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explore the essence of cool feeling.
Chewing a mint leaf does not lower the oral temperature, but it can feel cool like eating ice. Why? Autumn and winter are coming. How does the body feel the cold? Organisms constantly evolve to adapt to changing environmental conditions. The perception of cold, heat and touch is very important for human survival, and it is also the basis of human interaction with the surrounding world. When we perceive what is happening in the world around us and feel “used to it”, it was a new research field in the eyes of two scientists, David Julius and ADEM Patapoutian.
Today (December 10, Beijing time), the 2021 Nobel Prize in biology or medicine was awarded to David Julius and ADEM Patapoutian in recognition of the breakthrough contributions made by two scientists in “discovering temperature and tactile receptors”. They revealed the secret of how heat, cold and mechanical forces trigger nerve impulses, Let us know more about how the human body perceives and adapts to the world around us.
Explore the magical coolness behind the Nobel Prize
Last year, a vibrant fashion drink, mojito, became popular throughout the summer with Jay Chou’s new song of the same name. Mojito, a cocktail originated in Cuba, is made of five indispensable raw materials: light rum, sugarcane juice, soda, lime and mint. Among them, the refreshing fresh mint leaves are the finishing touch. They are not only added to the wine to reconcile the strength of rum, but also specially decorated at the mouth of the cup as decoration. This cool, fragrant and pleasing green leaf, mint, has become the “soul leaf” of mojito, a fashion drink.
There is also an interesting legend about the origin of the name “MINT”. It is said that Hades once met the beautiful and moving spirit menthe, fell in love with her at first sight, was deeply fascinated, and launched a warm pursuit of menthe. Persephone, the wife of Pluto, was very angry when she learned about it. Full of jealousy made her determined to revenge Mancy. Therefore, she used her magic to turn manci into a grass trampled by the river, hoping to make Pluto forget her little lover. Although manci with a strong heart has become an insignificant grass, she has a cool and pleasant unique fragrance, and the more she is destroyed and trampled, the stronger the fragrance will be. Therefore, people call this kind of fragrant grass near the water mint, and its Latin name is Mentha. Like many other flowers, the origin of this name is related to Greek mythology, which describes a strange love tragedy. Mentha is regarded as the incarnation of the water elf manci. Therefore, mint is a promising plant in people’s mind.
Mint was first abundant in the Mediterranean and Western Asia. Its fresh and pleasant aroma has always been widely favored by people. Like other herbs, ancient Egyptians, Greeks and Romans all knew how to use it. It is said that the ancient Romans and Greeks highly praised the cool taste of peppermint, and men in ancient Greece sprayed them with peppermint perfume to enhance their charm. Ancient Romans often put mint leaves in bath water, which can not only cool and refresh, but also nourish the skin; People also wear Mint wreaths at festivals and celebrations. The ancient Romans also wore a crown made of mint leaves at the banquet, obviously with the help of its detoxification function. Of course, they don’t object to making wine with mint. Hebrews use it to make perfume.
Later, peppermint was introduced into China from Europe through Siberia, Xinjiang and Himalayas. After more than 400 years of suitable cultivation, it gradually integrated into the land of China and became a neighbor herb widely planted in front of and behind houses and deeply loved by everyone.
Why is peppermint “cool”?
For thousands of years, the reason why Mint has always been loved by people is that the unique fragrance of mint gives people a refreshing feeling. Menthol, the special volatile oil with the highest content in the stems and leaves of menthol, plays a role in these characteristics of menthol. Among dozens of volatile oil substances in fresh mint leaves, menthol content is as high as 77%. This special volatile oil has three chiral centers and a total of 8 stereoisomers. Among them, l-menthol has a light and slightly sweet smell and has a strong cooling effect. The reason why peppermint makes people feel cool is that menthol can activate the ion channel of receptor protein specialized in feeling cold on the nerve endings of the mouth and skin, make it run quickly, and then receive a cold like stimulation. Therefore, when people crush the leaves of peppermint and are stimulated by the volatile menthol, the receptor protein on the human skin or oral nerve endings will transmit signals to the brain, causing people to have a chilly illusion. Because of such rich aromatic volatile oil components, peppermint has become a widely used flavoring agent, which is used in the production of food, beverage and other daily necessities.
