Wednesday, August 30, 2017

Role of cardiotrophin-1 in cardiovascular regulation

Cardiotrophin-1 (CT-1) is a transmembrane signaling glycoprotein (gp)130 ligand, a leukemia inhibitory factor (LIF) receptor and a heart-targeting cytokine. CT-1 is a new member of the interleukin IL-6 type cytokine family and has potent hypertrophic and survival effects on cardiac myocytes [1]. Several factors could stimulate cardiac CT-1 expression such as hypoxia, reactive oxygen species, angiotensin II, aldosterone, urocortin, glucose and insulin, and fibroblast growth factor-2. CT-1 mediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI-3) kinase, and nuclear factor kappa B (NFκB) pathways [2]. CT-1 was originally identified in cardiomyocytes (heart) but CT-1 gene (located on chromosome 16p11.1–16p11.2) and protein (that encodes 201 amino acids) expression also occurs in the liver, lung, kidney, skeletal muscle and adipose tissues (adipocytes is an important cellular source of CT-1).

Plasma cardiotrophin-1 (CT-1) levels are elevated in cardiovascular diseases (CVDs) such as hypertension, valve diseases, congestive heart failure, coronary artery diseases, metabolic syndrome, and chronic kidney diseases. Circulating levels of CT-1 increase with the severity of the CVDs [3]. CT-1 exerts a protective function in the adult heart by inducing cell hypertrophy (enlargement). Recent research says that CT-1 specifically protects the cardiac myocytes from ischaemic damage when given prior to the ischaemia and at the time of reoxygenation. CT-1 induces the pathological hypertrophic response and could be therapeutically used in the treatment of ischaemic damage in the heart [4].

Recent evidence suggests that CT-1 acts as a biomarker for LVH (left ventricular hypertrophy) and impaired cardiac function in patients with hypertension. Recent study, by a team of researchers from The Ottawa Hospital, the University of Ottawa, the University of Ottawa Heart Institute and Carleton University discovered that CT-1 protein could be used as an “exercise pill” that can trick the heart into repairing damage and improving blood flow. This “pill” i.e. CT-1 protein could help improve the function of a failing heart and boost blood flow by mimicking the effects of a visit to the gym that could revolutionize the lives of hundreds of thousands of heart disease sufferers [5].

Also local and systemic concentrations of CT-1 plays a critical role in obesity. A recent study showed that acute and chronic treatments with recombinant CT-1 were able to correct insulin resistance in animal models of genetic and acquired obesity. A recent study also found that cardiotrophin-1 induces Matrix Metalloproteinase-1 (MMP) in human aortic endothelial cells (HAECs) [6]. Recent research suggests that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and also suggests that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability. All data shows that CT-1 has a huge impact on cardiovascular regulation and heart disease protection.

References:

Sunday, July 30, 2017

Genes lead to mind reading capabilities

DNA influences the ability to read a person's thoughts and emotions from looking at their eyes, according to a new study. The ‘cognitive empathy'/'Reading the Mind in the Eyes' Test by the scientists of University of Cambridge revealed that people can rapidly interpret what another person is thinking or feeling from looking at their eyes alone and women on average score better on this test than men. The team found that genes influence the performance on the Eyes Test, and identified genetic variants on chromosome 3 in women that are associated with their ability to "read the mind in the eyes." Interestingly, performance on the Eyes Test in males was not associated with genes in this particular region of chromosome 3. The closest genes in this tiny stretch of chromosome 3 include LRRN1 (Leucine Rich Neuronal 1) which is highly active in a part of the human brain called the striatum, and which has been shown using brain scanning to play a role in cognitive empathy. Also the genetic variants that contribute to higher scores on the Eyes Test also increase the volume of the striatum in humans [1].

Studies also found that people with autism and anorexia tend to score lower on the Eyes Test and genetic variants that contribute to higher scores on the Eyes Test also increase the risk for anorexia, but not autism. The scientists speculate that this may be because autism involves both social and non-social traits, and this Eyes Test only measures a social trait [2].

