110-492: Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and Duboisia hopwoodii ) and is widely used recreationally as a stimulant and anxiolytic . As a pharmaceutical drug , it is used for smoking cessation to relieve withdrawal symptoms . Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits ( nAChRα9 and nAChRα10 ) where it acts as
220-445: A Mannich -like reaction. These steps form the core structure of many alkaloids and represent the initial committed steps in their production. Amino acids such as tryptophan , tyrosine , lysine , arginine , and ornithine serve as essential precursors. Their accumulation is facilitated by mechanisms like increased gene expression, gene duplication, or the evolution of enzymes with broader substrate specificities. The biosynthesis of
330-409: A nitrosation reaction. This occurs mostly in the curing and processing of tobacco. However, nicotine in the mouth and stomach can react to form N-nitrosonornicotine , a known type 1 carcinogen, suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis. Nicotine causes DNA damage in several types of human cells as judged by assays for genotoxicity such as
440-402: A receptor antagonist . Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco. Nicotine is also present at ppb concentrations in edible plants in the family Solanaceae , including potatoes , tomatoes , and eggplants , though sources disagree on whether this has any biological significance to human consumers. It functions as an antiherbivore toxin ; consequently, nicotine
550-506: A receptor antagonist . Such antagonism results in mild analgesia . By binding to nicotinic acetylcholine receptors in the brain, nicotine elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control". Nicotine has a higher affinity for nicotinic receptors in the brain than those in skeletal muscle , though at toxic doses it can induce contractions and respiratory paralysis. Nicotine's selectivity
660-440: A broad range of functions. These include pheromones that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate symbiotic organisms, agents that solubilize and transport nutrients ( siderophores etc.), and competitive weapons ( repellants , venoms , toxins etc.) that are used against competitors, prey, and predators. For many other secondary metabolites,
770-624: A carcinogen". The Surgeon General of the United States indicates that evidence is inadequate to infer the presence or absence of a causal relationship between exposure to nicotine and risk for cancer. Nicotine has been shown to produce birth defects in humans and is considered a teratogen . The median lethal dose of nicotine in humans is unknown. High doses are known to cause nicotine poisoning , organ failure, and death through paralysis of respiratory muscles, though serious or fatal overdoses are rare. The primary therapeutic use of nicotine
880-486: A central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics , dietary supplements , and foods produced from natural sources without added artificial ingredients. Within the field of organic chemistry, the definition of natural products is usually restricted to organic compounds isolated from natural sources that are produced by
990-592: A cofactor for enzymes, particularly transaminases, involved in amino acid metabolism. Vitamin B12 (cobalamins) contains a corrin ring structure, similar to porphyrin , and serves as a coenzyme in fatty acid catabolism and methionine synthesis. Other primary metabolite vitamins include retinol (vitamin A), synthesized in animals from plant-derived carotenoids via the mevalonate pathway , and ascorbic acid (vitamin C), which
1100-429: A dose of nicotine is delivered and absorbed, the higher the addiction risk. Investigative Nicotine is being researched in clinical trials for possible benefit in treating Parkinson's disease , dementia , attention deficit hyperactivity disorder (ADHD), and depression . Nicotine may partly attenuate sensory gating and attentional deficits associated with schizophrenia . Short-term use of transdermal nicotine
1210-522: A half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood with a half-life of 18–20 hours, making it easier to analyze. Natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature . In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis (both semisynthesis and total synthesis ) and have played
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#17327808894311320-496: A high incidence of ghostwriting and honorary authorship. In some cases Cochrane's internal structure may make it difficult to publish studies that run against the preconceived opinions of internal subject matter experts. Cochrane maintains an official relationship with the World Health Organization that affords Cochrane the right to appoint nonvoting representatives to WHO meetings, including sessions of
1430-411: A large-scale search for other environmental microorganisms that might produce anti-infective natural products. Soil and water samples were collected from all over the world, leading to the discovery of streptomycin (derived from Streptomyces griseus ), and the realization that bacteria, not just fungi, represent an important source of pharmacologically active natural products. This, in turn, led to
1540-405: A lead for a series of drugs that lower cholesterol levels, cyclosporin (from Tolypocladium inflatum ), which is used to suppress the immune response after organ transplant operations, and ergometrine (from Claviceps spp.), which acts as a vasoconstrictor , and is used to prevent bleeding after childbirth. Asperlicin (from Aspergillus alliaceus ) is another example. Asperlicin
1650-523: A negative effect on both mood and sleep. Nicotine exerts several significant effects on the cardiovascular system . Primarily, it stimulates the sympathetic nervous system , leading to the release of catecholamines . This activation results in an increase in heart rate and blood pressure , as well as enhanced myocardial contractility , which raises the workload on the heart. Additionally, nicotine causes systemic vasoconstriction , including constriction of coronary arteries, which can reduce blood flow to