Cool, is it taste, flavor or body sensation?
Different from the fact that we often mistakenly attribute the hot “spicy” to the so-called “sour, sweet, bitter, spicy and salty” combination of taste. In fact, the essence of both mint and ice is a chemical physics. Among the five senses (vision, hearing, taste, smell and Chemical Physics), the chemical receptive somatosensory (i.e. Chemical Physics) of skin or mucous membrane caused by chemical stimulants may be the most diverse and difficult to understand. It describes the ability to sense mechanical force (tactile), chemical stimulation (pain) and temperature (temperature).
The picture comes from the Internet: chemical and physical senses — feelings beyond taste and smell in diet, China Light Industry Press, August 2020
Temperature perception had been studied for more than a century before two scientists discovered temperature and tactile receptors. At the end of the 19th century, the famous neuroscientist Charles É douard brown-s é Quad found that the half section of the spinal cord may affect temperature perception. However, human understanding of how the nervous system perceives and interprets the environment still contains a basic unsolved mystery: how temperature and mechanical stimulation are transformed into electrical pulses in the nervous system.
At the end of 1990, David Julius analyzed how capsaicin caused the burning sensation of human contact, and determined that the human body has nerve cells that capsaicin can activate and cause pain sensation, but how this chemical can play this role remains to be solved.
Based on these findings, ADEM patabotien and his colleagues created a library containing millions of DNA fragments corresponding to the genes expressed by sensory neurons, which can respond to pain, heat and touch. ADEM and his colleagues assumed that the library would contain a DNA fragment encoding a protein that can react with capsaicin. After exploratory research, ADEM patabotti found a gene that can make cells sensitive to capsaicin. This newly discovered capsaicin receptor was later named TRPV1.
(David Julius used capsaicin in pepper to find TRPV1,
This ion channel is activated when the temperature reaches a painful level)
In addition, David Julius introduced on the official website of the National Academy of Sciences that his team’s research direction is to understand how the nervous system receives and transmits signals, and use the power of natural products to clarify the molecular mechanism of pain feeling, such as how capsaicin causes burning pain and how menthol, the refrigerant in peppermint leaves, causes cold feeling.
The breakthrough discovery of two scientists on the mechanism of human perception of pain and temperature has rapidly increased human understanding of how the nervous system perceives thermal, cold and mechanical stimuli, and opened a new chapter in the design of targeted drugs for chronic pain.
Surface view of cool agent market
Cool feeling agent (cool flavor) is a kind of flavor with cool effect, including natural cool flavor and synthetic cool flavor. Natural cool flavor refers to the flavor taken from nature and maintaining the original plant aroma characteristics. It is usually processed by physical or chemical methods such as crushing, distillation and extraction; Synthetic cool flavor is a monomer flavor prepared by chemical synthesis method using chemical raw materials.
It is reported that l-menthol is one of the most sold flavor monomers in the world, and the current menthol consumption in the world is about 40000 tons per year. At present, l-menthol is mainly extracted from plants, accounting for about 70% of the total global output, and the remaining 30% is prepared by organic synthesis. At present, the international synthetic menthol market is mainly monopolized by three giants, namely Japan Gaosha flavor company, Germany BASF company and Germany dezhixin company. The output of the latter two synthetic menthols accounts for about 86% of the total sales of international synthetic menthols, and that of Japan accounts for only 14%. According to the data of market research company Grandview research, the global market demand for peppermint essential oil is expected to reach US $1 billion by 2023.
