Black pepper / Golmarich(গোলমরিচ- Bengali)

General features: The botanical name is Piper nigrum (PN), commonly called Black pepper, which is well-known as “king of spices”. It is a perennial climbing flowering vine of the Piper genus and Piperaceae family. The genus Piper is related to another Asian species, Piper caninum [1]. Black pepper/PN is widely used as a hot, pungent spice worldwide. Its small, round-shaped fruits are known as peppercorns. The fruits are drupes by nature and ¼ inch in diameter, each containing a tiny seed. The fruits are either reddish or black in color. Dried and powdered peppercorns serve as both a culinary spice and in traditional medicinal practices.  The active component behind the hot, spicy taste is mainly piperine, which differs from capsaicin in the chilli pepper. The plant can reach 33 feet tall, presenting broad, shiny green leaves arranged alternately. It is native to India, possibly originating from the Malabar Coast on the east of the Western Ghats in the coastal regions of Karnataka and Kerala; these regions are famous for growing spices. Black pepper is considered to be the most used spice in the entire world. Although it helps with flatulence and stimulates gastric juice secretion, its medicinal use remains limited [2].

The plant grows small flowers, which blossom in slender spikes and are 50 in number. The seeds have a strong aromatic odor with biting, hot, and pungent taste, very similar to hot capsicum peppers/chillis. The hot and pungent taste is due to Piperine, although it contains piperidine, chavicine, piperettine, and several other alkaloids. Its essential oil content is about 3%. For daily use, the drupes/fruits are dried first. In that drying course, it shrinks and darkens to a thin wrinkled black layer around the seed, synthesizing melanoidins (High molecular-weight nitrogenous matter covalently linked with polysaccharides, proteins, and polyphenolic components like chlorogenic acids, produced particularly in roasted coffee seeds by the Maillard reaction). The dried material is called peppercorn, which is used for culinary purposes either intact or by grinding. The essential oil is extracted from the dried materials [3].

History of Black Pepper: The history of black pepper is intriguing. This spice has been used in India since ~2000 BC. It was once nicknamed ‘black gold.’ It was recognized later as the “king of spices”. Historically, it has been presumed that there was a good possibility that this spice had been introduced to the Western world by Alexander the Great after his global campaign in the 4^th century BC. Obviously, there could be other ways this spice was spread all over the Western Hemisphere. It is fascinating that the spice turned extremely expensive in ancient times, so people used it to pay taxes, rent, dowries, and even to pay tributes by using it. Like gold, it was even a common medium of exchange. In 410 AD, Rome’s captors, Alaric I (370 – 411 AD), king of the Visigoths, demanded about 3,000 pounds of peppercorn as ransom. In the Middle Ages, wealthy people kept their fortune hidden, and they were nicknamed “pepper sacks”. When Rome fell, the surrounding others, like the Persians and Arabs, took advantage of the spice trading. These trading documents were provided by the famed travelers and historians, presenting the facts that black pepper was then still being exported from India during the 4^th – 6^th century. In the early Middle Ages, the major part of the spice trade went under Islamic control. Once the Mediterranean was reached, the trading changed hands and eventually became monopolized by the Italians of Venice or Genoa. The rise of these sovereign cities was basically funded by the spice trade at that time. Although used in the aristocrats’ culinary items, it was then a common thought that the use of black pepper was for concealing the taste of rotten meat. Since at that time it was also applied to preserve the meat, which was rather questionable. In the future, it was noticed that the major compound that provides the hot spiciness, piperine, has strong antimicrobial properties. Since piperine exists at a very low concentration, that makes the effect minimal. But, acceptably, the use of pepper has a definite role in improving the taste of cooked meats.

