Neurokinin A known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is influential on the mammalian inflammatory and pain responses. Neurokinin A is a member of the tachykinin family of neuropeptide neurotransmitters. Tachykinins are important contributors to nociceptive processing and smooth muscle contraction. Tachykinins are known to be excitatory neurotransmitters in major central neural systems. Neurokinin A is ubiquitous in both the central and peripheral mammalian nervous systems, seems to be involved in reactions to pain and the inflammatory responses, it is produced from the same preprotachykinin A gene as the neuropeptide substance P. Both substance P and neurokinin A are encoded by the same mRNA, which when alternatively spliced can be translated into either compound, it has various roles in the body of humans and other animals stimulation of extravascular smooth muscle, hypertensive action, immune system activation, pain management.
The deduced amino acid sequence of neurokinin A is as follows: His Lys Asp Ser Phe Val Gly Leu Met with amidation at the C-terminus. Modified from: Sun J, Ramnath RD, Tamizhselvi R, Bhatia M."Neurokinin A engages neurokinin-1 receptor to induce NF-kappaB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways." Am J Physiol Cell Physiol. 2008 Sep. Additionally both SP neurokinin A is found in the neurosensory system and modulates a wide range of inflammatory and tissue repairing processes. In various tissues, such as the skin, the release of bioactive tachykinins by sensory nerve fibers C, that extend from the dorsal root ganglia into the epidermis, directly influence the activity of keratinocytes. Inflammation, tissue healing and cell proliferation have been linked to both SP and neurokinin A release into surrounding tissues; the overstimulation of the hypothalamic–pituitary–adrenal axis system and elevated secretion of corticotropin-releasing hormone from the hypothalamus, have been studied in many clinical manifestations of pathological depression.
Studies have shown that stress-induced activation of the noradrenergic prefrontal lobe system may be under the control of both endogenously released corticotrophin-releasing hormone and SP and neurokinin A. This study directly links the secretion of neurokinin A and SP to certain forms of depression characterized by the corticoid receptor hypothesis of depression. Inflammatory responses within the central nervous system are the result of traumatic injury or exposure to infectious agents. Inflammation provides a protective immune response to such stresses may result in progressive damage to the CNS. There is significant evidence to indicate that tachykinins are a major component of the neural inflammatory response at peripheral tissues as well as the CNS; the ability to regulate tachykinin secreation represents an important mechanism for designing useful drugs to treat inflammation. Neurokinin A has been associated with the chemokines interleukin-1 and interleukin-6, both of which are involved in the inflammatory process during infections.
Neuronal tissue can be damaged either through physical trauma or intracellular stresses, either chronic or acute. Either of these scenarios can result in calcium overload, protein degradation, the unfolded protein response or an accumulation of DNA damage. Endogenous cellular responses are activated within neurve tissue in response to damage in order to protect cellular and nucleic acid integrity. A large variety of neuroprotective signaling mechanisms exist, which can be manipulated by drugs to reduce damage from cellular damage in neurons. Tachykinins thus have a number of neuroprotective physiological roles in medical conditions The immune system is a integrated system which receives input from many sources, such as sites of injury and white blood cells. Chemical signals therefore are an important component of paracrine and endocrine signaling. Neurokinin A was shown to be a potent chemo attractor for T-cells increasing the migration into infected tissues; this migration is necessary for the pathogen seeking activity of T-cells.
Some chemokines trigger the intravascular adhesion of T-cells whereas others direct the migration of leukocytes into and within the extravascular space. Since lymphocytes must be positioned to interact with other cells, the pattern of chemokine receptors and the type and distribution of chemokines in tissues critically influence immune responses; the molecular mechanism behind neurokinin's role as a chemoattractor is unclear. Neurokinin A has an inhibitory effect on the formation of myeloid cells, appear to be involved in one specific receptor since the effect can be abolished by a NK-2 receptor-selective antagonist; the inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P. The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis; the binding of neurokinin A to the NKR-2 results in bronchoconstriction, mucus production in the lungs and process neurogenic inflammation.