Menthol generally has two isomers (D-type and L-type), and natural menthol is mainly L-isomer (l-menthol). Menthol has the characteristics of rapid cooling, fresh aroma and green nature. In recent years, it has been more and more popular. Therefore, the demand for end products has a gradual upward trend. Menthol can be used as a fragrance agent for toothpaste, perfume, beverages and sweets. It is used as an irritant in medicine. It acts on the skin or mucous membrane and has the effect of cooling and relieving itching. Oral administration can be used as a wind repellent for headache, nasopharynx and laryngitis. Its esters can also be used in spices and drugs.
Peppermint is not a perfect “fragrant pastry”
However, menthol also has its own application defects. For example, when extracted from peppermint plants, menthol will be different in supply, price and crop quality. In addition, menthol is easy to volatilize; The effect of high temperature resistance is poor, and some products requiring high temperature treatment can not meet the required requirements; Menthol can irritate the eyes. At higher concentration, it will cause burning sensation and bitter taste; In human skin and oral cavity, the cool feeling lasts for a short time, which can not achieve the long-term cooling effect; Menthol also has a characteristic odor that is not always needed; The peppermint flavor and associated coolness of the seasoning will not last long.
Therefore, personal care companies and flavors and fragrances manufacturers are motivated to find non volatile alternatives, which can eliminate the unnecessary characteristics of menthol, but still cause cold sensation. Consumers associate it with cleanliness and freshness. For the bitterness of menthol, most companies use sweeteners to cover up the bitterness of menthol. In addition, essential oils and spices are added to the product to reduce the burning sensation of menthol in the mouth.
Large family and characteristics of synthetic cooling agent WS series products
In the era of material scarcity, people first focus on cheap chemical synthesis. Since 1970, Wilkinson sword has conducted extensive research on synthetic coolants, during which they have developed about 1200 cool compounds, namely WS series products. These include ws-23, ws-3, ws-5 and other products that later achieved commercial success.
Compared with menthol, ws-23 has a long cool feeling and no bitter taste in the mouth; However, ws-23 lacks the explosive cool feeling of menthol and special mint aroma. Ws-3 is a long-acting cooling agent. The cooling intensity is 1.5 times that of menthol, and the cooling duration is 20 ~ 30min. The cooling effect site is mainly the throat, and there is also a cooling sensation in the mouth. Therefore, ws-3 is often used in throat moisturizing sugar products. However, it should be noted that ws-3 has the same bitter feeling as menthol. The dosage needs to be optimized during specific use. When the dosage is large, a small amount of sweetener can also be added to cover the bitterness. In addition, ws-3 is difficult to dissolve in water. If it is used in beverages, mouthwashes and other products, ws-3 needs to be dissolved in propylene glycol before adding tween or span solubilizers.
The cooling agent ws-5 is also called n (- ethoxycarbonylmethyl) – p-alkyl-3-formamide. The cooling sensation is mainly concentrated in the mouth and throat. The cooling intensity is about 3 ~ 4 times that of menthol. It is the variety with the highest cooling intensity in the WS series.
With the development of social economy, people’s demand for “Naturalization” of food additives is becoming stronger and stronger. The common synthetic cooling agents in the market not only have poor product performance, but also can not meet the “natural health” needs of consumers, and do not meet the sustainable development strategy of enterprises.
Explore the essence of cool feeling
Temperature perception is the main part of animal and human sensory experience. Mammals have evolved a protective nervous system that helps to survive in cold and hot temperatures. The sensitive response of the nervous system to temperature changes is very important for thermostatic animals to maintain a stable body core temperature. Organisms evolve to adapt to changing environmental conditions. The main ones are daily and seasonal temperature fluctuations. In terms of the actual physical value, the temperature fluctuation is relatively small, and a few degrees of temperature fluctuation will have a far-reaching impact on the body function. In vertebrates, temperature is detected by the primary afferent nerves of somatosensory neurons expressing hot ion channels.
