinase 1 (SK1)-dependent transactivation of G protein-coupled sphingosine 1-phosphate (S1P) receptors. Here, we investigated the mechanism of IGF-II/M6P receptor-dependent sphingosine kinase 1 (SK1) activation in human embryonic kidney 293 cells. Pretreating cells with protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, abolished IGF-II-stimulated translocation of green fluorescent protein (GFP)-tagged SK1 to the plasma membrane and activation of endogenous SK1, implicating PKC as an upstream regulator of SK1. Using confocal microscopy to examine membrane translocation of GFP-tagged PKCα, β1, β2, δ, and ζ, we found that IGF-II induced rapid, transient, and isoform-specific translocation of GFP-PKCβ2 to the plasma membrane. Immunoblotting of endogenous PKC phosphorylation confirmed PKCβ2 activation in response to IGF-II. Similarly, IGF-II stimulation caused persistent membrane translocation of the kinase-deficient GFP-PKCβ2 (K371R) mutant, which does not dissociate from the membrane after translocation. IGF-II stimulation increased diacylglycerol (DAG) levels, the established activator of classical PKC. Interestingly, the polyunsaturated fraction of DAG was increased, indicating involvement of phosphatidyl inositol/phospholipase C (PLC). Pretreating cells with the PLC inhibitor, U73122, attenuated IGF-II-dependent DAG production and PKCβ2 phosphorylation, blocked membrane translocation of the kinase-deficient GFP-PKCβ2 (K371R) mutant, and reduced sphingosine 1-phosphate production, suggesting that PLC/PKCβ2 are upstream regulators of SK1 in the pathway. Taken together, these data provide evidence that activation of PLC and PKCβ2 by the IGF-II/M6P receptor are required for the activation of SK1.

No abstract

BACKGROUND: Sepsis is a dysregulated host response to infection resulting in potentially life-threatening organ dysfunction. Elevation in red cell distribution width (RDW), a simple routinely done investigation, could be a prognostic marker in these patients. AIM: We performed this prospective observational study to assess role of dynamic variation of RDW in predicting 30-day mortality in patients with sepsis or septic shock presenting and getting admitted in intensive care unit (ICU) in Fayoum, Egypt. METHODS: Between January 2019 and January 2021, 150 patients with sepsis or septic shock at admission were prospectively evaluated for association between RDW value on admission, on day 4, on day 7, and 30-day mortality. To find out factors associated independently with 30-day mortality, we applied multivariate logistic regression analysis and used the analysis to develop nanogram for prediction of mortality on admission. RESULTS: Among 150 patients, 89 (59.3%) were male. Mean age of the patients was 59.6 ± 12.28 years. Regarding RDW on admission (RDW-0), the mean was 14.1 ± 1.9 while on day 4 (RDW-4), the mean was 14.5 ± 1.97, and on day 7 (RDW-7), the mean was 14.4 ± 2.03. Seventy-four (49.3%) patients died during the period of 30 days follow-up. Multiple logistic regression models for the parameters associated with the mortality outcome at admission were done, for age, higher age was associated with higher probability of mortality, OR = 1.07 (95% CI: 1.02, 1.13). Male sex was associated with lower probability of mortality as compared to females, OR = 0.02 (95% CI: 0.06, 0.80). Higher acute physiologic assessment and chronic health evaluation (APACHE) II score, RDW value, and procalcitonin level, all were associated with higher mortality probability. For APACHE II score, higher level was associated with higher odds of mortality, OR = 1.16. For RDW value on admission, higher value was associated with higher odds of mortality, OR = 1.66. For procalcitonin level at admission, higher level was associated with higher odds of mortality, OR = 1.54. Odds for mortality for those who showed any increase in RDW in day 4 as compared to day 0 are higher as compared to those who showed a decrease or no change in RDW, OR = 2.8, p-value = 0.007. CONCLUSIONS: We found that an increase in RDW value on admission and on day 4 is significantly associated with mortality. And that, an increase in RDW value from day 0 to day 4 is also significantly associated with mortality Therefore, a combination of baseline RDW value and an  increase in serial RDW values can be a promising independent prognostic marker in patients with sepsis or septic shock.