According to the Encyclopedic Dictionary of Traditional Mexican Medicine, inflammation is a synonym for swelling; it is caused by blows, infections, rheumatism, local pain, heat, and redness, among others. In traditional medicine, inflammation is almost always understood as a sign or symptom present in various diseases and rarely as a condition [23]. Thus, the search for literature describing traditional uses related to the inflammatory process include 33 genera and 106 species of the Nepetoideae subfamily worldwide (Table S1). Regions where they are used include Chile, Brazil, Ecuador, Nicaragua, Panama, Costa Rica, Mexico, USA, and Canada in the American continent [24,25,26,27,28,29,30,31], Spain, Greece, Italy, Turkey, Algeria, Libya, Morocco, Mauritania, Tunisia, and Israel from the Mediterranean Sea, and China, India, Nepal, and Pakistan from the Himalayan region [32,33,34,35,36,37,38,39,40]. Other regions include the Philippines, Malaysia, and Thailand from Southeast Asia, and some islands, such as Monserrat, Samoa, and Madagascar [41,42,43,44,45,46].

The genera with the most reports of traditional uses for inflammation-related conditions are Mentha, Ocimum, and Salvia. The most mentioned species was Mentha longifolia (L.) Hudson, M. spicata L., Ocimum sanctum L., and Salvia rosmarinus L. (Table S1). M. longifolia and M. spicata are used for inflammation of the throat, gums, and eyes. O. sanctum is used in India to treat everything from constipated flu to chronic pain. Meanwhile, S. rosmarinus is used against neuritis, rheumatism, and uterine fibrosis [33,36,37,47]. The genera distributed in the American continent are Agastache, Cunila, Hedeoma, and Hyptis, all of which are used to treat various conditions, such as gastrointestinal pain and inflammation, gingivitis, blows, rheumatism, wounds, earaches, bones, and colic [23,48,49].

Elsholtzia, Isodon, and Orthosiphon are widely used in Oriental medicine for skin conditions (e.g., wounds and psoriasis), the respiratory tract (tonsillitis and pharyngitis), and colic pain, respectively [50,51,52]. Some genera are part of the culinary culture of many countries, such as Mentha, Ocimum, Origanum, and Thymus, where they are used as condiments and for gastrointestinal ailments (diarrhea, dysentery, and colic), the respiratory system (asthma, colds, catarrh, and bronchitis), to reduce fever, to reduce swelling, and for some chronic issues, such as uterine fibrosis [32,53,54,55]. A highly cited genus is Salvia, known both in Mediterranean cuisine for its culinary use and in traditional medicine in different countries including Mexico, China, and India. Salvias are used to treat wounds, pain, infections, fever, rheumatism, uterine fibrosis, and burns, among others [31,34,52]. Asterohyptis mociniana (Benth.) Epling and Isodon rubescens (Hemsl.) H. Hara are used to treat gastroenteritis, whereas Clinopodium brownei Kuntze and Plectranthus scutellarioides Blume are used for swelling. In the cases of Minthostachys mollis (Kunth) Griseb. and Monarda fistulosa L., they have been reported for bronchitis, while Calamintha acinos Man. and Lepechinia spicata Willd. have been reported for lung problems [23,24,31,35,52,56,57,58]. All of these genera produce a considerable number of secondary metabolites, which alone or in synergy have beneficial biological properties for human health, making excellent functional foods, which could subsequently be developed as nutraceuticals [59].

In general, it is known that polar preparations are the most commonly used medicinal plants in folk medicine, and they are included in the most representative studies explored in bioassays and phytochemical studies [60]. In the case of the Nepetoideae subfamily species, preparations commonly used in folk medicine are produced through infusion or decoction of the whole plant or other independent parts. However, not only polar extractions but also non-polar extracts using different organic solvents and the essential oil have been reported to identify and isolate bioactive metabolites with anti-inflammatory activity. A total of 831 species of the Nepetoideae subfamily were obtained with at least one article indexed in any category in the Scopus database. From the 831 species, a total of 39 genera and 308 species were reported in 3124 articles, all of them associated with the anti-inflammatory activity. In this regard, the genera with the most publications (100–1400) were Salvia, Ocimum, Thymus, Mentha, Origanum, Lavandula, and Melissa. It was followed by 17 genera with 10 to 100 articles, of which 12 belong to the Menthae tribe (Prunella, Satureja, Zataria, Nepeta, Dracocephalum, Hyssopus, Agastache, Glechoma, Ziziphora, Clinopodium, Monarda, and Lycopus), 4 belong to the Ocimeae tribe (Isodon, Orthosiphon, Plectrathus, and Hyptis), and only 1 is from the Elsholtziae tribe (Elsholtzia).