This release is propagated through the stimulation of e-NANC nerves in the bronchial epithelium via an axon-reflex mechanism. Neurokinin has been shown to contribute to both bradycardia and myocardial infarctions through the activation of NK2 receptors; the du
Lipopolysaccharides known as lipoglycans and endotoxins, are large molecules consisting of a lipid and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond. The term lipooligosaccharide is used to refer to a low-molecular-weight form of bacterial lipopolysaccharides; the toxic activity of LPS was first discovered and termed "endotoxin" by Richard Friedrich Johannes Pfeiffer, who distinguished between exotoxins, which he classified as a toxin, released by bacteria into the surrounding environment, endotoxins, which he considered to be a toxin kept "within" the bacterial cell and released only after destruction of the bacterial cell wall. Subsequent work showed that release of LPS from gram negative microbes does not require the destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of membrane vesicle trafficking in the form of bacterial outer membrane vesicles, which may contain other virulence factors and proteins.
Today, the term'endotoxin' is used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins secreted by Bacillus thuringiensis. LPS is the major component of the outer membrane of Gram-negative bacteria, contributing to the structural integrity of the bacteria, protecting the membrane from certain kinds of chemical attack. LPS increases the negative charge of the cell membrane and helps stabilize the overall membrane structure, it is of crucial importance to many Gram-negative bacteria, which die if it is removed. LPS induces a strong response from normal animal immune systems, it has been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, bacteriophage sensitivity, interactions with predators such as amoebae. LPS is required for the proper conformation of Omptin activity, it comprises three parts: O antigen Core oligosaccharide Lipid A A repetitive glycan polymer contained within an LPS is referred to as the O antigen, O polysaccharide, or O side-chain of the bacteria.
The O antigen is attached to the core oligosaccharide, comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain. For example, there are over 160 different O antigen structures produced by different E. coli strains. The presence or absence of O chains determines whether the LPS is considered smooth. Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough. Bacteria with rough LPS have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more hydrophobic. O antigen is exposed on the outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies; the Core domain always contains an oligosaccharide component that attaches directly to lipid A and contains sugars such as heptose and 3-Deoxy-D-manno-oct-2-ulosonic acid. The LPS Cores of many bacteria contain non-carbohydrate components, such as phosphate, amino acids, ethanolamine substituents.
Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, the rest of the LPS projects from the cell surface; the lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever and possible fatal endotoxic shock; the Lipid A moiety is a conserved component of the LPS. However Lipid A structure varies among bacterial species and Lipid A structure defines an overall host immune activation. Lipooligosaccharides are glycolipids found in the outer membrane of some types of Gram-negative bacteria, such as Neisseria spp. and Haemophilus spp. The term is synonymous with the low molecular weight form of bacterial LPS. LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the Gram negative cell envelope.
Lipooligosaccharides play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as immunostimulators and immunomodulators. Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular mimicry and antigenic diversity, aiding in the evasion of host immune defenses and thus contributing to the virulence of these bacterial strains. Chemically, lipooligosaccharides lack O-antigens and possess only a lipid A-based outer membrane-anchoring moiety, an oligosaccharide core. In the case of Neisseria meningitidis, the lipid A portion of the molecule has a symmetrical structure and the inner core is composed of 3-deoxy-D-manno-2-octulosonic acid and heptose moieties; the outer core oligosaccharide chain varies depending on the bacterial strain. The term lipooligosaccharide is used to refer to the low molecular weight form of bacterial lipopolysaccharides, which can be categorized into two forms: the high molecular weight form possesses a high molecular weight, repeating polysaccharide O-chain, while the low molecular weight form, lacks the O-chain but possesses a short oligosaccharid
Food and Drug Administration
The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements and over-the-counter pharmaceutical drugs, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, animal foods & feed and veterinary products; as of 2017, 3/4th of the FDA budget is paid by people who consume pharmaceutical products, due to the Prescription Drug User Fee Act. The FDA was empowered by the United States Congress to enforce the Federal Food and Cosmetic Act, which serves as the primary focus for the Agency; these include regulating lasers, cellular phones and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate.
The Commissioner reports to the Secretary of Human Services. Scott Gottlieb, M. D. is the current commissioner, who took over in May 2017. The FDA has its headquarters in Maryland; the agency has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, Costa Rica, Chile and the United Kingdom. In recent years, the agency began undertaking a large-scale effort to consolidate its 25 operations in the Washington metropolitan area, moving from its main headquarters in Rockville and several fragmented office buildings to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring, Maryland; the site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. Only one original building from the naval facility was kept.