History also indicates that PN/black pepper appeared in Thailand and Malaysia around the 10th–11th century during the expedition of a South Indian King, and was later spread by the Chinese traders around 1840 AD. The earlier history further reveals that the lost ancient port city, Muziris (presently in Kerala state), during the Chera Dynasty (lasted 3^rd century BC to the 12^th century AD) used to export black pepper along with other spices while trading with the Roman Empire, Egypt, Yemen, the Levant, and Mesopotamia [4,5]. For these reasons, the ancient Romans and the Mediterranean became familiar with its use in food. Before the 16^th century, PN was seen to be cultivated in Java, Sumatra, Madagascar, and Malaysia, practically all over Southeast Asia. During that time, the trading majorly proceeded toward China. The ports on the Malabar coast served as major hubs for all kinds of spice trade. By virtue of it, the Maluku Islands acquired the nickname “ Spice Islands”. This region of Indonesia became the main trading place of major spices like cloves, nutmeg, cinnamon, pepper, and many others.  This ongoing event attracted the Europeans around the 16^th century to buy the spices right from here [6]. Before that time, in the Roman Empire, its use had already reached to the climax as evidenced by the Roman Cook Book, Apicius De Re Coquinaria, written in the 3^rd century. At that period, black pepper was the most favorite and costly substance, used only by the Roman elites in their cooking [7]. Around that time, this spice also made its appearance in China. Afterward, around the 12^th century, it became a very popular ingredient in Chinese cuisine, mostly among the wealthy people, slowly replacing native hot Sichuan pepper (unrelated to black pepper). In China, during the 13^th century, Marco Polo witnessed this practice and tasted this spice. He described it as a luxury commodity [8]. In the Medieval Period, its trade was monopolized by the traders of Venice. Owing to its exorbitant price, the Portuguese were compelled to discover a sea route to India. In 1498, Vasco da Gama, the first Portuguese sailor, arrived in Calicut, India via the Southern tip of Africa. Later, Portuguese traders monopolized the spice trade for about the next 150 years, subsequently making Portugal a very rich nation. But around the 17^th century, they lost all the spice trade to the Dutch and the English by force. In 1661- 1663, the famous Malabar Coast was used by the Dutch for trading all the spices. Since the supply volume to Europe has increased, the price has plummeted. This expensive spice, once reserved for aristocrats, eventually became a common seasoning for all ordinary people.  

Far before these historic events, in ancient Egypt, peppercorns were applied in the course of mumification, which has been identified inside the stuffed nostrils of Ramesses II in 1213 BC [9]. After the conquest of Egypt by the Romans in 30 BC, and concomitantly following the crossing of the Arabian Sea, thus reaching directly to the Malabar Coast of southern India, trading directly with the Chera Empire became a routine trend. The details of this voyage were inscribed in the book “Periplus of the Erythraean Sea”. At that time, during the return from the Malabar Coast, the ships routinely arrived at first at the Red Sea port, and the cargo was carried through the Nile River-Red Sea canal to the Alexandria port. From here, it journeyed to Italy and Rome. This trade route was followed for almost a millennium. Since ships took a more direct route to the Malabar Coast, the price of black pepper dropped over time. The fact has been mentioned in the “Natural History” written by Pliny the Elder.

Folk medicinal uses: PN has been admired in folk medicine around the world for its vigorous stimulating and warming roles. In ancient times, it was traditionally used to treat respiratory congestion, boost digestion, and reduce inflammation. In the highly esteemed ancient Indian apothecary, Ayurveda, it is characterized as “digestive fire”. It cures constipation, gas, diarrhea, the common cold, flu, and pain [10]. Historically, in ancient Rome or Greece, it was used to treat stomach pain and indigestion [11]. PN has also been widely used in pain management and inflammation. It even has antiseptic activity [12].

Phytocompounds: Black pepper/PN is a rich source of various phytochemicals with diverse physiological roles. Besides the main active principle, piperine, which is responsible for the hot taste, PN also synthesizes several alkaloids, flavonoids, terpenes, lignans, and essential oils.