Within the genus Salvia, there are approximately 111 species reported in relation to the inflammatory process. The most studied species are S. miltiorrhiza Bunge and S. officinalis L.. For S. miltiorrhiza, its properties have been reported using the root extracts, where a number of isolated diterpenes called tanshinones were also identified as responsible for the effect on the reduction of proinflammatory cytokines in in vitro assays [61]. The reduction of fibrosis in the liver, heart, lung, and kidney was reported in in vivo models, with improvement against allergies, asthma, and rhinitis using clinical tests [62,63]. Anti-inflammatory effects of S. officinalis have been described in in vivo tests prepared as organic extracts of different polarity and aqueous extracts, in which the main component was rosmarinic acid [64]. S. dolomitica Codd, S. frigida L., S. nipponica Miq., S. petrophilla G. X. Hu, E. D. Liu, and Yan Liu, S. plebeia R. Br., and S. sclareoides Brot. reduced the enzymatic activity of elastase and inflammatory mediator molecules, such as nitric oxide (NO), IL-4, IL-13, IL-5, TNF-α, cyclooxygenase (COX)-2, and prostaglandine PGE2 in RAW 264.7 macrophages induced with LPS in organic extracts of different polarities and aqueous extracts [65,66,67,68,69,70]. The polar extracts of S. chudei Batt. and Trab., S. fruticosa Mill., S. leriifolia Benth., S. macilenta Boiss., S. sclarea L., S. transsylvanica (Schur ex Griseb. and Schenk) Schur, and S. virgata Ortega demonstrated anti-inflammatory activity in the carrageenan-induced edema model in rats at a dose range of 250–1500 mg/kg. Finally, the acetone extract and the methanol extract of S. aegyptiaca L. and S. moorcroftiana Wall. ex Benth., respectively, showed antipyretic effects in murine models of hyperthermia (Table S2) [71,72,73,74,75,76,77,78]. After the genus Salvia, the species Ocimum tenuiflorum L. (syn. Ocimum sanctum L.), Thymus vulgaris L., Mentha spicata L., and Origanum vulgare L. are the most studied of their respective genera. The organic and aqueous extracts of O. tenuiflorum showed positive effects on the epithelialization and a reduction in the induced edema in murine models. Likewise, phenolic compounds isolated from this species, including rosmarinic acid, decreased the concentration of COX-1 in in vitro models [79,80]. The aerial part of T. vulgaris increased the activity of antioxidant enzymes in models of renal and hepatic dysfunction in rabbits, and it also had an effect against cholestasis, chronic hepatitis, and liver fibrosis in clinic studies [81]. Both the organic and aqueous extracts of M. spicata decreased edema, granulomas, and mucositis induced in murine models [82]. The essential oil of O. vulgare produced significant effects on the proinflammatory cytokines and chemokines [83]. Lavandula angustifolia Mill. and Melissa officinalis L. have been also explored for their anti-inflammatory effects. Regarding the genus Lavandula, several species have been evaluated, expect for Melissa, where only M. officinalis has been described. With respect to L. angustifolia, both the essential oil and the polyphenolic fraction reduced the levels of proinflammatory cytokines in murine models of induced edema, ischemia, chronic inflammatory pain, and sepsis [84,85,86,87,88,89,90,91]. In the case of Prunella, only P. vulgaris L. has been evaluated in this affection. The essential oil, polar extracts, as well as the isolated compounds from the inflorescences, such as the diterpene prunela diterpenol A and the phenolic compounds prunelanate A and prunelanate B, presented activity in the regulation of proinflammatory cytokines in in vitro tests [96,97,98,99]. Triterpenes, such as 2α,3α,23-trihydroxyursa-12,20(30)-dien-28-oic acid, β-amyrin, and eusapic acid, produced effects on histamine suppression in in vitro studies [100]. For the genera Satureja, Zataria, Nepeta, Glechoma, and Lycopus, few species have been studied in murine models using polar extracts of Satureja montana L. and Nepeta dschuparensis Bornm, which decreased IL-1β levels in the model of traumatic brain injury and artery occlusion infarction, respectively. Glechoma longituba (Nakai) Kuprian attenuated proinflammatory gene expression in retinas exposed to bright light, Lycopus lucidus Turcz. ex Benth. inhibited histamine release in allergy models, and Zataria multiflora