Advanced glycation end products (AGEs) are considered to be related to the pathogenesis of some inflammatory diseases. AGEs were reported to stimulate the receptor for AGEs (RAGE), which causes ...inflammatory reactions. However, recently, toll‐like receptors (TLRs), in addition to RAGE, have been reported to be related to AGE‐mediated cellular responses, and it remains unclear which receptor is responsible for AGE recognition. To reveal the role of pattern‐recognition receptors, including TLRs and/or RAGE, in AGE‐mediated cellular responses, we generated macrophage‐like RAW264.7 knockout (KO) cells lacking these receptors by genome editing using the CRISPR/Cas9 system and assessed AGE‐stimulated changes in these cells. Comparison of the established clones suggested that RAGE partially affects the expression of TLRs. In the KO clone lacking TLR4 and TLR2, AGE‐stimulated tumor necrosis factor alpha (TNF‐α) expression and phosphorylation of IκBα, p38, and extracellular signal‐regulated kinase (ERK) were significantly attenuated, suggesting that AGE‐mediated responses are largely dependent on TLRs. On the other hand, on comparison of the AGE‐stimulated responses between the KO clone lacking TLR4 and TLR2, and the clone lacking TLR4, TLR2, and RAGE, RAGE played little role in AGE‐stimulated TNF‐α transcription and ERK phosphorylation. Taken together, this study suggested that AGE‐stimulated inflammatory responses occur mainly through TLRs rather than RAGE.
To reveal the role of possible AGE cell‐surface receptors, we generated macrophage‐like RAW264.7 KO clones lacking TLR4, TLR2, and/or RAGE. AGE‐stimulated TNF‐α expression and phosphorylation of IκBα, p38, and ERK mainly depend on TLRs. The degree of contribution of RAGE to AGE‐stimulation was slight, and only affected TNF‐α expression and ERK phosphorylation.
Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present ...survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison.
Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry.
From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease.
Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.
Glyceraldehyde‐derived advanced glycation end products (glycer‐AGEs) could contribute to colorectal cancer development and progression due to their pro‐oxidative and pro‐inflammatory properties. ...However, the association of glycer‐AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer‐AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer‐AGEs concentrations with CRC‐specific and all‐cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow‐up, 529 participants died (409 from CRC). Glycer‐AGEs were statistically significantly positively associated with CRC‐specific (HRQ5 vs Q1 = 1.53, 95% CI: 1.04‐2.25, Ptrend = .002) and all‐cause (HRQ5 vs Q1 = 1.62, 95% CI: 1.16‐2.26, Ptrend < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer‐AGEs and CRC‐specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon = 1.02, 95% CI: 0.74‐1.42; HRdistal colon = 1.51, 95% CI: 1.20‐1.91; Peffect modification = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer‐AGEs category relative to lowest BMI and glycer‐AGEs category for both CRC‐specific (HR = 1.78, 95% CI: 1.02‐3.01) and all‐cause mortality (HR = 2.15, 95% CI: 1.33‐3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer‐AGEs are positively associated with CRC‐specific and all‐cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.
What's new?
Eating foods high in sugar has been associated with risk of colorectal cancer (CRC). As the body processes dietary sugars, it generates compounds called glyceraldehyde‐derived advanced glycation end products (glycer‐AGEs). Here, the authors investigated the relationship between glycer‐AGEs and CRC mortality. In an analysis of 1034 CRC cases from the EPIC cohort, they found that prediagnostic circulating glycer‐AGEs were associated with both CRC‐specific and all‐cause mortality.
Abstract Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. ...Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin–angiotensin–aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.
The receptor for advanced glycated end products (RAGE) is a multiligand receptor that is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative ...disorders, and inflammatory responses. The ability of RAGE to recognize advanced glycated end products (AGEs) formed by nonenzymatic glycoxidation of cellular proteins places RAGE in the category of pattern recognition receptors. The structural mechanism of AGE recognition was an enigma due to the diversity of chemical structures found in AGE-modified proteins. Here, using NMR spectroscopy we showed that the immunoglobulin V-type domain of RAGE is responsible for recognizing various classes of AGEs. Three distinct surfaces of the V domain were identified to mediate AGE-V domain interactions. They are located in the positively charged areas of the V domain. The first interaction surface consists of strand C and loop CC ′, the second interaction surface consists of strand C ′, strand F, and loop FG, and the third interaction surface consists of strand A ′ and loop EF. The secondary structure elements of the interaction surfaces exhibit significant flexibility on the ms-μs time scale. Despite highly specific AGE-V domain interactions, the binding affinity of AGEs for an isolated V domain is low, ∼10 μm. Using in-cell fluorescence resonance energy transfer we show that RAGE is a constitutive oligomer on the plasma membrane. We propose that constitutive oligomerization of RAGE is responsible for recognizing patterns of AGE-modified proteins with affinities less than 100 nm.
Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard ...reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE-RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE-RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of "metabolic memory", the "French paradox", and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.
Objective
Severe grief symptoms in family caregivers during end‐of‐life cancer trajectories are associated with complicated grief and depression after the loss. Nevertheless, severe grief symptoms ...during end‐of‐life caregiving in caregivers to cancer patients have been scarcely studied. We aimed to explore associations between severe preloss grief symptoms in caregivers and modifiable factors such as depressive symptoms, caregiver burden, preparedness for death, and end‐of‐life communication.
Methods
We conducted a population‐based prospective study of caregivers to 9512 patients registered with drug reimbursement due to terminal illness, and 3635 caregivers responded. Of these, 2865 caregivers to cancer patients completed a preloss grief scale (Prolonged Grief 13, preloss version). Associations with factors measured during end‐of‐life caregiving were analyzed using logistic regression.
Results
Severe preloss grief symptoms were reported by 432 caregivers (15.2%). These symptoms were associated with depressive symptoms (adjusted odds ratio OR = 12.4; 95% CI, 9.5‐16.3), high caregiver burden (adjusted OR = 8.3; 95% CI, 6.3‐11.1), low preparedness for death (adjusted OR = 3.3; 95% CI, 2.5‐4.4), low level of communication about dying (adjusted OR = 3.2; 95% CI, 2.2‐4.4), and “too much” prognostic information (adjusted OR = 2.8; 95%, 1.7‐4.6).
Conclusions
Severe preloss grief symptoms were significantly associated with distress, low preparedness, and little communication during caregiving. Thus, severe preloss grief symptoms may be a key indicator for complications in caregivers of cancer patients in an end‐of‐life trajectory. Targeted interventions are needed to support family caregivers with severe preloss grief symptoms. Development of preloss grief assessment tools and interventions should be a priority target in future research.
DNA double-strand breaks arise accidentally upon exposure of DNA to radiation and chemicals or result from faulty DNA metabolic processes. DNA breaks can also be introduced in a programmed manner, ...such as during the maturation of the immune system, meiosis, or cancer chemo- or radiotherapy. Cells have developed a variety of repair pathways, which are fine-tuned to the specific needs of a cell. Accordingly, vegetative cells employ mechanisms that restore the integrity of broken DNA with the highest efficiency at the lowest cost of mutagenesis. In contrast, meiotic cells or developing lymphocytes exploit DNA breakage to generate diversity. Here, we review the main pathways of eukaryotic DNA double-strand break repair with the focus on homologous recombination and its various subpathways. We highlight the differences between homologous recombination and end-joining mechanisms including non-homologous end-joining and microhomology-mediated end-joining and offer insights into how these pathways are regulated. Finally, we introduce noncanonical functions of the recombination proteins, in particular during DNA replication stress.
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