References:

1.http://www.cam.ac.uk/research/news/genes-influence-ability-to-read-a-persons-mind-from-their-eyes

2.https://www.sciencedaily.com/releases/2017/06/170607123843.htm

Friday, June 30, 2017

Broccoli : A weapon against diabetes and cancer

Type 2 diabetes affects around 300 million people globally, and as many as 15% of those patients cannot take the first-line therapy metformin because of kidney damage risks. Type 2 diabetes occurs when the body is not able to make enough insulin or to use the hormone to regulate blood glucose levels. This causes a build-up of sugar in the blood and for obese patients, their excess body fat makes it harder for the liver and muscle tissue to absorb this excess blood glucose. Researchers have identified an antioxidant sulforaphane (which is present in high amounts in broccoli) as a new anti-diabetic substance. This antioxidant also has huge impacts for the treatment of cancer and inflammatory diseases so it is identified as a secret weapon against diabetes and cancer. Sulforaphane stops the liver enzymes from over-producing glucose and thus offers a viable alternative for those who can't take metformin and as a naturally occurring compound, it could also have other benefits. When tested on rodents with dietary-induced diabetes, the researchers found that their blood sugar dropped by 23 percent in four weeks when they were given sulforaphane, which was comparable to the 24 percent drop in those that were given metformin [1].

Also research found that during food preparation the glucosinolates in broccoli and other cruciferous vegetables are broken down into biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates and among them indole-3-carbinol (an indole) and sulforaphane (an isothiocyanate) have been most frequently examined for their anticancer effects. Indoles and isothiocyanates have been found to inhibit the development of cancer by protecting cells from DNA damage and blocks DNA methylation, helping inactivate carcinogens, induce cell death (apoptosis) and inhibit tumor blood vessel formation (angiogenesis) and tumor cell migration [2]. A number of studies showed that sulforaphane may target CSC (cancer stem cells) in different types of cancer through modulation of NF-κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways [3]. Also sulforaphane works variably to help the body avoid genetic failures, and thus operates as a cancer antagonist and it is also a potent compound that boosts the body's protective enzymes and flushes out cancer-causing chemicals.

References:

Saturday, May 27, 2017

Exercise can make you young biologically

Regular exercise and physical activity could make you 9 to10 years young biologically. A new research from Brigham Young University reveals that exercise could slow down cellular aging. The study, published in the medical journal Preventive Medicine, finds that people who have consistently high levels of physical activity have significantly longer telomeres than those who have sedentary lifestyles. Telomeres are tiny protein end caps found on the end of DNA strands (chromosomes) and they protect the DNA from damage during cell division and replication. Telomeres are correlated with age, each time a cell replicates / ages, its telomeres naturally shorten and fray and exercise may slow the fraying of telomeres. A study found that shortest telomeres came from sedentary people and had 140 base pairs of DNA less at the end of their telomeres than highly active people [1].

Recent research found that adults with high physical activity levels have telomeres with a biological aging advantage of 9 to 10 years over those who are non active, and a 7 year advantage compared to those who are moderately active. Highly active means women had to engage in 30 minutes of jogging/brisk walk per day (40 minutes for men), five days a week.

Also physical activity can slow brain aging by as much as 10 years, according to a new study. Studies found that people who used to do more physical activity showed higher scores on cognitive tests and better brain health. Several factors such as high blood pressure, diabetes, smoking & alcohol consumption and heart disease could impair blood flow to the brain and therefore compromise cognitive/brain functions [2].

But over exercise may result in free radical-mediated oxidative damage / overproduction of reactive oxygen (ROS) and nitrogen species. Muscle fibers/myocytes contain both enzymatic and nonenzymatic (e.g., GSH/Glutathione, uric acid, bilirubin, etc) antioxidants defense networks that exist in both the extracellular and vascular space and work as a complex unit to regulate ROS. These antioxidants protect muscle fibers from oxidative injury during increased oxidant production (e.g., intense or prolonged exercise) [3]. Antioxidant enzymes (by which free radicals are neutralized) includes superoxide dismutase, glutathione peroxidase, and catalase, peroxiredoxin, glutaredoxin, and thioredoxin reductase that contribute to cellular protection against oxidation. Various dietary antioxidants may contribute to cellular protection against free radicals and other ROS including vitamin E, vitamin C, and carotenoids.