1760-830: A nominal stipend and travel expenses to support a Wikipedian in Residence at Cochrane. In 2014, the Cochrane blog hosted a rebuttal, written by four Misplaced Pages medical editors, of an article published in the Journal of the American Osteopathic Association that was critical of the accuracy of Misplaced Pages medical content. Cochrane receives funding from governments, supranational organizations , non-governmental organizations , academic institutions, hospitals, and foundations, while avoiding funding from corporate interests. Primary government donors include
1870-491: A normal state. Nicotine use as a tool for quitting smoking has a good safety history. Animal studies suggest that nicotine may adversely affect cognitive development in adolescence, but the relevance of these findings to human brain development is disputed. At low amounts, it has a mild analgesic effect. According to the International Agency for Research on Cancer , "nicotine is not generally considered to be
1980-596: A process involving transcription of DNA into messenger RNA (mRNA). The mRNA serves as a template for protein assembly on ribosomes . During translation, transfer RNA (tRNA) carries specific amino acids to match with mRNA codons, forming peptide bonds to create the protein chain. Peptide hormones , such as oxytocin and vasopressin , are short amino acid chains that regulate physiological processes, including social bonding and water retention. Modified peptides include antibiotics like penicillins and cephalosporins , characterized by their β-lactam ring structure, which
2090-571: A source of novel chemical compounds also, for example isoprenyl glycerol ethers 1 and 2 from Thermococcus S557 and Methanocaldococcus jannaschii , respectively. Several anti-infective medications have been derived from fungi including penicillin and the cephalosporins (antibacterial drugs from Penicillium rubens and Cephalosporium acremonium , respectively) and griseofulvin (an antifungal drug from Penicillium griseofulvum ). Other medicinally useful fungal metabolites include lovastatin (from Pleurotus ostreatus ), which became
2200-504: A vital role in modifying the core alkaloid structures through oxidation, contributing to their structural diversity and bioactivity. For instance, in the biosynthesis of morphine , oxidative coupling is essential for forming the complex polycyclic structures typical of these alkaloids. The biosynthetic pathways of alkaloids involve numerous enzymatic steps. For example, tropane alkaloids, derived from ornithine, undergo processes such as decarboxylation , oxidation, and cyclization. Similarly,
2310-754: A wide distribution across many phyla and often span more than one kingdom . Primary metabolites include the basic building blocks of life: carbohydrates , lipids , amino acids , and nucleic acids . Primary metabolites involved in energy production include enzymes essential for respiratory and photosynthetic processes. These enzymes are composed of amino acids and often require non-peptidic cofactors for proper function. The basic structures of cells and organisms are also built from primary metabolites, including components such as cell membranes (e.g., phospholipids ), cell walls (e.g., peptidoglycan , chitin ), and cytoskeletons (proteins). Enzymatic cofactors that are primary metabolites include several members of
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#17327808894312420-437: Is immediately dangerous to life and health . Nicotine and cigarette smoke both induce the expression of liver enzymes (e.g., certain cytochrome P450 proteins) which metabolize drugs, leading to the potential for alterations in drug metabolism . Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits ( nAChRα9 and nAChRα10 ) where it acts as
2530-587: Is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg). The initial symptoms of a nicotine overdose typically include nausea , vomiting, diarrhea, hypersalivation , abdominal pain, tachycardia (rapid heart rate), hypertension (high blood pressure), tachypnea (rapid breathing), headache, dizziness, pallor (pale skin), auditory or visual disturbances, and perspiration, followed shortly after by marked bradycardia (slow heart rate), bradypnea (slow breathing), and hypotension (low blood pressure). An increased respiratory rate (i.e., tachypnea )
2640-687: Is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg). Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence. Nicotine dependence involves tolerance, sensitization, physical dependence , psychological dependence , and can cause distress. Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances. Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette. On quitting, withdrawal symptoms worsen sharply, then gradually improve to
2750-489: Is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes 53 review groups that are based at research institutions worldwide. Cochrane has over 37,000 volunteer experts from around the world. The group conducts systematic reviews of healthcare interventions and diagnostic tests and publishes them in
2860-539: Is a novel antagonist of cholecystokinin , a neurotransmitter thought to be involved in panic attacks , and could potentially be used to treat anxiety . Plants are a major source of complex and highly structurally diverse chemical compounds ( phytochemicals ), this structural diversity attributed in part to the natural selection of organisms producing potent compounds to deter herbivory ( feeding deterrents ). Major classes of phytochemical include phenols , polyphenols , tannins , terpenes , and alkaloids. Though
2970-714: Is an essential part of the coenzymes NAD and NADP , necessary for electron transport in the Krebs cycle , oxidative phosphorylation , and other redox processes. Vitamin B5 (pantothenic acid), derived from α,β-dihydroxyisovalerate (a precursor to valine ) and aspartic acid, is a component of coenzyme A , which plays a vital role in carbohydrate and amino acid metabolism, as well as fatty acid biosynthesis. Vitamin B6 (pyridoxol, pyridoxal, and pyridoxamine, originating from erythrose 4-phosphate ), functions as pyridoxal 5′-phosphate and acts as
3080-593: Is anything that is produced by life, and includes the likes of biotic materials (e.g. wood, silk), bio-based materials (e.g. bioplastics , cornstarch), bodily fluids (e.g. milk, plant exudates), and other natural materials (e.g. soil, coal). Natural products may be classified according to their biological function, biosynthetic pathway, or source. Depending on the sources, the number of known natural product molecules ranges between 300,000 and 400,000. Following Albrecht Kossel 's original proposal in 1891, natural products are often divided into two major classes,