 Among the alkaloids, piperine is the highest, 2 – 9% of the fruit’s weight. The compound produces intense pungency, exerting several biological roles, acting as an anti-inflammatory, antioxidant, neuroprotective, and antimicrobial agent [13,14]. It also acts as an excellent bioenhancer, helping drug absorption [15]. Another important alkaloid derivative is chavicine, which is a piperine isomer. Interestingly, this compound is devoid of pungency, and owing to its instability, it switches to the stable conformation piperine if exposed to heat or light [16]. In addition to those ingredients, PN synthesizes several amides related to piperine, which also show pungency and bioactivities [17,18].

  PN has a large reservoir of oleoresins with volatile and nonvolatile components, which range from 4.27–12.73% depending on the cultivar. The oleoresin extracts have a strong flavor and therapeutic potential, and are therefore used in the food and pharmaceutical industries. The major components are composed of monoterpenes and sesquiterpenes such as β-caryophyllene, caryophyllene oxide, and similar others such as sabinene, linalool, Sylvestrene,  β-terpenine, δ-carene, β-phellandrene, β-myrcene, and a few others [17,18]. They are responsible for the aroma, antimicrobial, antioxidant, and other biochemical effects. No significant levels of steroids or triterpenes have been identified in PN.

This spice contains phenolic compounds, including flavonoids like catechin, quercetin, myricetin, and carotenoids such as lutein and β-carotene. All of them have numerous beneficial effects on health, particularly regarding cardiovascular and neuroprotective benefits [19].

Oleoresins

Phenolics and Carotenoids

Concerning the other phytochemical profile, PN contains a large source of vitamins, minerals, and other nutrients. As per the mineral contents, 100 g of spice has 400 mg calcium (Ca), ~ 250 mg magnesium (Mg), 1200 mg potassium (K), and 160 mg phosphorus (P), and lesser levels of sodium (Na), iron (Fe), and zinc (Zn). Regarding vitamins and others, it shows substantial levels of C (~ 30 mg), B1 (~0.7 mg), B2 (~ 0.5 mg), and B3 (0.7 mg), lutein (260 µg), and β-carotenoid (~150 µg) [20].

Pharmacological effects: In black pepper, piperine and its extracted essential oil have shown a myriad of pharmacological effects, which are largely beneficial for health.

Antioxidant effect – It is known that reactive oxygen species (ROS) exert several undesirable responses, causing many metabolic problems like cancers and cardiovascular illnesses [21]. PN shows a great antioxidant potential, reducing oxidative stress, maintaining the levels of enzymes like superoxide dismutase, glutathione peroxidase, catalase, and glutathione-s-transferase [22]. It has been identified that alkaloids piperine and its derivatives, along with the phenolics, oleoresins, and flavonoids, are mainly responsible for this antioxidant role [23].

Anti-inflammatory, analgesic, and anti-arthritic effects – The anti-inflammatory, analgesic, and anti-arthritic effects are largely interrelated. In all these categories, piperine exhibits a major role. In carrageenan-induced paw edema in laboratory rats, piperine exerts potent dose-dependent anti-inflammatory effects [24]. In cultured macrophage cell lines RAW264.7), piperine inhibits LPS-induced expression of inflammatory mediators by decreasing the expression of IL-6, MMP-13, and PGE2 [25]. A similar inhibitory behavior of piperine has been noticed in the case of IL-1β-treated synoviocytes, while preventing the migration of AP-1, not NF-κβ. In the laboratory rat model, piperine lowers nociceptive and arthritic symptoms within 4 – 8 days, which has been viewed as histologically significant, indicating the reduction of inflammation in the ankle joints [26]. The other alkaloids, including the essential oil of PN, have shown significant anti-inflammatory actions, which can be compared to the standard drug Diclofenac. In the chronic inflammatory model created by formalin, paw edema, the oil caused 50% inhibition, whereas diclofenac at a 10 mg/Kg dose the inhibition is 57.5% [27]. Regarding the effect of analgesia, piperine is seen as efficient in the proximity to indomethacin, a non-steroidal anti-inflammatory drug that works by preventing PGE2 and other inflammatory mediators, which has been proven by following the tail flick writhing assay model using acetic acid in mice. The intraperitoneal administration of piperine (30 – 50 mg/Kg) has increased the response time. A similar response is noticed in the case of morphine at 5 mg/Kg. The analgesic actions of both were reversed by pretreating the animals with naloxone, 5mg/Kg. So, the actions could be mediated following the opioid receptors’ pathway [28].