Boiss. improved levels of proinflammatory cytokines in asthma models [101,102,103,104,105]. From Agastache mexicana (Kunth) Lint and Epling and Dracocephalum moldavica L., which also belong to the Mentheae tribe, the glycosylated flavonoid tilianin has been isolated, where a reduction in the mRNA expression of proinflammatory cytokines was observed in in vivo and in vitro models [106,107]. Likewise, some little-known diterpenes have been isolated from D. moldavica, such as dracocephalumoids A-E, uncinatone, trichotomone F, and caryopterisoid C, which suppressed TNF-α, IL-1β, and NO in RAW 264.7 macrophages induced with LPS [108]. Finally, the aqueous extracts of Hyssopus officinalis L. and Ziziphora clinopodioides Lam. were used for the synthesis of Zn and Fe nanoparticles, demonstrating their anti-inflammatory effect in murine models of carrageenan-induced edema and hemolytic anemia, respectively [109,110]. Diterpenoid-type compounds isolated from the aqueous extracts of species of the Ocimeae tribe have presented anti-inflammatory activity in both in vitro and in vivo models, such as the case of orthosiphol A and B obtained from Orthosiphon stamineus Benth., parvifloron D from Plectranthus ecklonii Benth., as well as suaveolol and methyl suveolate from Hyptis suaveolens (L.) Poit. [111,112,113]. Regarding the genus Isodon, such as I. adenanthus (Diels) Kudô, I. enanderianus (Hand.-Mazz.) H.W. Li, I. eriocalyx (Dunn) Kudô, I. henryi (Hemsl.) Kudô, I. leucophyllus (Dunn) Kudô, I. rugosiformis (Hand.-Mazz.) H. Hara, I. scoparius C.Y. Wu and H.W. Li) H. Hara, and I. rubescens (Hemsl.) H. Hara, a significant amount of kaurane-type diterpenes have been isolated as responsible for the activity on proinflammatory cytokines both in RAW 264.7 macrophages induced with LPS as well as in a variety of models, such as in murine infections of encephalomyelitis, prostatitis, peritonitis, gouty arthritis, and type II diabetes [114,115,116,117,118,119,120]. In the case of I. ternifolius (D.Don) Kudô, the lignans ternifoliuslignans A, B, C, D, and E and the glycosylated phenylethanoid 3-carboxy-6,7-dihydroxy-1-(3′,4′-dihydroxyphenyl)-naphthalene were characterized to suppress activity of PGE2 and TNF-α in macrophages induced with LPS [121]. I. eriocalyx, from which endophytic fungus Phomopsis sp. was first isolated, allowed the isolation of the phomopchalasins A, B, and C with NO inhibitory activity in in vitro assays [122]. Species with few studies reported in the literature were Cedronella canariensis (L.) Webb and Berthel., Hoslundia opposita Vahl, and Micromeria biflora (Buch. Ham. ex D.Don) Benth., prepared as chloroform extracts of flowers, root, and aerial part, respectively, which demonstrated anti-inflammatory effects in the murine model of edema induced with carrageenan [123,124,125]. Polar extracts of Asterohyptis stellulata (Benth.) Epling promoted skin regeneration in CD-1 mice. Micromeria croatica (Pers.) reduced the expression of proinflammatory cytokines in models of liver injury, and Mosla chinensis Maxim. and M. scabra attenuated levels of inflammatory mediators in models of ulcerative colitis [126,127,128,129]. From the petroleum ether extracts of Horminum pyrenaicum L., abietane-type diterpenes were isolated that suppressed the activity in immunometabolic pathways related to inflammatory processes in murine models [130]. All of this information together demonstrates that different classes of natural compounds are investigated for their anti-inflammatory potential properties in the species of the Nepetoideae subfamily. The chemical structure diversity found in natural products has served as an attractive approach in searching for relevant anti-inflammatory drugs, as it can be possible from this subfamily. Thus, the chemical structure diversity is not a factor in producing similar biological activity; however, the bioactivity can be improved by modifying the structure [131,132]. Due to this, it is important to notice that natural chemical compounds show a wide spectrum of activities and interaction in several molecular targets responsible for the anti-inflammatory activity of these species because it can be more than one at the same time. As an example, several compounds possessing antioxidant properties can prevent and/or reduce oxidative stress, which is relevant in inflammation and neurodegenerative diseases. The activity–structure relationship of several common polyphenols in plants, such as gallic acid reported in some species of the Nepetoideae subfamily, have demonstrated that the higher the number of phenolic hydroxyl groups, the stronger the antioxidant activity that regulates inflammatory mechanisms and pathways [132]. The interaction of some flavonoids in several targets at the same time, such as quercetin derivatives, has been reported using antagonists of inhibitory receptors, such as endogenous opioids, and those of serotoninergic and/or dopaminergic neurotransmission involved in neurodegenerative diseases have been explored by using predictive molecular docking, too, in order to support their important role at peripheral and central levels [131]. Some natural products from a terpenoid nature, such as sclareol, which are also found in species of this subfamily, produced their anti-inflammatory activity by inhibiting not only NO production but also the expression of iNOS and COX-2 proteins, as well as in the MAPK signaling pathway [63]. Meanwhile, tanshinone II activity has been supported by regulating the CCNA2-CDK2 complex and AURKA/PLK1 pathways [133]. Further structure activity relationship studies are encouraged for metabolites found in the Nepetoideae subfamily species, as in other plants, to identify not only the chemical compounds but also their mechanisms of action involved in their potential biological activities as anti-inflammatory therapy to improve health.

Chemical secondary metabolites have been identified and isolated using dissolvents of different polarity through several techniques of extraction [194]. Therefore, phytochemical techniques have allowed for the determination of the main components of some species of the subfamily Nepetoideae. This section generally describes some of the compounds commonly identified in the subfamily (mono- and tri-terpenoids, phenolic acids, and flavonoids). It also mentions the case of clerodane and kaurano-type diterpenes, which have different biological activities (see Section 2.2) and have only been isolated in certain genera, such as Salvia and Isodon. Table S3 lists the species studied phytochemically and the secondary metabolites isolated from them. Monoterpenes have been the most identified, such as thymol (C1) and carvacrol (C2), which are important components of the essential oils of Collinsonia, Monarda, Ocimum, Origanum, Satureja, Thymbra, Thymus, and Zataria [83,101,195,196,197,198,199,200]. On the contrary, there are exclusive molecules of certain genera, as exemplified by Mentha, where menthol (C3), menthone (C4), and eucalyptol (C5) predominate. In the case of Lavandula and Melissa, linalool and nerol have been identified as the most important constituents, respectively [94,201,202]. Different phenolic acids have been reported throughout the subfamily, such as caffeic acid, ferulic acid, gallic acid, chlorogenic acid, sinapic acid, and a high presence of rosmarinic acid (C6) [203,204,205,206,207,208]. Similarly, the presence of flavonoids and their glycosylated derivatives, such as quercetin, luteolin, and naringenin, have been very common [126,198,200,201,202]. In contrast, the presence of the flavonoid tilianin (C7) has been reported only in Agastache and Dracocephalum [104,105]. It is important to notice that diterpenes are the chemical group less explored throughout the subfamily. The species of Dracocephalum taliense Forrest and Horminum pyrenaicum L. included the abietanes sugiol, ferruginol, cryptojaponol, and totarol isolated from roots. Dracocephalumoids A, B, C, and D (C8–C11), and orthosiphol A and B (C12–C13) were purified from Dracocephalum moldavica L. and Orthosiphon stamineus Benth. [108,111,209]. Other genera, such as Salvia and Isodon, stand out for the great diversity of diterpenes that have been isolated and identified in several of their species. In the case of Salvia, terpenes of abietane, clerodane, labdane, and pimarane-type structures have been described. Some examples are tanshinone IIA (C14) and sclareol (C15) isolated from S. miltiorrhiza and S. sclarea, respectively [61,62,63,64,65,66,67,68,69,70,71]. In the case of the genus Isodon, compounds with a Kaurano-type skeleton predominated, and some common cases among the species were adenanthine (C16), eriocalyxin B (C17), and oridonine (C18) [114,117,169].