The RAGE Inhibitor TTP488 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer Cell Lines.

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, and promoting a pro-tumor microenvironment via activation of the nuclear factor-kappa B (NF-κB) signaling pathways. This study validated pathway activation in human pancreatic cancer and evaluated the therapeutic efficacy of TTP488 (Azeliragon), a small-molecule RAGE inhibitor, alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer.

Hypobaric hypoxia drives selection of altitude-associated adaptative alleles in the Himalayan population.

Genetic variants play a crucial role in shaping the adaptive phenotypes associated with high-altitude populations. Nevertheless, a comprehensive understanding of the specific impacts of different environments associated with increasing altitudes on the natural selection of these genetic variants remains undetermined. Hence, this study aimed to identify genetic markers responsible for high-altitude adaptation with specific reference to different altitudes, majorly focussing on an altitude elevation range of ∼1500 m and a corresponding decrease of ≥5 % in ambient oxygen availability.

Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.

Retinopathy fails to halt even after diabetic patients in poor glycemic control try to institute tight glycemic control, suggesting a "metabolic memory" phenomenon, and the experimental models have demonstrated that mitochondria continue to be damaged/dysfunctional, fueling into the vicious cycle of free radicals. Our aim was to investigate the role of removal of the damaged mitochondria in the metabolic memory. Using human retinal endothelial cells (HRECs), incubated in 20 mM D-glucose for 4 days, followed by 5 mM D-glucose for 4 additional days, mitochondrial turnover, formation of mitophagosome, and mitophagy flux were evaluated.

Mitochondrial Genome-Encoded Long Noncoding RNA Cytochrome B and Mitochondrial Dysfunction in Diabetic Retinopathy.

Mitochondrial dysfunction is closely associated with the development of diabetic complications. In diabetic retinopathy, electron transport chain is compromised and mitochondrial DNA (mtDNA) is damaged, downregulating transcription of mtDNA-encoded cytochrome B () and its antisense long noncoding RNA, long noncoding RNA cytochrome B (Lnc). Our goal was to investigate the role of Lnc in the regulation of and mitochondrial function in diabetic retinopathy.

The Telomere-Telomerase System Is Detrimental to Health at High-Altitude.

The hypobaric-hypoxia environment at high-altitude (HA, >2500 m) may influence DNA damage due to the production of reactive molecular species and high UV radiation. The telomere system, vital to chromosomal integrity and cellular viability, is prone to oxidative damages contributing to the severity of high-altitude disorders such as high-altitude pulmonary edema (HAPE). However, at the same time, it is suggested to sustain physical performance.

Mitochondrial Genome-Encoded Long Noncoding RNA and Mitochondrial Stability in Diabetic Retinopathy.

Mitochondria experience genomic and functional instability in diabetes, and mitochondrial dysfunction has a critical role in the development of diabetic retinopathy. Diabetes also alters expressions of many long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame. LncRNAs are mainly encoded by the nuclear genome, but mtDNA also encodes three LncRNAs.

An efficient computer vision-based approach for acute lymphoblastic leukemia prediction.

Leukemia (blood cancer) diseases arise when the number of White blood cells (WBCs) is imbalanced in the human body. When the bone marrow produces many immature WBCs that kill healthy cells, acute lymphocytic leukemia (ALL) impacts people of all ages. Thus, timely predicting this disease can increase the chance of survival, and the patient can get his therapy early.

Regulation of serine palmitoyl-transferase and Rac1-Nox2 signaling in diabetic retinopathy.

Hyperlipidemia is considered as one of the major systemic factors associated with the development of diabetic retinopathy, and animal models have documented that its presence in a hyperglycemic environment exacerbates cytosolic ROS production (via activation of the Rac1-Nox2 axis) and mitochondrial damage. Hyperglycemia also accelerates Rac1 transcription via dynamic DNA methylation-hydroxymethylation of its promoter. In diabetes, ceramide metabolism in the retina is impaired and its accumulation is increased.

Involvement of High Mobility Group Box 1 Protein in Optic Nerve Damage in Diabetes.

Introduction: Diabetic patients routinely have high levels of high mobility group box 1 (HMGB1) protein in their plasma, vitreous and ocular membranes, which is strongly correlated with subclinical chronic inflammation in the eye. Our previous work has suggested that high HMGB1 in diabetes plays a role in retinal inflammation and angiogenesis, but its role in the optic nerve damage is unclear. Therefore, our goal is to examine the role of HMGB1 in optic nerve damage in diabetes.

Mitochondrial Dynamics in the Metabolic Memory of Diabetic Retinopathy.

Mitochondria play a central role in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. Mitochondria have a regulated fusion fission process, which is essential for their homeostasis. One of the major fission proteins, dynamin-related protein 1 (Drp1), is recruited to the mitochondria by fission protein 1 (Fis1) to initiate fragmentation.

