Introduction found in people of all ages,

Introduction The essential part of any communication process is cell signaling because it governs basic activities of cells. It also coordinates all cell actions. Basis of development, tissue repair, and immunity, as well as normal tissue homeostasis, is the ability of cells to perceive and correctly respond to their microenvironment. Errors in signaling interactions and cellular information processing cause diseases such as cancer, autoimmunity, and diabetes. 121314 By understanding cell signaling, diseases may be treated more effectively and, theoretically, artificial tissues may be created. 15 G protein–coupled receptors (seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein–linked receptors) constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. 16 G protein–coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, and animals. 17 The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein–coupled receptors are involved in many diseases, and are also the target of approximately 34% of all modern medicinal drugs.181920Disease 1Type 2 DiabetesDescription:Type 2 diabetes is a problem with your body that causes blood glucose (sugar) levels to rise higher than normal, also called hyperglycemia. It is the most common form of diabetes. If you have type 2 diabetes your body does not use insulin properly,thus called insulin resistance. At first, your pancreas makes extra insulin to make up for it. However, over time your pancreas is not able to keep up and can not make enough insulin to keep your blood glucose at normal levels. 1 Over time it raises your risk for heart disease, blindness, nerve and organ damage, and other serious conditions. This is found in people of all ages, and early symptoms are mild. Around one-third of people with type 2 diabetes are unaware of when they have it. An early symptom of type 2 diabetes could be being thirsty a lot. Others symptoms could be dry mouth, bigger appetite, urinating a lot, and unusual weight gain or loss. 16 While not everyone with type 2 diabetes is overweight, obesity and lack of physical activity are two of the most common causes of this form of diabetes. It is also responsible for about 90% to 95% of diabetes cases in the United States, according to the CDC. 17 Role of cell signaling in diseased condition:Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. There is reported a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, dynamic mathematical model of insulin signaling was developed. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: reduced concentration of insulin receptor, reduced concentration of insulin-regulated glucose transporter GLUT4, and changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. There is a demonstrated potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and using a multilevel model, at the whole body level. The findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis. 4 Type I and type II diabetes have very similar symptoms, but they have different causes. While people who have type I diabetes are unable to produce the insulin signal, those with type II diabetes do produce insulin. However, the cells of type II diabetics have lost the ability to respond to insulin. The end result is the same: blood sugar levels become dangerously high. 11Advancement/breakthrough:Management of type 2 diabetes includes healthy eating, regular exercise, diabetes medication, insulin therapy, or blood sugar monitoring. These steps will help keep your blood sugar level closer to normal, which can delay or prevent complications. 2 Insulin Treatments: New types of insulin have come to market. Most are variations of the usual rapid-, short- or long-acting injectable insulin. One very recent newcomer is a totally different form of insulin—Afrezza inhaled human insulin. You take this type of insulin by breathing it in. It is a rapid-acting insulin. You use it at mealtime and in combination with a long-acting injectable insulin.GLP-1 agonists are a group of drugs that are useful if you have type 2 diabetes. Amylin analogs will help both type 1 and type 2 diabetes. That’s exciting because insulin was the primary treatment for type 1 diabetes until this new class. DDP-4 inhibitors help trigger insulin release. But they work differently than other drugs that stimulate insulin release. As a result, they don’t cause low blood sugar the way other drugs can. SGLT inhibitors lower blood sugar by getting rid of extra sugar in the urine. This is a completely new way of working. But there is a downside to this group—they tend to cause urinary tract and yeast infections. Bromocriptine (Parlodel) has many uses including treating menstrual problems, infertility, and Parkinson’s disease. The FDA approved it in type 2 diabetes under the brand name, Cycloset. Cycloset helps people have better long-term blood sugar control. Doctors check this with a lab test called an A1c. If you have diabetes, you know how important your A1c number is. Doctors can prescribe Cycloset