Many ancient cultures believed that heat (fire) was a classic element of nature. In order to quantify the heat existing in an object, modern science uses temperature (defined by the third law of thermodynamics) as a measure of the motion and vibration of particles in an object. All biochemical reactions have a temperature coefficient, which refers to the change rate of biochemical reaction with the increase of temperature. Therefore, environmental and internal body temperature affect almost all aspects of animal physiology, including feeding and mating behavior, circadian rhythm and seasonal rhythm. Temperature fluctuations will affect the function of the whole organism at many levels, resulting in complex evolutionary adaptation to sudden and long-term environmental temperature changes. Whether exposed to extremely cold or hot environment for a short time or in cold or warm environment for a long time, organisms will respond through the rapid adjustment of cell metabolism, and finally affect all organs and systems. For example, many essential enzymes have an optimal temperature range for their enzyme activity. In addition, temperature regulates the development, reproduction, aging and sex ratio of many species. Therefore, temperature has a far-reaching impact on the behavior of many animals, from acute heat avoidance to hibernation and animal migration.
Interestingly, although fish can tolerate cold, they are still very sensitive to warm and hot temperatures. Compared with other vertebrates, they are much less tolerant to the warm temperature range. Temperatures above 32 ° C are beyond the comfort zone of many fish. The body temperature of most mammals is set in a narrow range of 36 ℃ to 38 ℃. However, despite being thermostatic, some mammals have the ability to adjust their core body temperature and the temperature sensitivity of primary afferent nerves according to environmental changes and behavioral and feeding needs. Desert species are a good example of this adaptability. The round tailed ground squirrel (spremophilus tereticaudus) lives in an extremely hot desert climate and can withstand high temperatures up to 46 ℃. Some mammals that cannot migrate long distances have evolved the ability to hibernate – a unique form of adaptation to harsh temperatures and lack of food. Almost all mammalian orders have hibernating species. For example, among primates, it is the fat tailed dwarf lemur (Cheirogaleus medius), from two suborders of rodents (rats, mice, hamsters) and sciuromorpha (squirrels, marmots, Chipmunks), which are the most prominent examples of hibernating mammals.
The above examples show that the essence of temperature perception is the “sense of protection” evolved by mammals. Different from the “desire” of human body for more and better caused by “sweet and fresh” as a high-quality energy recognition feature, “cool” is a luxury flavor enjoyment of adventure after the material life is fully guaranteed.
Ibisi made a great discovery! Coolness can be sensed by multiple ion channel proteins
Scientists around the world have been struggling and unremitting to find natural compounds that trigger physiological coolness. In November 2001, Hoffmann of Germany found a compound many times stronger than mint in natural malt. However, the effect in practical use is far from expected. In 2017, Tomohiro Shirai of Kao company isolated a TRPM8 cooling enhancer from nutmeg, but it is difficult to be commercialized because of its low content in plants.
Consumers’ demands for natural and sustainable product choices have prompted ibisi’s scientists to find natural cooling compounds that can provide stronger and more lasting ingredients than the current ingredients. For example, these ingredients can be used in toothpaste, which can give people a fresh feeling of breathing all morning; Or chewing gum, cool until your chin is too tired to chew. The persistent pursuit of this goal promotes ibisi’s innovative way to improve its flavor by using the most advanced technology to supplement the traditional methods on the market.
The discovery of ion channels can be used to evaluate the chilling activity of compounds in vitro. The latest physiological principle information behind cool perception enables ibisi to combine bioassay technologies such as patch clamp and ion channel with quantitative sensory methods, so as to produce an efficient screening method to evaluate the newly discovered natural cool components, and continuously optimize the structure and performance of its new natural components. Although the time characteristics of cooling rate, intensity and duration of cooling agents are mainly determined by their physicochemical properties, such as solubility and volatility, the effectiveness depends more on the chemical structure. By dividing the molecular structure into different groups, ibisi scientists determined the molecular and structural characteristics required for activity and their relative spatial distribution, and put forward a hypothesis about the combination of core effective groups for the structure of effective coolants. Ibisi’s interdisciplinary thinking and all this hard work are ultimately best rewarded by the discovery of new natural compounds that are durable and effective.