Mitochondrial Fragmentation in a High Homocysteine Environment in Diabetic Retinopathy.

Diabetic patients routinely have elevated homocysteine levels, and due to increase in oxidative stress, hyperhomocysteinemia is associated with increased mitochondrial damage. Mitochondrial homeostasis is directly related to the balance between their fission and fusion, and in diabetes this balance is disturbed. The aim of this study was to investigate the role of homocysteine in mitochondrial fission in diabetic retinopathy.

Thymoquinone Attenuates Retinal Expression of Mediators and Markers of Neurodegeneration in a Diabetic Animal Model.

Background: Diabetic retinopathy (DR) is a slow eye disease that affects the retina due to a long-standing uncontrolled diabetes mellitus. Hyperglycemia-induced oxidative stress can lead to neuronal damage leading to DR.

Objective: The aim of the current investigation is to assess the protective effects of thymoquinone (TQ) as a potential compound for the treatment and/or prevention of neurovascular complications of diabetes, including DR.

Nuclear Genome-Encoded Long Noncoding RNAs and Mitochondrial Damage in Diabetic Retinopathy.

Retinal mitochondria are damaged in diabetes-accelerating apoptosis of capillary cells, and ultimately, leading to degenerative capillaries. Diabetes also upregulates many long noncoding RNAs (LncRNAs), including Lnc and Lnc. These RNAs have more than 200 nucleotides and no open reading frame for translation.

Epigenetic modifications in diabetes.

Diabetes is now considered as a 'silent epidemic' that claims over four million lives every year, and the disease knows no socioeconomic boundaries. Despite extensive efforts by the National and International organizations, and cutting-edge research, about 11% world's population is expected to suffer from diabetes (and its complications) by year 2045. This life-long disease damages both the microvasculature and the macrovasculature of the body, and affects many metabolic and molecular pathways, altering the expression of many genes.

Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy.

Cytosolic ROS, generated by NADPH oxidase 2 (Nox2) in diabetes, damage retinal mitochondria, which leads to the development of retinopathy. A small molecular weight G-protein essential for Nox2 activation, Rac1, is also transcriptionally activated via active DNA methylation-hydroxymethylation. DNA methylation is a dynamic process, and can also be regulated by histone modifications; diabetes alters retinal histone methylation machinery.

Gain-of-function Tibetan PHD2 variant suppresses monocyte function: A lesson in inflammatory response to inspired hypoxia.

Background: We have previously described an evolutionarily selected Tibetan prolyl hydroxylase-2 (PHD2) variant that degrades the hypoxia-inducible factor (HIFα) more efficiently and protects these highlanders from hypoxia-triggered elevation in haemoglobin concentration. High altitude is known to cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) in a section of rapidly ascending non-acclimatised lowlanders. These morbidities are often accompanied by inflammatory response and exposure to hypobaric hypoxia is presumed to be the principal causative agent.

High-altitude pulmonary edema is aggravated by risk loci and associated transcription factors in HIF-prolyl hydroxylases.

High-altitude (HA, >2500 m) hypoxic exposure evokes several physiological processes that may be abetted by differential genetic distribution in sojourners, who are susceptible to various HA disorders, such as high-altitude pulmonary edema (HAPE). The genetic variants in hypoxia-sensing genes influence the transcriptional output; however the functional role has not been investigated in HAPE. This study explored the two hypoxia-sensing genes, prolyl hydroxylase domain protein 2 (EGLN1) and factor inhibiting HIF-1α (HIF1AN) in HA adaptation and maladaptation in three well-characterized groups: highland natives, HAPE-free controls and HAPE-patients.

Hydrogen Sulfide: A Potential Therapeutic Target in the Development of Diabetic Retinopathy.

Purpose: Hyperglycemia damages the retinal mitochondria, and the mitochondrial damage plays a central role in the development of diabetic retinopathy. Patients with diabetes also have higher homocysteine levels, and abnormalities in homocysteine metabolism result in decreased levels of hydrogen sulfide (H2S), an endogenous gasotransmitter signaling molecule with antioxidant properties. This study aimed to investigate the role of H2S in the development of diabetic retinopathy.

Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs.

Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE).

Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.

Retinopathy continues to progress even when diabetic patients try to control their blood sugar, but the molecular mechanism of this 'metabolic memory' phenomenon remains elusive. Retinal mitochondria remain damaged and vicious cycle of free radicals continues to self-propagate. DNA methylation suppresses gene expression, and diabetes activates DNA methylation machinery.

Correction to: Faulty homocysteine recycling in diabetic retinopathy.

[This corrects the article DOI: 10.1186/s40662-019-0167-9.].

Homocysteine Disrupts Balance between MMP-9 and Its Tissue Inhibitor in Diabetic Retinopathy: The Role of DNA Methylation.

High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is implicated in increased oxidative stress and activation of MMP-9, and in diabetic retinopathy, the activation of MMP-9 facilitates capillary cell apoptosis.