Wednesday, May 23, 2018

Role of DPP4 in obesity

Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins (a hormone that stimulates insulin secretion). DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. DPP4 (also known as adenosine deaminase binding protein), is a serine exopeptidase able to inactivate various oligopeptides through the removal of N-terminal dipeptides. Human white preadipocyte and adipocyte cells express DPP4 in high amounts. In humans, the DPP4 gene is located on chromosome 2q23, encoding a protein of 766 amino acids.

DPP4 degrades incretin peptides (e.g. GLP1/glucagon-like peptide 1) and is known for its regulatory effect in glucose metabolism [1]. Recent study found a connection of DPP4 with obesity and the metabolic syndrome or insulin resistance. DPP4 expression and release are higher in obese patients with metabolic syndrome and type 2 diabetes. Researches on DPP4 knockout mice revealed that absence of this enzyme improves glycemic control and leads to reduced fat mass which made DPP4 inhibitors promising candidates for treating human Type 2 diabetes (T2DM). So DPP4 inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production. Recent research found that adipocytes release DPP4 in a differentiation-dependent manner. Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT). DPP4 overexpression in visceral adipose tissue (VAT) is a marker of adipose tissue inflammation, which is known to be associated with insulin resistance and the metabolic syndrome [2].

Several DPP4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, and alogliptin) have been launched in the market and are now being used for the treatment of T2DM. All of them have proved efficacy in glycemic control with impressive safety and tolerance profiles. Gliptins (small molecular inhibitors of the peptidase DPP4) can be used as monotherapy or in combination with other oral agents (in dual or triple therapy) and even with insulin [3]. The adipose tissue is a major endocrine and energy storage organ that plays an important role in metabolic systems and insulin action which make this a target for another class of antidiabetics, the glitazones. DPP4 plays a functional role within adipose tissue, because DPP4 inhibition has been seen to prevent adipose tissue inflammation and development of glucose intolerance in high fat diet induced obesity in mice.

References:

1.https://www.hindawi.com/journals/bmri/2015/816164/

2.http://care.diabetesjournals.org/content/36/12/4083

3.https://www.nature.com/articles/srep23074

Wednesday, February 28, 2018

Aspirin: The wonder drug

Aspirin or salicyclate is a non-steroidal anti-inflammatory drug that works as a wonder drug. Its various aspects are:

1. Inhibition of Prostaglandin Synthesis and Antithrombotic action: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme now called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain and fever.The predominant product of cyclooxygenase in platelets is thromboxane A2 that is necessary for platelet aggregation.

The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine at position 529. This prevents the access of the substrate (arachidonic acid) to the catalytic site of the enzyme at tyrosine and results in an irreversible inhibition of platelet-dependent thromboxane formation. Aspirin is an approximately 150- to 200-fold more potent inhibitor of the (constitutive) isoform of the platelet enzyme (COX-1) than the (inducible) isoform (COX-2) which is expressed by cytokines, inflammatory stimuli, and some growth factors [1].

2. Ischemic stroke prevention: Aspirin reduces the incidence of recurrent myocardial infarction and stroke. It also reduces significantly the incidence of a first nonfatal myocardial infarction. Aspirin works by inhibiting platelet function (platelets are the tiny blood cells that trigger blood clotting). Thromboxane B2 (TxB2) is an indicator of platelet activation that drops as platelet function is inhibited by aspirin during heart attack and stroke [2].

3. Aspirin reduces risk of pre-eclampsia: Pre-eclampsia and other hypertensive disorders of pregnancy are leading causes of maternal and infant illness and death globally. Such disorders are estimated to cause 76,000 maternal and 500,000 infant deaths each year, according to the Pre-eclampsia Foundation. Pre-eclampsia is characterized by a sudden increase in blood pressure and protein in the urine, which can occur after the 20th week of pregnancy and often results in pre-term birth [3]. It can lead to eclampsia, renal or liver failure, cardiac, pulmonary and other maternal health complications. Low-dose aspirin (81 mg) initiated in early pregnancy is an efficient method of reducing the incidence of preeclampsia and IUGR (intrauterine growth restriction). Preeclampsia is associated with an imbalance of increased thromboxane and decreased prostacyclin and an abnormal increase of lipid peroxides (lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis) [4]. The protective effect of aspirin is mediated by a decrease in thromboxane A2 production without a reduction in prostacyclin production, which thus prevents the vasoconstriction and coagulation problems that are characteristic of preeclampsia.

Though aspirin has several health benefits, combining this drug with other anticoagulant drug (ibuprofen or heparin) may result into internal/gastrointestinal bleeding that could be life threatening.

References:

Sunday, December 31, 2017

To my readers -

Wish you and your family a very Happy and Prosperous New Year!