alone or in combination with insulin or another oral medicine. Colesevelam (Welchol). Doctors usually use this drug to treat high cholesterol. It turns out that people with type 2 diabetes who took this drug in combination with their usual diabetes therapy had better A1c results than those who didn’t take it. Now, doctors can prescribe it along with other diabetes treatments.3Disease 2CholeraDescription:Cholera is an acute diarrhoeal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. Cholera remains a global threat to public health and an indicator of inequity and lack of social development. Researchers have estimated that every year, there are roughly 1.3 to 4.0 million cases, and 21 000 to 143 000 deaths worldwide due to cholera. Most of those infected will have no or mild symptoms, and can be successfully treated with oral rehydration solution. Severe cases will need rapid treatment with intravenous fluids and antibiotics. Provision of safe water and sanitation is critical to control the transmission of cholera and other waterborne diseases. Oral cholera vaccines are an additional way to control cholera, but should not replace conventional control measures. Safe oral cholera vaccines should be used in conjunction with improvements in water and sanitation to control cholera outbreaks and for prevention in areas known to be high risk for cholera. Cholera is an extremely virulent disease that can cause severe acute watery diarrhoea. It takes between 12 hours and 5 days for a person to show symptoms after ingesting contaminated food or water (2). Cholera affects both children and adults and can kill within hours if untreated. Most people infected with V. cholerae do not develop any symptoms, although the bacteria are present in their faeces for 1-10 days after infection and are shed back into the environment, potentially infecting other people. Among people who develop symptoms, the majority have mild or moderate symptoms, while a minority develop acute watery diarrhoea with severe dehydration. This can lead to death if left untreated.During the 19th century, cholera spread across the world from its original reservoir in the Ganges delta in India. Six subsequent pandemics killed millions of people across all continents. The current (seventh) pandemic started in South Asia in 1961, and reached Africa in 1971 and the Americas in 1991. Cholera is now endemic in many countries. 5 Role of cell signaling in diseased condition:The bacterium discovered by Robert Koch in 1884, can be killed by antibiotics, but the disease is caused by a bacterial toxin, which irreversibly activates the G proteins of epithelial cells in the intestine. This results in an often life-threatening loss of water and salts. From Koch’s discovery of the cholera bacterium in 1884 it took researchers about 100 years to expose the real cause of the disease – the effect of the bacterial toxin on G proteins 6The first method used to build super-deadly toxins is to use a targeting mechanism to deliver the toxin directly to the unlucky cell. Cholera toxin has a ring of five identical protein chains, which binds to carbohydrates on the surface of cells. This delivers the toxic part of the molecule to the cell, where it can wreak its havoc. The second deadly method is to use a toxic enzyme instead of a chemical poison. Enzymes are designed to perform their reactions over and over again, hopping from target to target and making their chemical changes. Thus, one enzyme can modify a whole cell full of molecules. Cholera uses this strategy once it gets inside cells. The toxic portion hops from molecule to molecule, disabling each one in turn, until the entire cell is killed.The catalytic portion of cholera toxin performs a single function: it seeks out the G proteins used for cellular signaling and attaches an ADP molecule to them. This converts the G-protein into a permanently active state, so it sends a never-ending signal. This confuses the cell, and among other things, it begins to transport lots of water and sodium outwards. This floods the intestine, leading to life-threatening dehydration. 18When cholera toxin is released from the bacteria in the infected intestine, it binds to the intestinal cells known as enterocytes (epithelial cell in above diagram) through the interaction of the pentameric B subunit of the toxin with the GM1 ganglioside receptor on the intestinal cell, triggering endocytosis of the toxin. Next, the A/B cholera toxin must undergo cleavage of the A1 domain from the A2 domain in order for A1 to become an active enzyme. Once inside the enterocyte, the enzymatic A1 fragment of the toxin A subunit enters the cytosol, where it activates the G protein Gsa through an ADP-ribosylation reaction that acts to lock the G protein in its GTP-bound form, thereby continually stimulating adenylate cyclase to produce cAMP. The high cAMP levels activate the cystic fibrosis transmembrane conductance regulator (CFTR), causing a dramatic efflux of ions and water from infected enterocytes, leading to watery diarrhoea. One area of anti-diarrhoea treatment lies in the stimulation of enkephalins, which regulate intestinal secretion by acting directly on enterocytes. Enkephalins bind to the opioid receptors on enterocytes, which act through G proteins to inhibit the stimulation of cAMP synthesis induced by cholera toxin, thereby directly controlling ion transport. 19Advancement/breakthrough:Cholera is an easily treatable disease. The majority of people can be treated successfully through prompt administration of oral rehydration solution (ORS). The WHO/UNICEF ORS standard sachet is dissolved in 1 litre (L) of clean water. Adult patients may require up to 6 L of ORS to treat moderate dehydration on the first day. Severely dehydrated patients are at risk of shock and require the rapid administration of intravenous fluids. A 70 kg adult will require at least 7 L of intravenous fluid, plus ORS during their treatment. These patients are also given appropriate antibiotics to diminish the duration of diarrhoea, reduce the volume of rehydration fluids needed, and shorten the amount and duration of V. cholerae excretion in their stool. Mass administration of antibiotics is not recommended, as it has no proven effect on the spread of cholera and contributes to increasing antimicrobial resistance. Rapid access to treatment is essential during a cholera outbreak. Oral rehydration should be available in communities, in addition to larger centres that can provide intravenous fluids and 24 hour care. With early and proper treatment, the case fatality rate should remain below 1%. 5Hydration is the mainstay of treatment for cholera. Although there is a vaccine against cholera, the CDC and World Health Organization don’t normally recommend it, because it may not protect up to half of the people who receive it and it lasts only a few months. However, you can protect yourself and your family by using only water that has been boiled, water that has been chemically disinfected, or bottled water. 20 Research has shown that zinc may decrease and shorten the duration of diarrhea in children with cholera. 21 Disease 3Pertussis (Whooping Cough)Description:A bacterial infection that gets into your nose and throat. It is very contagious, but vaccines like DTaP and Tdap can help prevent it in children and adults. 7 It is a respiratory illness, commonly known as whooping cough, caused by a type of bacteria called Bordetella pertussis. These bacteria attach to the cilia (tiny, hair-like extensions) that line part of the upper respiratory system. The bacteria release toxins (poisons), which damage the cilia and cause airways to swell. 22Pertussis (whooping cough) can cause serious illness in babies, children, teens, and adults. Symptoms of pertussis usually develop within 5 to 10 days after you are exposed. Sometimes pertussis symptoms do not develop for as long as 3 weeks. The disease usually starts with cold-like symptoms and maybe a mild cough or fever. In babies, the cough can be minimal or not even there. Babies may have a symptom known as “apnea.” Apnea is a pause in the child’s breathing pattern. Pertussis is most dangerous for babies. About half of babies younger than 1 year who get the disease need care in the hospital. Early symptoms can last for 1 to 2 weeks and usually include runny nose, low-grade fever (generally minimal throughout the course of the disease), mild occasional cough, and apnea – a pause in breathing (in babies). Pertussis in its early stages appears to be nothing more than the common cold. Therefore, healthcare professionals often do not suspect or diagnose it until the more severe symptoms appear. Later-stage Symptoms After 1 to 2 weeks and as the disease progresses, the traditional symptoms of pertussis may appear and include paroxysms of many, rapid coughs followed by a high-pitched “whoop” sound, vomiting during or after coughing fits, and exhaustion after coughing fits. It is important to know that many babies with pertussis don’t cough at all. Instead it causes them to stop breathing and turn blue. Pertussis can cause violent and rapid coughing, over and over, until the air is gone from your lungs. When there is no more air in the lungs, you are forced to inhale with a loud “whooping” sound. This extreme coughing can cause you to throw up and be very tired. Although you are often exhausted after a coughing fit, you usually appear fairly well in-between. Coughing fits generally become more common and bad as the illness continues, and can occur more often at night. The coughing fits can go on for up to 10 weeks or more. In China, pertussis is known as the “100 day cough.” The “whoop” is often not there if you have milder (less serious) disease. The infection is generally milder in teens and adults, especially those who have gotten the pertussis vaccine. 23Pertussis is a very contagious disease only found in humans. Pertussis spreads from person to person. People with pertussis usually spread the disease to another person by coughing or sneezing or when spending a lot of time near one another where you share breathing space. Many babies who get pertussis are infected by older siblings, parents, or caregivers who might not even know they have the disease. Infected people are most contagious up to about 2 weeks after the cough begins. Antibiotics may shorten the amount of time someone is contagious. While pertussis vaccines are the most effective tool to prevent this disease, no vaccine is 100% effective. When pertussis circulates in the community, there is a chance that a fully vaccinated person, of any age, can catch this disease. If you have gotten the pertussis vaccine but still get sick, the infection is usually not as bad. 22Role of cell signaling in diseased condition:Pertussis toxin (PT) and adenylate cyclase toxin (ACT) are two important virulence factors of Bordetella pertussis, the bacterial cause of the respiratory disease pertussis or whooping cough. In addition to studies on the structure, function and role in pathogenesis of these two toxins, they are both used as cell biology tools for a variety of applications owing to their ability to enter mammalian cells, perform enzymatic activities and modify cell signaling events. In this article, recent data from the research literature that enhance our understanding of the nature of these two toxins, their role in the pathogenesis of B. pertussis infection and disease, particularly in modulating host immune responses, and their use as tools for other areas of research will be outlined. 9The adenylate cyclase toxin (ACT), has been suggested to directly penetrate human phagocytes and disrupt their normal function by direct production of intracellular cyclic AMP (cAMP). 30PT is released from B. pertussis in an inactive form. Following PT binding to a cell membrane receptor, it is taken up in an endosome, after which it undergoes retrograde transport to the trans-Golgi network and endoplasmic reticulum. 24 At some point during this transport, the A subunit (or protomer) becomes activated, perhaps through the action of glutathione and ATP. 2526 PT catalyzes the ADP-ribosylation of the ?i subunits of the heterotrimeric G protein. This prevents the G proteins from interacting with G protein-coupled receptors on the cell membrane, thus interfering with intracellular communication. 27The Gi subunits remain locked in their GDP-bound, inactive state, thus unable to inhibit adenylate cyclase activity, leading to increased cellular concentrations of cAMP. Increased intracellular cAMP affects normal biological signaling. The toxin causes several systemic effects, among which is an increased release of insulin, causing hypoglycemia. Whether the effects of pertussis toxin are responsible for the paroxysmal cough remains unknown. 28 As a result of this unique mechanism, PT has also become widely used as a biochemical tool to ADP-ribosylate GTP-binding proteins in the study of signal transduction. It has also become an essential component of new acellular vaccines. 29Advancement/breakthrough:If doctors diagnose whooping cough early on, antibiotics can help cut down coughing and other symptoms. They can also help prevent the infection from spreading to others. Most people are diagnosed too late for antibiotics to work well, though. Over-the-counter cough medicines, cough suppressants, and expectorants (medicines that make you cough up mucus) to treat whooping cough do not work. 7 In 1997, the United States introduced a newer version of the whooping cough vaccine, called the acellular pertussis vaccine. While this newer vaccine is thought to cause fewer side effects than the old, the protection offered by the newer vaccine fades more quickly — within a few years, according to a 2011 study, and several other studies. This waning immunity may be in part responsible for spikes in whooping cough cases among teens in recent years. Still, experts remain unsure of whether another whooping cough booster shot should be added to the vaccination schedule. However, if a vaccinated child does develop pertussis, the child’s condition is usually less severe if he or she is up to date with the pertussis vaccinations. Still, some researchers have proposed to bring back the old version of the vaccine, called the whole-cell pertussis vaccine. In a 2016 study, researchers modeled what would happen if children received one dose of the whole-cell vaccine, followed by four doses of the acellular vaccine in early childhood. The study suggested that this “combined” vaccination strategy could reduce the rate of whooping cough infections by up to 95 percent, and save millions of dollars in health care costs. But some experts are skeptical that parents would accept bringing back the whole-cell pertussis vaccine, because this vaccine has a higher rate of side effects than the acellular vaccine. These side effects are rare, but include fever and seizures. Overall, the 2016 study found that the combined vaccination strategy would lead to a 96 percent decrease in hospitalizations due to either whooping cough or vaccine-related side effects. 8