All other buildings are new construction. The project is slated to be completed by 2021, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. area as part of the Headquarters divisions, two offices – the Office of Regulatory Affairs and the Office of Criminal Investigations – are field offices with a workforce spread across the country. The Office of Regulatory Affairs is considered the "eyes and ears" of the agency, conducting the vast majority of the FDA's work in the field. Consumer Safety Officers, more called Investigators, are the individuals who inspect production and warehousing facilities, investigate complaints, illnesses, or outbreaks, review documentation in the case of medical devices, biological products, other items where it may be difficult to conduct a physical examination or take a physical sample of the product; the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based on the geographic divisions of the federal court system.
Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are food-related, some laboratories are equipped to analyze drugs and radiation-emitting devices; the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, don't focus on technical aspects of the regulated industries. OCI agents pursue and develop cases where individuals and companies have committed criminal actions, such as fraudulent claims, or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving Title 18 violations, in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents come from other criminal investigations backgrounds, work with the Federal Bureau of Investigation, Assistant Attorney General, Interpol.
OCI receives cases from a variety of sources—including ORA, local agencies, the FBI—and works with ORA Investigators to help develop the technical and science-based aspects of a case. OCI is a smaller branch; the FDA works with other federal agencies, including the Department of Agriculture, Drug Enforcement Administration and Border Protection, Consumer Product Safety Commission. Local and state government agencies work with the FDA to provide regulatory inspections and enforcement action; the FDA regulates more than US$2.4 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements. Much of these expenditures are for goods imported into the United States; the FDA's federal budget request for fiscal year 2012 totaled $4.36 billion, while the proposed 2014 budget is $4.7 billion. About $2 billion of this budget is generated by user fees.
Pharmaceutical firms pay th
Nitric oxide is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. Nitric oxide is a free radical, i.e. it has an unpaired electron, sometimes denoted by a dot in its chemical formula, i.e. ·NO. Nitric oxide is a heteronuclear diatomic molecule, a historic class that drew researches which spawned early modern theories of chemical bonding. An important intermediate in chemical industry, nitric oxide forms in combustion systems and can be generated by lightning in thunderstorms. In mammals, including humans, nitric oxide is a signaling molecule in many physiological and pathological processes, it was proclaimed the "Molecule of the Year" in 1992. The 1998 Nobel Prize in Physiology or Medicine was awarded for discovering nitric oxide's role as a cardiovascular signalling molecule. Nitric oxide should not be confused with nitrous oxide, an anesthetic, or with nitrogen dioxide, a brown toxic gas and a major air pollutant. Upon condensing to a liquid, nitric oxide dimerizes to dinitrogen dioxide, but the association is weak and reversible.
The N–N distance in crystalline NO is 218 pm, nearly twice the N–O distance. Since the heat of formation of ·NO is endothermic, NO can be decomposed to the elements. Catalytic converters in cars exploit this reaction: 2 NO → O2 + N2; when exposed to oxygen, nitric oxide converts into nitrogen dioxide: 2 NO + O2 → 2 NO2. This conversion has been speculated as occurring via the ONOONO intermediate. In water, nitric oxide reacts with water to form nitrous acid; the reaction is thought to proceed via the following stoichiometry: 4 NO + O2 + 2 H2O → 4 HNO2. Nitric oxide reacts with fluorine and bromine to form the nitrosyl halides, such as nitrosyl chloride: 2 NO + Cl2 → 2 NOCl. With NO2 a radical, NO combines to form the intensely blue dinitrogen trioxide: NO + NO2 ⇌ ON−NO2; the addition of a nitric oxide moiety to another molecule is referred to as nitrosylation. Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or nitrosohydroxylamine and methyl acetate: This reaction, discovered around 1898, remains of interest in nitric oxide prodrug research.
Nitric oxide can react directly with sodium methoxide, forming sodium formate and nitrous oxide. Nitric oxide reacts with transition metals to give complexes called metal nitrosyls; the most common bonding mode of nitric oxide is the terminal linear type. Alternatively, nitric oxide can serve as a one-electron pseudohalide. In such complexes, the M−N−O group is characterized by an angle between 120° and 140°; the NO group can bridge between metal centers through the nitrogen atom in a variety of geometries. In commercial settings, nitric oxide is produced by the oxidation of ammonia at 750–900 °C with platinum as catalyst: 4 NH3 + 5 O2 → 4 NO + 6 H2OThe uncatalyzed endothermic reaction of oxygen and nitrogen, effected at high temperature by lightning has not been developed into a practical commercial synthesis: N2 + O2 → 2 NO In the laboratory, nitric oxide is conveniently generated by reduction of dilute nitric acid with copper: 8 HNO3 + 3 Cu → 3 Cu2 + 4 H2O + 2 NOAn alternative route involves the reduction of nitrous acid in the form of sodium nitrite or potassium nitrite: 2 NaNO2 + 2 NaI + 2 H2SO4 → I2 + 4 NaHSO4 + 2 NO 2 NaNO2 + 2 FeSO4 + 3 H2SO4 → Fe23 + 2 NaHSO4 + 2 H2O + 2 NO 3 KNO2 + KNO3 + Cr2O3 → 2 K2CrO4 + 4 NOThe iron sulfate route is simple and has been used in undergraduate laboratory experiments.
So-called NONOate compounds are used for nitric oxide generation. Nitric oxide concentration can be determined using a chemiluminescent reaction involving ozone. A sample containing nitric oxide is mixed with a large quantity of ozone; the nitric oxide reacts with the ozone to produce oxygen and nitrogen dioxide, accompanied with emission of light: NO + O3 → NO2 + O2 + hνwhich can be measured with a photodetector. The amount of light produced is proportional to the amount of nitric oxide in the sample. Other methods of testing include electroanalysis, where ·NO reacts with an electrode to induce a current or voltage change; the detection of NO radicals in biological tissues is difficult due to the short lifetime and concentration of these radicals in tissues. One of the few practical methods is spin trapping of nitric oxide with iron-dithiocarbamate complexes and subsequent detection of the mono-nitrosyl-iron complex with electron paramagnetic resonance. A group of fluorescent dye indicators that are available in acetylated form for intracellular measurements exist.
The most common compound is 4,5-diaminofluorescein. Nitric oxide reacts with the hydroperoxy radical to form nitrogen dioxide, which can react with a hydroxyl radical to produce nitric acid: ·NO + HO2•→ •NO2 + •OH ·NO2 + •OH → HNO3Nitric acid, along with sulfuric acid, contribute acid rain deposition. Furthermore, ·NO participates in ozone layer depletion. In this process, nitric oxide reacts with stratospheric ozone to form O2 and nitrogen dioxide: ·NO + O3 → NO2 + O2As seen in the Concentration Measurement section, this reaction is utilized to measure concentrations of ·NO in control volumes; as seen in the Acid deposition section, nitric oxide can transform into nitrogen dioxide. Symptoms of short-term nitrogen dioxide exposure include nausea and headache. Long-term effects could include impaired respiratory function. NO is a gaseous signaling molecule, it is a key vertebrate biological messenger. It is
Botulinum toxin is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction and thus causes flaccid paralysis. Infection with the bacterium causes the disease botulism; the toxin is used commercially in medicine and research. Botulinum is the most acutely lethal toxin known, with an estimated human median lethal dose of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled. There are eight types of botulinum toxin, named type A–H. Types A and B are capable of causing disease in humans, are used commercially and medically. Types C–G are less common. Type H is considered the deadliest substance in the world – an injection of only 2 ng can cause death to an adult. Botulinum toxin types A and B are used in medicine to treat various muscle spasms and diseases characterized by overactive muscle. Commercial forms are marketed among others. Botulinum toxin is used to treat a number of problems.
Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck, vagina, limbs and vocal cords. Botulinum toxin is used to relax clenching of muscles, including those of the oesophagus, lower urinary tract and bladder, or clenching of the anus which can exacerbate anal fissure, it may be used for improper eye alignment. Botulinum toxin appears to be effective for refractory overactive bladder. Strabismus is caused by imbalances in the actions of muscles that rotate the eyes, can sometimes be relieved by weakening a muscle that pulls too or pulls against one, weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so it might seem that injection would need to be repeated. However, muscles adapt to the lengths at which they are chronically held, so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect.
If there is good binocular vision, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment. In January 2014, botulinum toxin was approved by UK's Medicines and Healthcare Products Regulatory Agency for treatment of restricted ankle motion due to lower limb spasticity associated with stroke in adults. On July 29, 2016, Food and Drug Administration, of the United States of America approved abobotulinumtoxinA for injection for the treatment of lower limb spasticity in pediatric patients two years of age and older. AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the United States of America, the FDA approves the text of the labels of prescription medicines; the FDA approves. However, those approved by the FDA to prescribe these drugs may prescribe them for any condition they wish, called off-label use. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.
Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, so are useful in treating hyperhidrosis. BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis, which cannot be managed by topical agents. In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache. In cosmetic applications, botulinum toxin is considered safe and effective for reduction of facial wrinkles in the uppermost third of the face. Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin. Smoothing of wrinkles is visible three days after treatment and is maximally visible two weeks following injection; the treated muscles regain function, return to their former appearance three to four months after treatment.
Muscles can be treated to maintain the smoothed appearance. Botulinum toxin is used to treat disorders of hyperactive nerves including excessive sweating, neuropathic pain, some allergy symptoms. In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain. While botulinum toxin is considered safe in a clinical setting, there can be serious side effects from its use. Most botulinum toxin can be injected into the wrong muscle group or spread from the injection site, causing paralysis of unintended muscles. Side effects from cosmetic use result from unintended paralysis of facial muscles; these include partial facial paralysis, muscle weakness, trouble swallowing. Side effects are not limited to direct paralysis however, can include headaches, flu-like symptoms, allergic reactions. Just as cosmetic treatments only last a number of months, paralysis side-effects can have the same durations. At least in some cases, these effects are reported to dissipate in the weeks after treatment.
Bruising at the site of injection is not a side effect of the toxin but rather of the mode of administration, is reported as preventable if the clinician applies pressure to the injection site.
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, is a protective response involving immune cells, blood vessels, molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, initiate tissue repair; the five classical signs of inflammation are heat, redness and loss of function. Inflammation is a generic response, therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, atherosclerosis, rheumatoid arthritis, cancer. Inflammation is therefore closely regulated by the body. Inflammation can be classified as either chronic.
Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together when discussing an infection, the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be.
But because of how the two are correlated, words ending in the suffix -itis are sometimes informally described as referring to infection. For example, the word urethritis means only "urethral inflammation", but clinical health care providers discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis, it is useful to differentiate inflammation and infection because there are typical situations in pathology and medical diagnosis where inflammation is not driven by microbial invasion – for example, trauma and autoimmune diseases including type III hypersensitivity. Conversely, there is pathology where microbial invasion does not cause the classic inflammatory response – for example, parasitosis or eosinophilia. Acute inflammation is a short-term process appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus, it involves a coordinated and systemic mobilization response locally of various immune and neurological mediators of acute inflammation.
In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and ceases. It is characterized by five cardinal signs:An acronym that may be used to remember the key symptoms is "PRISH", for pain, immobility and heat; the traditional names for signs of inflammation come from Latin: Dolor Calor Rubor Tumor Functio laesa The first four were described by Celsus, while loss of function was added by Galen. However, the addition of this fifth sign has been ascribed to Thomas Sydenham and Virchow. Redness and heat are due to increased blood flow at body core temperature to the inflamed site. Loss of function has multiple causes. Acute inflammation of the lung does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings; the process of acute inflammation is initiated by resident immune cells present in the involved tissue resident macrophages, dendritic cells, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors, which recognize two subclasses of molecules: pathogen-associated molecular patterns and damage-associated molecular patterns.
PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related cell damage. At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes increased heat. Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue, which manifests itself as swelling; some of the released mediators such as bradykinin increase the sensitivity to pain. The mediator molecules alter the blood vessels to
Capsaicin is an active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related compounds are called capsaicinoids and are produced as secondary metabolites by chili peppers as deterrents against certain mammals and fungi. Pure capsaicin is a hydrophobic, colorless pungent, crystalline to waxy solid compound; the compound was first extracted in impure form in 1816 by Christian Friedrich Bucholz. He called it "capsicin", after the genus Capsicum. John Clough Thresh, who had isolated capsaicin in pure form, gave it the name "capsaicin" in 1876. Karl Micko isolated capsaicin in its pure form in 1898. Capsaicin's chemical composition was first determined by E. K. Nelson in 1919, who partially elucidated capsaicin's chemical structure. Capsaicin was first synthesized in 1930 by Stephen F. Darling. In 1961, similar substances were isolated from chili peppers by the Japanese chemists S. Kosuge and Y.
Inagaki, who named them capsaicinoids. In 1873 German pharmacologist Rudolf Buchheim and in 1878 the Hungarian doctor Endre Hőgyes stated that "capsicol" caused the burning feeling when in contact with mucous membranes and increased secretion of gastric acid; the most occurring capsaicinoids are capsaicin, nordihydrocapsaicin and homodihydrocapsaicin. Capsaicin and dihydrocapsaicin are the most pungent capsaicinoids. Nordihydrocapsaicin and homodihydrocapsaicin are about half as hot. Besides the five natural capsaicinoids, one synthetic member of the capsaicinoid family exists: vanillylamide of n-nonanoic acid; the general biosynthetic pathway of capsaicin and other capsaicinoids was elucidated in the 1960s by Bennett and Kirby, Leete and Louden. Radiolabeling studies identified valine as the precursors to capsaicin. Enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase, cinnamate 4-hydroxylase, caffeic acid O-methyltransferase and their function in capsaicinoid biosynthesis were identified by Fujiwake et al. and Sukrasno and Yeoman.
Suzuki et al. are responsible for identifying leucine as another precursor to the branched-chain fatty acid pathway. It was discovered in 1999 that pungency of chili peppers is related to higher transcription levels of key enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase, cinnamate 4-hydroxylase, caffeic acid O-methyltransferase. Similar studies showed high transcription levels in the placenta of chili peppers with high pungency of genes responsible for branched-chain fatty acid pathway. Plants of the genus Capsicum produce capsaicinoids, which are alkaloids. Capsaicin is believed to be synthesized in the interlocular septum of chili peppers and depends on the gene AT3, which resides at the pun1 locus, which encodes a putative acyltransferase. Biosynthesis of the capsaicinoids occurs in the glands of the pepper fruit where capsaicin synthase condenses vanillylamine from the phenylpropanoid pathway with an acyl-CoA moiety produced by the branched-chain fatty acid pathway. Capsaicin is the most abundant capsaicinoid found in the genus Capsicum, but at least ten other capsaicinoid variants exist.
Phenylalanine supplies the precursor to the phenylpropanoid pathway while leucine or valine provide the precursor for the branched-chain fatty acid pathway. To produce capsaicin, 8-methyl-6-nonenoyl-CoA is produced by the branched-chain fatty acid pathway and condensed with vanillamine. Other capsaicinoids are produced by the condensation of vanillamine with various acyl-CoA products from the branched-chain fatty acid pathway, capable of producing a variety of acyl-CoA moieties of different chain length and degrees of unsaturation. All condensation reactions between the products of the phenylpropanoid and branched-chain fatty acid pathway are mediated by capsaicin synthase to produce the final capsacinoid product. Capsaicin is present in large quantities in the placental tissue, the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genus Capsicum; the seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith of the inner wall, where the seeds are attached.
The seeds of Capsicum plants are dispersed predominantly by birds: in birds, the TRPV1 channel does not respond to capsaicin or related chemicals. This is advantageous to the plant, as chili pepper seeds consumed by birds pass through the digestive tract and can germinate whereas mammals have molar teeth which destroy such seeds and prevent them from germinating. Thus, natural selection may have led to increasing capsaicin production because it makes the plant less to be eaten by animals that do not help it disperse. There is evidence that capsaicin may have evolved as an anti-fungal agent: the fungal pathogen Fusarium, known to infect wild chilies and thereby reduce seed viability, is deterred by capsaicin, which thus limits this form of predispersal seed mortality. In 2006, it was discovered that the venom of a certain tarantula species activates the same pathway of pain as is activated by capsaicin; because of the burning sensat