Selenium as an antioxidant and protector of brain

Selenium (Se) is a trace element, a powerful antioxidant and an important micronutrient that’s absolutely essential for human health. Selenium plays an important role in human cell function - it strengthens and protects cell structure and supports cellular metabolism. As an antioxidant, selenium helps fight free radical damage and moderates reactive oxygen species (ROS), which cause cellular oxidative stress. In addition to acting as an essential nutrient for the immune system and overall body function, selenium also plays a critical role in the operation of the nervous system and in human brain function.The functions of selenium are carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine (21st amino acid).

Human beings have 25 selenoproteins in their genome and majority of these are relative to the antioxidant defence of the body. The three well-studied subfamilies of selenoproteins include thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and iodothyronine deiodinases (DIO). Three of these TrxR selenoproteins have been identified in mammals that includes TrxR1, which functions in the cytosol and nucleus, TrxR2, which functions in the mitochondria, and TrxR3, which functions in testis. The TrxRs are also important components of the mechanism to reduce peroxide. This group of selenoproteins is required for reduction of thioredoxin (Trx), which uses a cysteine thiol-disulfide exchange for reduction of thiol groups in protein residues. Trx can inhibit apoptosis signaling regulating kinase1 (ASK1) and prevent apoptosis to control cell division, longevity, and cell death. The Trx–TrxR systems are also important for reducing proteins that have cysteine in DNA-binding domains, which include NF-kB, AP-1, p53, and glucocorticoid receptors [1]. Also Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival according to recent research. Selenium and selenoproteins are also involved in brain metabolism and brain signalling pathways. Selenoproteins have special importance to the neuronal cells, which utilise γ-aminobutyric acid (GABA) as their signalling molecule (GABAergic neurons). In both selenium deficient organisms and organism with genetic impairment of selenoprotein biosynthesis this kind of neurons are affected most heavily [2]. Severe selenium deficiency or malfunction of selenium transporting protein, selenoprotein P, causes degeneration of special group of GABAergic neurons leading to impaired neuronal function that results in motor function disorders, including seizures, and cognitive impairments like affected learning. This is because of the abundance of the GABA-utilising neurons in the corresponding brain regions – hippocampus, cerebral cortex and cerebellum.

Through selenoproteins selenium is involved in the diverse functions of the brain including motor performance, coordination, memory and cognition. Selenoproteins are important for normal brain function, and decreased function of selenoproteins can lead to impaired cognitive function and neurological disorders such as Alzheimer's disease, Parkinson's disease (impaired function of glutathione peroxidase selenoenzymes), Huntington's disease (here selenium deters lipid peroxidation by increasing specific glutathione peroxidases/GPX), amyotrophic lateral sclerosis and epilepsy [3]. Since the human body cannot produce selenium, it must be consumed from an external source and generally an adult human requires a minimum of 55 micrograms per day. Women who are pregnant or breastfeeding require slightly more.

References:

Pillai, R., Uyehara-Lock, J. H. and Bellinger, F. P. (2014), Selenium and selenoprotein function in brain disorders. IUBMB Life, 66: 229–239. doi:10.1002/iub.1262
https://atlasofscience.org/importance-of-selenium-for-brain-function/
https://www.ncbi.nlm.nih.gov/pubmed/12807419

Sunday, December 17, 2017

Dengue virus pathogenesis

Dengue virus (DENV) is a mosquito-transmitted (primarily from the female mosquitoes of genus Aedes) RNA virus that infects an estimated 390 million humans each year. DENV is a member of the Flavivirus genus of single-stranded positive-sense RNA viruses that cause visceral and central nervous system disease in humans. Dengue is currently the most prevalent arthropod-borne viral disease of humans that is caused by four antigenically distinct serotypes of dengue virus (DENV 1–4) that are genetically similar and share approximately 65% of their genomes. Infection with any of the DENV serotypes may result in a wide spectrum of clinical symptoms, ranging from a mild flu-like syndrome (known as dengue fever [DF]) to the most severe forms of the disease, which are characterized by coagulopathy, increased vascular permeability (increased hemoconcentration or fluid effusion in chest or abdominal cavities), fragility (dengue hemorrhagic fever [DHF]) and dengue shock syndrome [DSS]. Severe dengue is a potentially deadly complication due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding and organ impairment [1]. The World Health Organization (WHO) classifies DHF in four grades (I to IV). DHF grades I and II represent relatively mild cases without shock, whereas grade III and IV cases are more severe and accompanied by shock. Recovery from infection by one serotype provides lifelong immunity against that particular serotype, and does not provide cross-immunity against other serotypes.