According to traditional science, menthol’s unique cooling sensation comes from its ability to activate a special protein, which mainly expresses TRPM8 (transient receptor potential channel M8 type) on the cell membrane of temperature neurons. Many existing cooling agents on the market also act by stimulating TRPM8 ion channel. In fact, trmp8 is not the only ion channel formed by human cold perception. The TRP channel family responsible for sensing cold and heat can interact with each other. Mastering the mystery of regulating the interaction of TRP channel family is the most favorable weapon for ibisi to develop a new cooling agent with faster release of cooling sensation, stronger cooling sensation, lasting and lasting, and no bitter smell.
In fact, except for the well-known TRPM8 channels of peppermint and WS series, all neurons and ion channels are affected by temperature changes, especially because channel gating is usually a temperature dependent process. However, only some neurons can be called. Temperature sensors and few ion channel types can be specified as temperature sensors. In general, only channels with a temperature coefficient (Q10) ≥ 2 – 5 are considered temperature dependent. To date, at least TRPA1, TRPV1, TRPV2, TRPV3, TRPM2, trpm3, Trpm4 and trpm5 have been found to be temperature related channels. These receptors were divided into two groups according to whether the discharge frequency increased during heating or cooling (Fig. 1). According to this classification, four temperature related feelings are usually mentioned (cold – 10 to 15 ℃, cold – 16 to 30 ℃, warm – 31 to 42 ℃, hot – 43 to 60 ℃). It is worth mentioning that external stimulation is not only a single channel stimulation, but also the signals between channels work together to regulate the body’s response. Menthol with strong effect on TRPM8 can also activate TRPV3 slightly, and thymol and camphor with obvious response signal to TRPV3 can also activate TRPM8 slightly.
Take advanced technology as the cornerstone of product innovation:
Patch clamp, ion channel / G-coupled protein technology
Cell is the basic unit of animal and human body. Since the establishment of the theory of cell membrane and ion in the late 1940s, the study of cell electrical activity has gradually deepened. During 1976-1981, patch clamp technology initiated by Erwin Neher and Bert Sakmann, two German cell biologists, brought a revolutionary change to the research of cell physiology, and won the Nobel Prize in physiology or medicine in 1991. Patch clamp technology is like a key, which opens the door to the study of cell electrophysiology.
Patch clamp technology is known as the “gold standard” for the study of ion channels. It is a microelectrode technology that records the electrical activities of ion channels on biofilm by clamping voltage or current. The results of nerve cells showed that the action potential of cell membrane was related to the opening of Na + channel. The generation of action potential comes from external stimulation signals, which successively activate Na +, K + channels and the resting state of membrane. The amplitude of action potential mainly depends on the equilibrium potential of Na +. The key of patch clamp technology is to form a high impedance seal between the edge of glass microelectrode tip and cell membrane. Patch clamp is a “virtual short” concept formed by high gain operational amplifier, which makes the cell membrane clamp at the applied command voltage to ensure that the measured cells are not affected by the outside world.
Source: time history of cell membrane potential, ResearchGATE, 2019 Sep
Patch clamp technology has a wide range of applications, including ion channel research, myocardial ion channel related to drug action, action mechanism of ion channel under physiological and pathological conditions, relationship between single cell morphology and function, drug action mechanism, application in cardiovascular pharmacology research, innovative drug research and high-throughput screening, And research in neuroscience.
De Yueliang ™ Cooling agent makes natural mint “faster, cooler and more pleasant”
Ibisi’s researchers first studied the existing cooling agents on the market to evaluate the effect of structure on activity. Ibisi developed a natural cooling agent of “faster, cooler and happier” by using the mechanism that natural extract can activate a variety of TRP channels related to temperature and the signals between channels interact together. At the same time, ibicii cold sensing molecules can activate cold sensitive ion channels in neurons, which helps to prolong the cooling effect of menthol. Ibisid Yueliang ™ Natural cooling agents help mint flavor release faster, cool sensation erupts more strongly, mint cool sensation and flavor last longer, and achieve the refreshing and pleasant effects of “straight to the head” and “straight to the lungs”. It can be widely used in food and daily chemical products, including Mint tablet candy, chewing gum, mint flavor drinks and snacks, toothpaste, mouthwash, dental floss, nasal breathing products, mint smearing products, etc.
Ibisi sensory evaluation team bought a popular Mint mouthwash on the market, as shown in the figure below, with de Yue cool added ™ After the natural cooling agent, the cooling sensation of the original Mint mouthwash was increased by 45%, the refreshing sensation was increased by 33%, the bitterness of Mint was reduced by 62%, and the comprehensive preference was increased by 45%. The performance advantages of the product in the above flavor release speed, duration and pleasure of mint cool feeling were verified.
Numb life! The taste of being awakened by “cool”
Ibisi natural cooling enhancer “de Yue Liang” ™” It can create “extremely eager” sensory experience of novel food and drink for young consumers in Z era who are full of curiosity and adventure spirit.
“I have been running a bar in Beijing for six years. More than 50% of the cocktails are original cocktails and have a group of loyal consumers. New products will attract peers to learn from and learn from each quarter. The uniqueness of cocktails lies in the richer taste and more diversified taste choices through the combination of base wine, liqueur and accessories. Even if an experienced bartender is faced with difficulties Customers who drink less can also recommend cocktails that “fall in love with one mouthful” for TA Cao Lixiang, founder of penguin walk, a cutting-edge cocktail brand, said.
“Against the background of the epidemic, I reconsidered the future and form of cocktails. How wonderful it would be to industrialized produce handmade cocktails produced by bars so that more people can enjoy high-quality cocktails!”
“Take mojito as an example. Mojito was born in Cuba and is the most famous cocktail in the world. For every 10 cocktails sold in the world, 7 are mojito. We use the authentic Cuban mojito as a model to develop ready to drink mojito. After thousands of blind tests, it has been finalized as our green Penguin mojito. Chinese people prefer to have a distinctive flavor of rum, green mint and We also precipitate basic application schemes in the process, such as “0 sugar scheme” for penguin walking “There are some 0 sugar products on the market, and you will find that it tastes very fake. Although we are 0 sugar products, we can hardly drink it different from real sugar. One of the achievements is in cooperation with Beijing ibixi Plant Medicine Co., Ltd., which is related to the true perception of sweetness, and makes the mint taste in the wine cooler and fresher.”
Photo source: Penguin walking
According to the research of Yale University, 80% of people’s taste comes from the perception behind the nose. When swallowing, the air flow will be transmitted from the throat to the area behind the nose. The rich olfactory nerve behind the nose receives information and transmits it to the brain. The brain tells us “you eat delicious food”, “you drink sugar” and “you feel cold”.
For humans and animals, temperature perception provides basic information about their environment. The success of discovering a new generation of natural cooling enhancement molecules is an example of ibisi’s use of neural sensing system development methods to identify high impact taste, smell and chemical physical substances. Ibisi and several other projects are using similar technology platforms to obtain new flavor components of different tastes, so as to provide more new generation of natural substances for taste, smell and body perception in the sugar reduction era.
 Nutshell net, 2021 Nobel Prize reveals how humans feel warm and cold
 Spice intelligence agency, the latest trend of global mint oil cooler Market
 Why does chewing Mint produce a cool feeling on things, especially when breathing in cold air? Wang Tianxiang, China HowNet
 Chemical physical sense — the feeling beyond taste and smell in diet, [US] Shane T. McDonald, [US] David A. LITT, [US] John E. Hayes, China Light Industry Press, August 2020
 In the 007 edition of Beijing Science and technology news on October 11, 2021, pepper and mint uncover the secret of body feeling, Lai Tianying and Ding Lin
 Chinese Journal of medical devices, cell electrophysiology and patch clamp technology, Kang Huaguang, Institute of Biophysics and biochemistry, Huazhong University of technology, Vol. 24, No. 3, 2000
Evolutionary adaptation tothermosensation, ELSEVIER, ScienceDirect, Elena O Gracheva and Sviatoslav NBagriantsev, 2015
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