Anticonvulsant effect – The active principle of PN, piperine, has a potent anticonvulsant property, as proven in electroshock and pentylenetetrazol (PTZ) treated models in mice. Further, piperine, interacting with the TRPV1 cation channel receptor, shows a definite role in inhibiting PTZ-induced convulsions [29]. This compound significantly delays the initiation of myoclonic jerks and generalized clonic seizures. Considerable reduction is also observed in the event of electric shock-induced tonic hind limb extension and PTZ-induced Fos immunoreactivity in the dentate gyrus after piperine addition. Capsazepine (a selective TRPV1 antagonist) blocks the anti-seizure effects of piperine. This event establishes the anti-seizure/anticonvulsant role of piperine [20,30]. Additional investigation in the picrotoxin-induced epilepsy model in mice, PTZ has been used to evaluate the in vivo anticonvulsant actions of piperine. The evidence suggests that the anticonvulsant effect of piperine is possibly mediated via GABAergic pathways [31].

Antipyretic effect – In traditional medicine around the world, PN is widely known for its antipyretic role in lowering fever and acting as a remedy for cold, cough, sore throat, sinusitis, asthma, and even bronchitis. Due to its versatile phytocomponents, it is even used to treat malaria [32]. The antipyretic effect may be due to piperine, which primarily acts by inhibiting prostaglandin (PG) production [33]. It also has significant antitussive and bronchodilator abilities that help prevent cough and cold. So, adding peppercorn to green tea often reduces the asthma problem. Experiments have shown that oral administration of piperine to mice reduces and suppresses the hyperresponsiveness, infiltration of eosinophils, and subsequent inflammation by reducing the production of histamine, IgG, IL-4, IL-6, and IL-1β while modulating NF-κβ, p38MAPK, and STAT3 [34].

Antibacterial and antimicrobial effect – The antimicrobial and antifungal action of black pepper mostly relies on piperine [35]. The effects are directed against Staphylococcus, Bacillus subtilis, E. coli, Aspergillus niger, and several more. Besides piperine, the phenolic extracts and essential oil fraction also have potential in inhibiting those bacteria [35,36,37].

Anti-Alzheimer effect – Consuming black pepper or its major active component, piperine, provides a neuroprotective effect, preventing several age-related neurological disorders, which include Alzheimer’s disorder (AD). Piperine can modulate cell survival and death in animal models. It plays a significant role in preventing the progression of AD when studied in the in vivo animal model. The compound improves memory, reduces oxidative stress in the brain, and simultaneously lowers the formation of β-amyloid plaque [38]. Like piperine, the PN/black pepper extract also inhibits the enzyme acetylcholine esterase, enhancing the level of acetylcholine, thus helping improve the cognitive function within AD patients. Besides piperine, chavicine also reduces the buildup of β-amyloid plaque, which harms healthy neurons in the brain. Acting as a powerful antioxidant, the extract scavenges the generated free radicals, thus reducing the neural inflammation, protecting the hippocampus, the memory center in the brain. Uniquely, piperine hugely increases the bioavailability/absorption of curcumin(turmeric) by nearly 2000%, synergizing the anti-inflammatory role and concomitantly reducing the β-amyloid plaque formation inside the brain [39,40].

Antiparkinsonian effect – Black pepper, along with its bioactive alkaloids, particularly piperine, shows an efficient neuroprotective behavior, preventing Parkinson’s disorder (PD). The animal and cellular experiments indicate that black pepper maintains dopamine levels and simultaneously lowers the endogenous inflammation [38]. One of the active compounds, piperine, inhibits the enzyme monoamine oxidase B (MAO-B) highly involved in dopamine degradation; therefore, in a way, it helps raise the dopamine level, deficient in PD. The loss of neurons within the substantia nigra region in the brain is usually associated with PD. Further, piperine reinstates the tyrosine hydroxylase activity needed for dopamine synthesis. Additionally, the extract reduces microglial activation (immune cells), lowering levels of the pro-inflammatory cytokines IL-1β and TNF-α. It also scavenges the endogenously generated free radicals, boosting the antioxidant enzyme superoxide dismutase (SOD) level, lessening the oxidative stress, and concomitantly protecting the brain neurons [41]. Piperine also functions as an efficient bioenhancer by boosting curcumin absorption, amplifying its neuroprotective efficacy [42]. Besides piperine, the other beneficial components controlling PD are chavicine, piperlonguminine, and α-linoleic acid [43].

Anticancer effect – Laboratory studies indicate that either the PN or piperine has considerable anticancer properties. Piperine, by itself, can control cancer progression via diverse signaling pathways, indicating its immense potential as a hopeful anticancer agent. The major pathways involved are STAT-3, NF-κβ, PI3K/AKT, and JNK/p-38-MAPK [44]. It is also noticed that piperine impedes cell proliferation and migration, causes cell cycle arrest at G0/G1, S, or G2M phases, depending on the tumor’s nature. It stimulates apoptosis by activating caspases and altering the Bax/Bcl-2 ratio, restrains angiogenesis and metastasis of malignant cells, by inhibiting the expression of matrix metalloproteinases. The spice extract and piperine are known antioxidants, but at lower doses. However, at high doses, it acts in reverse, enhancing the level of reactive oxygen species (ROS) and selectively damaging the cancer cells [45,46].

Antidepressant effect –  Piperine in black pepper might act as an antidepressant owing to its enhancing role in dopamine and serotonin levels, since those neurotransmitters control emotions and pleasure while working in the hippocampus and frontal cortex of the brain, alleviating depression [47]. In the animal model, by inducing depression using corticosterone, treatment with piperine later greatly reduced the manifestation of depressive behavior due to the steroid [48]. Additionally, the anti-inflammatory and antioxidant behavior of piperine or PN extract prevents neuroinflammation, which protects neuronal cells from stress that contributes to stress and anxiety [49].

Effect on platelets – Piperine in PN/black pepper is a natural inhibitor of platelet aggregation, thereby lowering the risk of blood clots. It works by preventing the generation of thromboxane A2, a potent clotting agent, which lessens platelet aggregation, without affecting the COX-1 enzymes. In that way, it provides cardiovascular benefits [50]. Interestingly, it alleviates arachidonic acid (AA) production by inhibiting the cytosolic phospholipase A2 in platelets, an important step during the activation process [50]. Further, by regulating the platelet-derived growth factor-BB induced muscle cell proliferation and, in addition to its anti-clotting activities, consumption of black pepper can improve blood flow and simultaneously offer cardiovascular protection. Owing to the improved blood flow also in the penis, several studies indicate that it helps enhance sexual performance, reducing erectile dysfunction [51,52].

Hepatoprotective effect – The active principle, piperine, as well as the essential oil in black pepper, has shown considerable hepatoprotective actions, owing to their antioxidant, anti-inflammatory, and anti-apoptotic roles. Both the spice extract and its bioactive components reduce liver damage by lowering AST and ALT, preventing lipid peroxidation, reinstating glutathione concentrations, and protecting against toxin-induced fibrosis [53]. The essential oil enriched with flavonoids and polyphenols scavenges free radicals, reducing oxidative stress. Additionally, pretreatment with the extract or piperine can decrease liver damage induced by CCl₄ or acetaminophen, diminishing inflammation and apoptosis [54]. This compound reduces fat in the liver in non-alcoholic fatty liver disease and also potently reduces the damage caused by dexamethasone [55,56].

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