The primary vector of dengue is Aedes aegypti mosquito that lives in urban habitats and breeds mostly in man-made containers. Ae. aegypti is a day-time feeder and its peak biting periods are early in the morning and in the evening before dusk. Aedes albopictus is the secondary dengue vector in Asia, has spread to North America and more than 25 countries in the European Region. During the feeding of mosquitoes on humans, DENV is presumably injected into the bloodstream, with spillover in the epidermis and dermis, resulting in infection of immature Langerhans cells (epidermal dendritic cells [DC]) and keratinocytes. Infected cells then migrate from site of infection to lymph nodes, where monocytes and macrophages are recruited, which become targets of infection. Consequently the infection is amplified and virus is disseminated through the lymphatic system. As a result of this primary viremia, several cells of the mononuclear lineage, including blood-derived monocytes, myeloid DC, and splenic and liver macrophages are infected [2]. There are several immune cells associated with the pathogenesis of DENV infection and systemic spread, including dendritic cells, macrophages, and mast cells (MCs). MCs are widely recognized for their immune functions and as cellular regulators of vascular integrity in human skin [3].

Several genetic factors have been shown to be associated with the development of DHF/DSS and some have been shown to be protective. Certain HLA- class I and class II allele polymorphisms in the tumor necrosis factor alpha (TNF-α), Vitamin D receptor, CTLA-4 and transforming growth factor ß (TGF-β) have been shown to be associated with development of DHF/DSS. Several studies have shown that concentrations of multiple cytokines and other mediators, as well as soluble receptors, are significantly increased during severe dengue infections. Higher plasma levels of IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-18, TGF-1β, TNF-α, and IFN-γ have been found in patients with severe DENV infections, in particular in patients with DSS [4].

There is no specific treatment for dengue fever. Maintenance of the patient's body fluid volume is critical to severe dengue care. In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was registered in several countries for use in individuals 9-45 years of age living in endemic areas. WHO recommends that countries should consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease.

References:

Tuesday, October 31, 2017

Herbal supplements and cancer

Herbal supplements as well as dietary supplements could cause cancer. According to recent research one in five cases of chemical-induced liver damage come from herbal and dietary supplements. Herbal remedies containing aristolochic acids (AA), a compound found in leafy, flowery vines called Aristolochia (or birthwort) and Asarum is the most potent carcinogen that have been linked to several types of cancer. Aristolochic Acid is a natural product of plants used in some weight loss supplements too. A study, published in Science Translational Medicine found that in 78 percent of liver cancer samples collected in Taiwan showed a distinctive mutation consistent with AA exposure. The research team looked at 98 samples of hepatocellular carcinoma, the most common type of liver cancer, and the most common cause of death in people with cirrhosis [1]. Also cancers of the upper urinary tract (renal pelvis and ureter) and bladder have been reported among individuals who had kidney damage caused by the consumption of herbal products containing AA.

Aristolochic acid is absorbed from the gastrointestinal tract and distributed unchanged and/or in metabolized form throughout the body. The major activation pathway of AA involves reduction of the nitrogroup, and is catalysed by several human cytosolic and microsomal enzymes such as hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase (NQO1), hepatic microsomal cytochrome P450 (CYP)1A2 and renal microsomal NADPH:CYP reductase – NQO1 being the most important [2]. During reductive activation, aristolochic acids form an electrophilic cyclic N-acylnitrenium ion that reacts with purine bases to form DNA adducts. These DNA adducts found in patients with liver, bladder and renal cancer, act as biomarker for exposure to AA.

AA has been officially banned in Europe since 2001 and in Singapore since 2004. Some herbs that contain AA have been banned in Taiwan since 2003, and in China, the use of some, but not all, AA-containing herbs in traditional medicine is restricted. But the United States Food and Drug Administration has issued strong warnings about herbs containing AA. Food and Drug Administration (FDA) is advising consumers to immediately discontinue use of any botanical products containing aristolochic acid. These products may have been sold as "traditional medicines" or as ingredients in dietary supplements [3].

References:

Wednesday, October 11, 2017

Neuroligin-3 and brain cancer

NLGN3 (neuroligin 3) is a mitogen/synaptic protein that promotes glioma proliferation through the PI3K–mTOR pathway. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K–mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. The tumors, called high-grade gliomas (HGG), are a group of deadly brain cancers that include adult glioblastoma, anaplastic oligodendroglioma, pediatric glioblastoma (GBM) and pediatric diffuse intrinsic pontine glioma (DIPG) [1]. Recent research in Stanford University found that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Neuroligin-3 activates multiple cancer promoting signaling pathways and increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function [2]. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors block the release of NLGN3 into the tumor microenvironment and robustly pause HGG xenograft growth [3]. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth [4]. Recent research suggests that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain.