Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

http://europepmc.org/articles/PMC4741373?pdf=render

Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.

Background In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. Methods In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. Results Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P<0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P<0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P<0.001), and...

https://www.nejm.org/doi/pdf/10.1056/NEJM199505183322001

Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia

Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1510865

Sickle Cell Disease

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(10)00091-5.pdf

Glutamine addiction: a new therapeutic target in cancer.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

/pdf/reactive-astrocyte-nomenclature-definitions-and-future-30mrcayhyo.pdf

Reactive astrocyte nomenclature, definitions, and future directions

The plantar sweat glands of the rat have been studied by light and electron microscopy. These glands differ from conventional eccrine sweat glands of man, other primates, and cats in that the secretory segment contains only one type of secretory cell. This cell is characterized by a relatively nondescript cytoplasm containing numerous vesicles, extensive interdigitations of adjacent plasma membranes and small microvilli projecting into the lumen. In the resting gland, two types of cells can be distinguished on the basis of mitochondrial morphology. Some cells contain mitochondria in condensed configurations, and others contain mitochondria in the more orthodox configuration. Following stimulation, these differences are not pronounced; and the condensed mitochondria have evidently changed into more orthodox mitochondria in appearance. No distinct cytologic pathway for secretion could be defined, correlated with the most unusual ionic composition of the sweat in this animal (very high levels of potassium). The sweat glands of the rat foot pad then are unique as compared with other cutaneous glands both in their cytologic appearance and in the chemical composition of the sweat they elaborate.

The histophysiology of rat plantar sweat glands

THE ratio of the concentration of urea in the sweat to that in the plasma (s/p) is known to be greater than unity. Schwartz1 attributed this gradient to back diffusion of water because he found that raising the plasma urea concentration had little effect on the s/p ratio for urea. Recent evidence2,3 suggests that (a) s/p for urea is not entirely independent of plasma urea concentration; (b) s/p for urea is independent of s/p osmolality in man and the cat (for example, the s/p urea is greater than 1 in the hyperosmotic sweat obtained from the hairless footpad of the cat); (c) compounds related to urea by virtue of similar volumes of distribution (ethanol, antipyrine, creatinine) or similar molecular configuration (thiourea, methylurea, acetamide) all behave differently from urea in sweat in that none of these compounds is present in sweat at higher concentrations than in plasma.

/pdf/evidence-for-a-non-plasma-source-of-urea-in-sweat-51on665b0c.pdf

Evidence for a non-plasma source of urea in sweat.

Effects of indomethacin on cholera toxin-induced cerebrospinal fluid production.

In addition to its effects on purine metabolism, AP, via its metabolite, oxipurinol ribonucleotide, inhibits pyrimidine biosynthesis (PB) at the level of orotidine mono-phosphate decarboxylase. This inhibition results in increased ODNU. Women heterozygous at the OTC locus have 2 populations of hepatocytes; OTC normal and OTC deficient. We hypothesize that, as a consequence of carbamyl phosphate accumulation in the latter cells, PB is chronically increased. Therefore, inhibition of PB by AP should result in an even greater increase in ODNU in OTCH as compared to controls. The AP test includes administration of 300mg of AP followed by four pooled consecutive 6 hr urine collections. Urinary orotidine was measured by reverse phase HPLC after isolation of nucleosides on a boronate affinity column. We studied 11 control women (C) and 12 obligate OTC heterozygotes (OTCH). The mean (±SEM) peak urine orotidine (umol/mmol creatinine) of C and OTCH was respectively 7.36±0.46 (range 5.7-10.1) and 39.7±7.3. One OTCH fell in the normal range (7.71); other OTCH values ranged from 17.9 to 97.9. Comparison of these results with a protein tolerance test (PTT) administered to the same subjects, shows that the diagnostic sensitivity of the 2 tests are the same and that the same OTCH was negative in both. We conclude that PB is chronically increased in OTCH; and that the AP test identifies OTCH as well as the PTT, eliminates the risk of hyperammonemia, and is more convenient and acceptable.

/pdf/allopurinol-ap-induced-orotidinuria-odnu-a-test-of-1cw2nvnifq.pdf

Allopurinol (ap) induced orotidinuria (odnu): a test of heterozygosity for ornithine trans-carbahylase (otc) deficiency

SummarySweat obtained from the sweat glands situated in the footpad of the rat was found to be a hypertonic solution with the following concentration of electrolytes (meq/liter): potassium, 149; sodium, 30; chloride, 80. Based on the descriptions of the fine structure of the rat sweat gland it is concluded that the “dark” (electron transparent cells of the secretory coil of the sweat are responsible for the secretion of potassium in sweat.

Comparative physiological aspects of solute secretion by the eccrine sweat gland of the rat.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Saul W. Brusilow

Author Tools

Chat about Author