3190-496: Is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a macromolecular target in the body (e.g. α-bungarotoxin from cobras ). As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and/or defending themselves against predators being more likely to survive and reproduce. Cochrane Collaboration Cochrane
3300-816: Is called nicotini . Nicotine use for tobacco cessation has few contraindications. It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014. It is therefore not recommended to adolescents. It is not safe to use nicotine during pregnancy or breastfeeding, although it is safer than smoking. The desirability of NRT use in pregnancy is therefore debated. Randomized trials and observational studies of nicotine replacement therapy in cardiovascular patients show no increase in adverse cardiovascular events compared to those treated with placebo. Using nicotine products during cancer treatment may be contraindicated, as nicotine may promote tumour growth, but temporary use of NRTs to quit smoking may be advised for harm reduction . Nicotine gum
3410-465: Is contraindicated in individuals with temporomandibular joint disease . People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays. Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine. Nicotine is classified as a poison, and it is "extremely hazardous". However, at doses typically used by consumers, it presents little if any hazard to
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3520-618: Is crucial for the synthesis of plastid terpenoids like carotenoids and chlorophylls . Both pathways converge at IPP and DMAPP, which combine to form longer prenyl diphosphates like geranyl (C10), farnesyl (C15), and geranylgeranyl (C20). These compounds serve as precursors for a wide range of terpenoids, including monoterpenes , sesquiterpenes , and triterpenes . The diversity of terpenoids arises from modifications such as cyclization , oxidation , and glycosylation , enabling them to play roles in plant defense, pollinator attraction, and signaling. Steroids, primarily synthesized via
3630-709: Is essential for their antibacterial activity. These compounds undergo complex enzymatic modifications during biosynthesis. Cyanogenic glycosides are amino acid derivatives in plants that can release hydrogen cyanide when tissues are damaged, serving as a defense mechanism. Their biosynthesis involves converting amino acids into cyanohydrins, which are then glycosylated. Glucosinolates are sulfur -containing compounds in cruciferous vegetables like broccoli and mustard . Their biosynthesis starts with amino acids such as methionine or tryptophan and involves adding sulfur and glucose groups. When tissues are damaged, glucosinolates break down into isothiocyanates, which contribute to
3740-1167: Is highly addictive but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals. Its addictiveness depends on how it is administered and also depends upon form in which nicotine is used. Animal research suggests that monoamine oxidase inhibitors , acetaldehyde and other constituents in tobacco smoke may enhance its addictiveness. Nicotine dependence involves aspects of both psychological dependence and physical dependence , since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia ) and somatic (mild motor dysfunctions such as tremor ) withdrawal symptoms. Withdrawal symptoms peak in one to three days and can persist for several weeks. Even though other drugs of dependence can have withdrawal states lasting 6 months or longer, this does not appear to occur with cigarette withdrawal. Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms. These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with
3850-586: Is known as a "hit". Subsequent scientific and legal work is then performed to validate the hit (e.g. elucidation of mechanism of action , confirmation that there is no intellectual property conflict). This is followed by the hit to lead stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve its potency and safety . In this and related ways, modern medicines can be developed directly from natural sources. Although traditional medicines and other biological material are considered an excellent source of novel compounds,
3960-565: Is less commonly used in agricultural insecticides , which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness (GTS), accidental ingestion of tobacco or tobacco products , or ingestion of nicotine-containing plants. People who harvest or cultivate tobacco may experience GTS, a type of nicotine poisoning caused by dermal exposure to wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco. People can be exposed to nicotine in
4070-434: Is one of the primary signs of nicotine poisoning. At sufficiently high doses, somnolence (sleepiness or drowsiness), confusion , syncope (loss of consciousness from fainting), shortness of breath , marked weakness , seizures , and coma may occur. Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis . Today nicotine
4180-565: Is synthesized from glucose in the liver of animals, though not in humans. DNA and RNA , which store and transmit genetic information , are synthesized from primary metabolites, specifically nucleic acids and carbohydrates. First messengers are signaling molecules that regulate metabolism and cellular differentiation . These include hormones and growth factors composed of peptides, biogenic amines , steroid hormones , auxins , and gibberellins . These first messengers interact with cellular receptors, which are protein-based, and trigger
4290-704: Is thought to be due to a particular amino acid difference on these receptor subtypes. Nicotine is unusual in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages , a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969. At very high doses it dampens neuronal activity . Nicotine induces both behavioral stimulation and anxiety in animals. Research into nicotine's most predominant metabolite, cotinine , suggests that some of nicotine's psychoactive effects are mediated by cotinine. Nicotine activates nicotinic receptors (particularly α4β2 nicotinic receptors , but also α5 nAChRs ) on neurons that innervate
4400-425: Is treating nicotine dependence to eliminate smoking and the damage it does to health. Controlled levels of nicotine are given to patients through gums , dermal patches , lozenges, inhalers, or nasal sprays to wean them off their dependence. A 2018 Cochrane Collaboration review found high-quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) increase
4510-494: Is unlikely to translate into increased risk of human cancer." Although nicotine is classified as a non-carcinogenic substance, it can still promote tumor growth and metastasis. It induces several processes that contribute to cancer progression, including cell cycle progression, epithelial-to-mesenchymal transition , migration , invasion, angiogenesis , and evasion of apoptosis . These effects are primarily mediated through nicotinic acetylcholine receptors (nAChRs), particularly
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4620-418: Is unrelated to a heart attack ) and heart palpitations , but does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, stroke , and cardiac death ) relative to controls. In the short term, nicotine causes a transient increase in blood pressure . Long term, epidemiological studies generally show increased blood pressure and hypertension among nicotine users. Nicotine
4730-441: Is used as a recreational drug . It is widely used, highly addictive and hard to discontinue. Nicotine is often used compulsively , and dependence can develop within days. Recreational drug users commonly use nicotine for its mood-altering effects. Recreational nicotine products include chewing tobacco , cigars , cigarettes , e-cigarettes , snuff , pipe tobacco , snus , and nicotine pouches . Alcohol infused with nicotine
4840-500: Is used by the mevalonate pathway to produce steroids. In fatty acid synthesis , one molecule of acetyl-CoA (the "starter unit") and several molecules of malonyl-CoA (the "extender units") are condensed by fatty acid synthase . After each round of elongation, the keto group is reduced, the intermediate alcohol dehydrated, and resulting enoyl-CoAs are reduced to acyl-CoAs. Fatty acids are essential components of lipid bilayers that form cell membranes and serve as energy storage in
4950-753: Is why they are of such interest to chemists. Natural sources may lead to basic research on potential bioactive components for commercial development as lead compounds in drug discovery . Although natural products have inspired numerous drugs, drug development from natural sources has received declining attention in the 21st century by pharmaceutical companies, partly due to unreliable access and supply, intellectual property, cost, and profit concerns, seasonal or environmental variability of composition, and loss of sources due to rising extinction rates. Despite this, natural products and their derivatives still accounted for about 10% of new drug approvals between 2017 and 2019. The broadest definition of natural product
5060-620: The Campbell Collaboration joined with the CEMG to form the Campbell & Cochrane Economics Methods Group (CCEMG). In 2013 the organization published an editorial describing its efforts to train people in developing nations to perform Cochrane reviews. A 2017 editorial briefly discussed the history of Cochrane methodological approaches, such as including studies that use methodologies in lieu of randomised control trials and
5170-525: The Cochrane Library . According to the Library, articles are available via one-click access, but some require paid subscription or registration before reading. A few reviews, in occupational health for example, incorporate results from non-randomised observational studies as well as controlled before–after (CBA) studies and interrupted time-series studies. Cochrane, previously known as
5280-1008: The World Health Assembly , and make statements on WHO resolutions. In 2014, the Cochrane-Misplaced Pages partnership was formalised. This supports the inclusion of relevant evidence within all Misplaced Pages medical articles, as well as processes to help ensure that medical information included in Misplaced Pages is of the highest quality and accuracy. Misplaced Pages and Cochrane collaborate to increase the incorporation of Cochrane research into Misplaced Pages articles and provide Misplaced Pages editors with resources for interpreting medical data. Cochrane and John Wiley and Sons, publisher of Cochrane reviews, make one hundred free Cochrane accounts available to Misplaced Pages medical editors—the financial value of which has been estimated by Cochrane at between thirty thousand and eighty thousand US dollars per annum—and pay
5390-507: The acetylcholinesterase inhibitor galantamine (from Galanthus spp.), used to treat Alzheimer's disease . Other plant-derived drugs, used medicinally and/or recreationally include morphine , cocaine , quinine , tubocurarine , muscarine , and nicotine . Animals also represent a source of bioactive natural products. In particular, venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This
5500-478: The cell walls of bacteria and plants. During photosynthesis, plants initially produce 3-phosphoglyceraldehyde , a three-carbon triose . This can be converted into glucose (a six-carbon sugar) or various pentoses (five-carbon sugars) through the Calvin cycle . In animals, three-carbon precursors like lactate or glycerol are converted into pyruvate , which can then be synthesized into carbohydrates in
5610-518: The comet assay , cytokinesis-block micronucleus test and chromosome aberrations test. In humans, this damage can happen in primary parotid gland cells, lymphocytes , and respiratory tract cells. Nicotine has been shown to produce birth defects in some animal species, but not others; consequently, it is considered to be a possible teratogen in humans. In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes;
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#17327808894315720-644: The glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin's lymphoma , head and neck cancer , and testicular cancer . Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments. Examples include symbionts or endophytes from tropical environments, subterranean bacteria found deep underground via mining/drilling, and marine bacteria. Because many Archaea have adapted to life in extreme environments such as polar regions , hot springs , acidic springs, alkaline springs, salt lakes , and
5830-577: The high pressure of deep ocean water , they possess enzymes that are functional under quite unusual conditions. These enzymes are of potential use in the food , chemical , and pharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and / or high pressure. Examples of enzymes identified to date include amylases , pullulanases , cyclodextrin glycosyltransferases , cellulases , xylanases , chitinases , proteases , alcohol dehydrogenase , and esterases . Archaea represent
5940-402: The nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (k i =1 nM ), which is also the biological target that mediates nicotine's addictive properties. Nicotine has potential beneficial effects, but it also has paradoxical effects , which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features. Nicotine
6050-729: The pathways of primary or secondary metabolism . Within the field of medicinal chemistry , the definition is often further restricted to secondary metabolites. Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. Many secondary metabolites are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms. Secondary or specialized metabolites are often unique to specific species, whereas primary metabolites are commonly found across multiple kingdoms. Secondary metabolites are marked by chemical complexity which
6160-453: The performance-enhancing effects of nicotine on cognition. A 2010 meta-analysis of 41 double-blind , placebo -controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory. A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance; among
6270-399: The ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine . This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area . Nicotine can modulate the firing rate of the ventral tegmental area neurons. These actions are largely responsible for
6380-674: The vitamin B family. For instance, Vitamin B1 (thiamine diphosphate), synthesized from 1-deoxy-D-xylulose 5-phosphate , serves as a coenzyme for enzymes such as pyruvate dehydrogenase , 2-oxoglutarate dehydrogenase , and transketolase —all involved in carbohydrate metabolism. Vitamin B2 (riboflavin), derived from ribulose 5-phosphate and guanosine triphosphate , is a precursor to FMN and FAD , which are crucial for various redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan,
6490-673: The α7 subtype , and to a lesser extent, β-adrenergic receptors (β-ARs). Activation of these receptors triggers several signaling cascades crucial in cancer biology, notably the MAPK/ERK pathway , PI3K/AKT pathway , and JAK-STAT signaling . Nicotine promotes lung cancer development by enhancing proliferation, angiogenesis, migration, invasion, and epithelial–mesenchymal transition (EMT) via nAChRs, which are present in lung cancer cells. Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells. Nicotine in tobacco can form carcinogenic tobacco-specific nitrosamines through
6600-808: The Cochrane Collaboration, was founded in 1993 under the leadership of Iain Chalmers . It was developed in response to Archie Cochrane 's call for up-to-date, systematic reviews of all relevant randomised controlled trials in the field of healthcare. In 1998, the Cochrane Economics Methods Group (CEMG) was established to facilitate the basing of decisions on health economics , evidence-based medicine , and systematic reviews . Cochrane's suggestion that methods used to prepare and maintain reviews of controlled trials in pregnancy and childbirth be applied more widely
6710-682: The Gerber Foundation. Cochrane involves patients and the public via community curation , to produce systematic reviews and other outputs. Tasks can be organised as 'entry level' or higher. Tasks include: A recent systematic review of how people were involved in systematic reviews aimed to document the evidence-base relating to stakeholder involvement in systematic reviews and to use this evidence to describe how stakeholders have been involved in systematic reviews. Thirty per cent involved patients and/or carers. While there has been some criticism of how Cochrane prioritises systematic reviews,
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#17327808894316820-787: The MVA pathway, are derived from farnesyl diphosphate through intermediates like squalene and lanosterol , which are precursors to cholesterol and other steroid molecules. Alkaloids are nitrogen-containing organic compounds produced by plants through complex biosynthetic pathways, starting from amino acids. The biosynthesis of alkaloids from amino acids is essential for producing many biologically active compounds in plants. These compounds range from simple cycloaliphatic amines to complex polycyclic nitrogen heterocycles . Alkaloid biosynthesis generally follows four key steps: (i) synthesis of an amine precursor, (ii) synthesis of an aldehyde precursor, (iii) formation of an iminium cation , and (iv)
6930-638: The US since 2014, homemade pesticides are banned on organic crops, and caution is recommended for small gardeners. Nicotine pesticides have been banned in the EU since 2009. Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels. Neonicotinoids , such as imidacloprid , which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016. Nicotine-containing products are sometimes used for
7040-809: The United Kingdom's National Institute for Health and Care Research (NIHR), the Danish Health Authority , the Federal Ministry of Health (Germany) , and the National Institutes of Health (NIH). Academic funders include McMaster University , Amsterdam University Medical Centers , Kazan Federal University , and University of Copenhagen , among others. Funding from foundations includes the National Research Foundation (South Africa) and
7150-418: The activation of second messengers to relay the extracellular signal to intracellular targets. Second messengers often include primary metabolites such as cyclic nucleotides and diacyl glycerol . Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution. Secondary metabolites have
7260-449: The adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream . By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to
7370-522: The amount of rapid eye movement (REM) sleep, slow-wave sleep (SWS), and total sleep time in healthy nonsmokers given nicotine via a transdermal patch , and the reduction is dose-dependent . Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, sleep onset latency , and non-rapid eye movement (NREM) stage 2 sleep time. Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has
7480-427: The biosynthesis of aromatic amino acids (AAAs) — phenylalanine , tyrosine , and tryptophan . This pathway is vital as it connects primary metabolism to specialized metabolic processes, directing an estimated 20-50% of all fixed carbon through its reactions. It begins with the condensation of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), leading through several enzymatic steps to form chorismate ,
7590-478: The biosynthesis of isoquinoline alkaloids from tyrosine involves complex transformations, including the formation of (S)- reticuline , a key intermediate in the pathway. Biosynthesis of peptides, proteins, and other amino acid derivatives assembles amino acids into biologically active molecules, producing compounds like peptide hormones, modified peptides, and plant-derived substances. Peptides and proteins are synthesized through protein synthesis or translation,
7700-408: The board to cut two appointed members in order to comply with the ratio of elected to appointed members required by the organization's charter. Gøtzsche announced that this had happened via an open letter, in which he said there is a "growing top-down authoritarian culture and an increasingly commercial business model" taking root at Cochrane that "threaten the scientific, moral and social objectives of
7810-454: The body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation. The elimination half-life of nicotine in the body is around two hours. Nicotine is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH . The amount of nicotine absorbed by the body from smoking can depend on many factors, including
7920-503: The building blocks for all terpenoids. The MVA pathway, discovered in the 1950s, functions in eukaryotes, some bacteria, and plants. It converts acetyl-CoA to IPP via HMG-CoA and mevalonate, and is essential for steroid biosynthesis. Statins , which lower cholesterol, work by inhibiting HMG-CoA reductase in this pathway. The MEP pathway, found in bacteria, some parasites, and plant chloroplasts, starts with pyruvate and glyceraldehyde 3-phosphate to produce IPP and DMAPP. This pathway
8030-461: The cardiovascular toxicity of nicotine concluded, "Based on current knowledge, we believe that the cardiovascular risks of nicotine from e-cigarette use in people without cardiovascular disease are quite low. We have concerns that nicotine from e-cigarettes could pose some risk for users with cardiovascular disease." A 2018 Cochrane review found that, in rare cases, nicotine replacement therapy can cause non- ischemic chest pain (i.e., chest pain that
8140-593: The challenge of having evidence adopted in practice. During its 2018 annual meeting, the Cochrane board expelled Peter C. Gøtzsche , board member and director of Cochrane's Nordic center, from the organization, telling Nature that it had received "numerous complaints" about Gøtzsche after he co-authored an article in BMJ Evidence-Based Medicine alleging bias in Cochrane's May 2018 review of HPV vaccines . Gøtzsche's expulsion led four elected board members to resign in protest, which in turn led
8250-424: The chances of successfully quitting smoking by 50–60% , regardless of setting. Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success. In contrast to recreational nicotine products, which have been designed to maximize the likelihood of addiction, nicotine replacement products (NRTs) are designed to minimize addictiveness. The more quickly
8360-415: The development of an impressive arsenal of antibacterial and antifungal agents including amphotericin B , chloramphenicol , daptomycin and tetracycline (from Streptomyces spp. ), the polymyxins (from Paenibacillus polymyxa ), and the rifamycins (from Amycolatopsis rifamycinica ). Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites. Although most of
8470-403: The drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine. Botulinum toxin (from Clostridium botulinum ) and bleomycin (from Streptomyces verticillus ) are two examples. Botulinum, the neurotoxin responsible for botulism , can be injected into specific muscles (such as those controlling the eyelid) to prevent muscle spasm . Also,
8580-616: The extraction and isolation of these compounds can be a slow, expensive and inefficient process. For large scale manufacture therefore, attempts may be made to produce the new compound by total synthesis or semisynthesis. Because natural products are generally secondary metabolites with complex chemical structures , their total/semisynthesis is not always commercially viable. In these cases, efforts can be made to design simpler analogues with comparable potency and safety that are amenable to total/semisynthesis. The serendipitous discovery and subsequent clinical success of penicillin prompted
8690-530: The field of organic chemistry are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry and pharmacognosy . Primary metabolites, as defined by Kossel , are essential components of basic metabolic pathways required for life. They are associated with fundamental cellular functions such as nutrient assimilation, energy production, and growth and development. These metabolites have
8800-404: The form of fat in animals. The plant-derived fatty acid linoleic acid is converted in animals through elongation and desaturation into arachidonic acid , which is then transformed into various eicosanoids , including leukotrienes , prostaglandins , and thromboxanes . These eicosanoids act as signaling molecules, playing key roles in inflammation and immune responses . Alternatively
8910-573: The function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them. An alternative view is that, in analogy to the immune system , these secondary metabolites have no specific function, but having the machinery in place to produce these diverse chemical structures is important and a few secondary metabolites are therefore produced and selected for. General structural classes of secondary metabolites include alkaloids , phenylpropanoids , polyketides , and terpenoids . The biosynthetic pathways leading to
9020-1026: The heart. Long-term exposure to nicotine may impair endothelial function, potentially contributing to atherosclerosis . Furthermore, nicotine has been associated with the development of cardiac arrhythmias , particularly in individuals who already have underlying heart disease. The effects of nicotine can be differentiated between short-term and long-term use. Short-term nicotine use, such as that associated with nicotine replacement therapy (NRT) for smoking cessation, appears to pose little cardiovascular risk, even for patients with known cardiovascular conditions. In contrast, longer-term nicotine use may not accelerate atherosclerosis but could contribute to acute cardiovascular events in those with pre-existing cardiovascular disease. Many severe cardiovascular effects traditionally associated with smoking may not be solely attributable to nicotine itself. Cigarette smoke contains numerous other potentially cardiotoxic substances, including carbon monoxide and oxidant gases. A 2016 review of
9130-530: The intermediates from additional condensation reactions are left unreduced to generate poly-β-keto chains, which are subsequently converted into various polyketides. The polyketide class of natural products has diverse structures and functions and includes important compounds such as macrolide antibiotics . The shikimate pathway is a key metabolic route responsible for the production of aromatic amino acids and their derivatives in plants, fungi, bacteria, and some protozoans: The shikimate pathway leads to
9240-429: The liver. Fatty acids and polyketides are synthesized via the acetate pathway , which starts from basic building blocks derived from sugars: During glycolysis , sugars are broken down into acetyl-CoA . In an ATP-dependent enzymatic reaction, acetyl-CoA is carboxylated to form malonyl-CoA . Acetyl-CoA and malonyl-CoA then undergo a Claisen condensation , releasing carbon dioxide to form acetoacetyl-CoA which
9350-515: The major classes of natural products are described below. Carbohydrates are organic molecules essential for energy storage, structural support, and various biological processes in living organisms. They are produced through photosynthesis in plants or gluconeogenesis in animals and can be converted into larger polysaccharides : Carbohydrates serve as a primary energy source for most life forms. Additionally, polysaccharides derived from simpler sugars are vital structural components, forming
9460-626: The negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function. Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke . Nicotine exposure in utero is responsible for several complications of pregnancy and birth: pregnant women who smoke are at greater risk for both miscarriage and stillbirth and infants exposed to nicotine in utero tend to have lower birth weights . A McMaster University research group observed in 2010 that rats exposed to nicotine in
9570-600: The next cigarette. Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking. Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers. In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels. The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal. Therefore,
9680-508: The nucleus accumbens, resulting in nicotine addiction. Contrary to popular belief , nicotine itself does not cause cancer in humans, although it is unclear whether it functions as a tumor promoter as of 2012. A 2018 report by the US National Academies of Sciences, Engineering, and Medicine concludes, "[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this
9790-408: The number of plants that have been extensively studied is relatively small, many pharmacologically active natural products have already been identified. Clinically useful examples include the anticancer agents paclitaxel and omacetaxine mepesuccinate (from Taxus brevifolia and Cephalotaxus harringtonii , respectively), the antimalarial agent artemisinin (from Artemisia annua ), and
9900-604: The organization". Gøtzsche remains an outspoken critic of Cochrane's relationship with the pharmaceutical industry. The Cochrane board stated that Gøtzsche was expelled for his behavior, which had been reviewed by an independent counsel hired by Cochrane. A 2004 editorial in the Canadian Medical Association Journal noted that Cochrane reviews appear to be more up to date and of better quality than other reviews, describing them as "the best single resource for methodologic research and for developing
10010-452: The overall daily cognitive levels of smokers and non-smokers are roughly similar. Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression (i.e., produces phosphorylated ΔFosB isoforms ) in the nucleus accumbens when inhaled or injected frequently or at high doses, but not necessarily when ingested. Consequently, high daily exposure (possibly excluding oral route ) to nicotine can cause ΔFosB overexpression in
10120-634: The precursor for all three AAAs. From chorismate, biosynthesis branches out to produce the individual AAAs. In plants, unlike in bacteria, the production of phenylalanine and tyrosine typically occurs via the intermediate arogenate . Phenylalanine serves as the starting point for the phenylpropanoid pathway , which leads to a diverse array of secondary metabolites. Beyond protein synthesis, AAAs and their derivatives have crucial roles in plant physiology, including pigment production, hormone synthesis, cell wall formation, and defense against various stresses. Because animals cannot synthesize these amino acids,
10230-768: The primary and secondary metabolites. Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment. For instance, alkaloids like morphine and nicotine act as defense chemicals against herbivores, while flavonoids attract pollinators, and terpenes such as menthol serve to repel insects. Because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties. Natural products especially within
10340-455: The pungent flavors of these vegetables and offer potential health benefits. Natural products may be extracted from the cells , tissues , and secretions of microorganisms , plants and animals. A crude ( unfractionated ) extract from any one of these sources will contain a range of structurally diverse and often novel chemical compounds. Chemical diversity in nature is based on biological diversity, so researchers collect samples from around
10450-430: The receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream . The release of epinephrine (adrenaline) causes an increase in heart rate , blood pressure and respiration , as well as higher blood glucose levels. As nicotine enters
10560-634: The same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes. The median lethal dose of nicotine in humans is unknown. Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine , which has an LD 50 of 127 mg/kg when administered to mice. At sufficiently high doses, it is associated with nicotine poisoning, which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight) rarely results in significant morbidity or death. The estimated lower dose limit for fatal outcomes
10670-457: The science of meta- epidemiology " and crediting them with leading to methodological improvements in the medical literature. Studies comparing the quality of Cochrane meta-analyses in the fields of infertility , physiotherapy , and orthodontics to those published by other sources have concluded that Cochrane reviews incorporate superior methodological rigor. A broader analysis across multiple therapeutic areas reached similar conclusions but
10780-474: The shikimate pathway has also become a target for herbicides, most notably glyphosate, which inhibits one of the key enzymes in this pathway. The biosynthesis of terpenoids and steroids involves two primary pathways, which produce essential building blocks for these compounds: The mevalonate (MVA) and methylerythritol phosphate (MEP) pathways produce the five-carbon units isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are
10890-400: The strongly reinforcing effects of nicotine, which often occur in the absence of euphoria ; however, mild euphoria from nicotine use can occur in some individuals. Chronic nicotine use inhibits class I and II histone deacetylases in the striatum , where this effect plays a role in nicotine addiction. Nicotine also activates the sympathetic nervous system , acting via splanchnic nerves to
11000-550: The tropane alkaloid cocaine follows this general pathway. A key reaction in alkaloid biosynthesis is the Pictet-Spengler reaction , which is crucial for forming the β-carboline structure found in many alkaloids. This reaction involves the condensation of an aldehyde with an amine, as seen in the biosynthesis of strictosidine , a precursor to numerous monoterpene indole alkaloids. Oxidoreductases , including cytochrome P450s and flavin-containing monooxygenases , play
11110-428: The types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine, suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation". Nicotine has
11220-470: The user. A 2018 Cochrane Collaboration review lists nine main adverse events related to nicotine replacement therapy: headache , dizziness , lightheadedness , nausea , vomiting , gastrointestinal symptoms, insomnia , abnormal dreams , non- ischemic palpitations and chest pain, skin reactions, oral/nasal reactions, and hiccups . Many of these were also common in the placebo group without nicotine. Palpitations and chest pain were deemed "rare" and there
11330-482: The womb (via parenteral infusion) later in life had conditions including type 2 diabetes , obesity , hypertension , neurobehavioral defects, respiratory dysfunction, and infertility . It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013 that there are no significant safety concerns associated with the use of more than one form of over-the-counter (OTC) nicotine replacement therapy at
11440-509: The workplace by breathing it in, skin absorption, swallowing it, or eye contact. The Occupational Safety and Health Administration (OSHA) has set the legal limit ( permissible exposure limit ) for nicotine exposure in the workplace as 0.5 mg/m skin exposure over an 8-hour workday. The US National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5 mg/m skin exposure over an 8-hour workday. At environmental levels of 5 mg/m, nicotine
11550-415: The world to analyze and evaluate in drug discovery screens or bioassays . This effort to search for biologically active natural products is known as bioprospecting . Pharmacognosy provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use. When an "active principle" is isolated from a traditional medicine or other biological material, this
11660-414: Was found to improve subjects’ reaction time and alertness in given tasks. Nicotine was not found to improve negative , positive , or other cognitive symptoms of schizophrenia. Nicotine has been used as an insecticide since at least 1690, in the form of tobacco extracts (although other components of tobacco also seem to have pesticide effects). Nicotine pesticides have not been commercially available in
11770-557: Was no evidence of an increased number of serious cardiac problems compared to the placebo group, even in people with established cardiac disease. The common side effects from nicotine exposure are listed in the table below. Serious adverse events due to the use of nicotine replacement therapy are extremely rare. At low amounts, it has a mild analgesic effect. However, at sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea , salivation , bradycardia , and possibly seizures , hypoventilation , and death. Nicotine reduces
11880-532: Was performed by Cochrane authors. Compared to non-Cochrane reviews, those from Cochrane are less likely to reach a positive conclusion about the utility of medical interventions. Key criticisms that have been directed at Cochrane's studies include a failure to include a sufficiently large number of unpublished studies, failure to pre-specify or failure to abide by pre-specified rules for endpoint or trial inclusion, insufficiently frequent updating of reviews, an excessively high percentage of inconclusive reviews, and
11990-632: Was taken up by the Research and Development Programme, initiated to support the National Health Service . Through the NHS research and development programme, led by Michael Peckham , funds were provided to establish a "Cochrane Centre", to collaborate with others, in the UK and elsewhere, to facilitate systematic reviews of randomised controlled trials across all areas of healthcare. In 2004,
12100-576: Was widely used as an insecticide in the past, and neonicotinoids (structurally similar to nicotine), such as imidacloprid , are some of the most effective and widely used insecticides. Nicotine is highly addictive . Slow-release forms (gums and patches, when used correctly) can be less addictive and help in quitting. Animal research suggests that monoamine oxidase inhibitors present in tobacco smoke may enhance nicotine's addictive properties. An average cigarette yields about 2 mg of absorbed nicotine. The estimated lower dose limit for fatal outcomes
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