References:

Saturday, April 29, 2017

Role of Berries in cancer prevention

Berries are loaded with antioxidants that can prevent cancer by mopping up the free radicals i.e. the oxygen molecules. Also all types of berries particularly strawberries and raspberries have high content of ellagic acid that can fight various types of cancers (skin, bladder, lung, esophagus and breast). Ellagic acid acts as an antioxidant, helps to deactivate specific carcinogens, slowing down the reproduction of cancer cells and it is also a potent anti-angiogenetic factor, which can slow the growth of blood vessels that feed new tumor cells. Another phytonutrient Quercetin that is found in abundance in strawberries, can induce apoptosis (programmed death of cancer cells). According to a recent study published in the Journal of Agriculture and Food Chemistry, Quercetin and whole strawberry extract inhibited the proliferation of human liver cancer cells, produced a dramatic increase in cell death (up to 80 percent) after 18 hours of treatment and retarded the proliferation of these cells prior to their death [1].

Blueberries contain a family of phenolic compounds called anthocyanosides (because of which these berries are blue), which are among the most potent antioxidants yet discovered [2]. Recent research found that black raspberry and strawberry extracts have the most effective apoptosis inducing effects. Recent studies from the College of Public Health at Ohio State University, Comprehensive Cancer Center in Columbus, Ohio, discovered that black raspberries prevent cervical cancer cell growth and tumor formation and also they inhibit inflammation and induce apoptosis in esophageal and colorectal cancer tissues [3]. The ellagic acid in strawberries can deactivate specific carcinogens and decrease the replication of cancer cells. Also The College of Pharmacy at the University of Rhode Island analyzed the Jamun berries (Indian blackberry) extract and found that it exhibited pro-apoptotic effects against breast cancer cells.

But it is very important to consume only organic berries because recent report from the U.S. Department of Agriculture found that a single sample of berries contained 13 different pesticides. Also a Pesticide Action Network analysis found 54 different pesticides among strawberry samples, including nine probable carcinogens, 24 suspected hormone disruptors, 11 neurotoxins and 12 reproductive toxins. Also the phytonutrient content of organic strawberries is higher than in conventionally grown strawberries, especially vitamin C. Compost as a soil supplement increases the level of antioxidant compounds in strawberries. A Swedish research found the most effective extracts at inhibiting cell proliferation contained 48 percent more ascorbate and five times more dehydroascorbate (Vitamin C is ascorbate plus dehydroascorbate.) The organic strawberries had more antioxidants and a higher ratio of ascorbate to dehydroascorbate. So adding a cup of cancer-fighting berries a day to diet may reduce many risk factors, and help battle certain types of cancers.

References:

https://www.wsj.com/articles/SB10001424052748703280904576246854013624530

Friday, March 31, 2017

Electronic nose

The electronic nose or nano nose is an artificial olfactory device that has a small array of flexible gold nanoparticle sensors that can accurately detect compounds in a breathing sample. Currently researchers tried to use this nano nose to detect various types of cancer such as ovarian, lung and brain cancer and got 82% accuracy. Disease detection by electronic nose is safer, simpler, more portable, inexpensive and less invasive diagnostic method than traditional methods such as imaging technique, biopsies etc. The nano nose comprises of a large number of flexible sensors that are based on molecularly modified gold nanoparticles (GNPs) [1]. These sensors are integrated into a dynamic cross-reactive diagnostic sensing array. Gold nanoparticles are highly sensitive in the detection of biomarkers at lower concentration levels and they are biocompatible. Each bending state of the flexible sensor gives unique nanoparticle spatial organization, altering the interaction between GNP ligands and volatile organic compounds (VOCs) that increases the amount of data obtainable from each sensor.

The individual dynamic flexible sensor of the nano nose could selectively detect ppb (parts per billion) level VOCs that are linked with cancers in exhaled breath. VOCs can be produced endogenously or exogenously and are used as biomarkers to detect diseases such as cancer in early stages fast and accurately. For example, lung cancer tissue emits some specific VOC biomarkers such as acetaldehyde, formaldehyde, undecane, isopropene, methanol, ethylbenzene and acetone that can be detected by sensors/chemiresistors coated with gold nanoparticles of a nano nose [2]. Breast cancer patients emit VOC biomarkers that includes derivatives of alkanes such as tridecane, hexanol, formaldehyde etc and bladder, and prostate cancer patients exhaled toluene, p-xylene, acetic acid etc. This electronic nose has a huge potential to detect and diagnose various types of diseases including cancer that can enhance the opportunities to save lives.

References:

1. https://phys.org/news/2015-09-sniffing-cancer-electronic-nose-sensors.html

2.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645969/

Monday, February 20, 2017

KRAS - the protooncogene

KRAS gene is Kirsten ras oncogene homolog of mammalian ras gene family and encodes K-Ras protein which regulates cell division and proliferation. Cytogenetically this gene is located in the short arm of chromosome 12 (12p12.1), encoded by 189 amino acids [1]. KRAS protein (also called p21) is a member of RAS/MAPK signalling pathway (for cellular signal transduction) and acts as molecular switch which is turned on by GTP (for cell growth and differentiation) and turned off by GDP molecules. KRAS gene is activated by guanine nucleotide exchange factor (GEF) and inactivated by GTPase activating proteins (GAP) [2]. KRAS is the most frequently mutated oncogene and somatic mutation in this gene results in various types of cancer such as lung, colon and pancreatic.

Around 15 - 25% lung adenocarcinoma/non small cell lung cancer (NSCLC) is related with KRAS mutation (missense mutation that introduces an amino acid substitution most frequently at codons 12, 13 and less frequently codon 61) which affects the KRAS signalling pathways (MAP kinase pathway, AKT/MTOR pathway etc.). The unregulated signalling of RAS through these pathways results in increased cell proliferation, decreased apoptosis, disrupted cellular metabolism and increased angiogenesis that leads to tumor cell proliferation [3]. Currently there is no targeted therapy for the NSCLC patients with KRAS mutation except some promising drug agents such as mitogen activated enzyme kinase inhibitors/MEKi (Trametinib and Selumetinib in combination with chemotherapy), CDK/Cyclin dependent kinase inhibitors (Palbociclib, Abemaciclib) in clinical trial.

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer which develops via acinar-ductal metaplasia and pancreatic intraepithelial neoplasia (PIN/PanIN), IPMN (intraductal papillary mucinous neoplasia) and AFLs (atypical flat lesions). 90% of PDAC is driven by mutationally (point mutation at codon G12) active KRAS oncogene/oncogenic KRAS signalling which results in intrinsic GTPase activity that block the KRAS and GAP interaction. Oncogenic KRAS signalling involves Raf/Mek/Erk pathway and P13K/Pdk1/Akt pathway and signalling in pancreas generates a fibro-inflammatory microenvironment which promotes neoplastic progression by paracrine stimulation. Also oncogenic KRAS drives metabolic reprogramming in tumor cells by aerobic glycolysis (by increasing glycolytic enzyme expression). Until now there is no cure for PDAC and average life expectancy is less than 5 years.

Around 30% to 50% colorectal cancer (CRC) is associated with KRAS mutation/point substitution (the most frequent is glycine for aspartate) mutation in codon 12, 13, 61, 146 and 154. KRAS gene is an important member of EGFR signalling cascade and involved in intracellular signal transduction [4]. EGFR is a transmembrane receptor tyrosine kinase that is overexpressed in 25% to 75% colorectal tumor/cancer. CRC carcinogenesis involves 3 pathways including chromosomal instability pathway/CIN (defects in chromosomal segregation and telomere stability), microsatellite (short tandem repeats/STRs) instability pathway/MSI (loss of DNA mismatch repair which is most common in CRC) and serrated pathway (progression of serrated polyps)/CpG island methylator phenotype pathway [5]. CIN pathway (also known as adenoma-carcinoma sequence) is the most common one (70%) which involves activation of KRAS proto-oncogene and inactivation of tumor suppressor genes such as APC (that normally blocks transition from G1 to S phase in cell cycle), p53 (that is involved in cell cycle control). CIN also results in aneuploid karyotype, loss of heterozygosity at tumor suppressor gene loci and chromosomal rearrangements [6]. Cetuximab and panitumumab are anti EGFR monoclonal antibodies which are engineered to block the EGFR signalling pathway at the extracellular domain of EGFR receptor. These are currently FDA approved CRC drugs but KRAS mutated patients showed no response to these drugs.