Anti-Inflammatory Effects of Taurine and Terpenes

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Laura Kate Gadanec	--	3522	2023-06-06 13:50:32	\|
2	references update	Fanny Huang	-4 word(s)	3518	2023-06-07 05:16:53	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu15112562

Taurine, black pepper, and the major terpene constituents found in black pepper (i.e., β-caryophyllene; α-pinene; β-pinene; α-humulene; limonene; and sabinene) that are present in PhytoCann BP^® have been shown to have cardioprotective effects based on anti-inflammatory, antioxidative, anti-hypertensive and anti-atherosclerotic mechanisms.

black pepper taurine terpenes

1. Introduction

Natural products are well-known for their therapeutic value ^[1]. Throughout human history, they have played an important role in traditional medicine by treating a wide range of pathological ailments, offering effective alternatives to modern medicine ^[2]. Thanks to recent advances in scientific research and growing environmental awareness ^[3], there has been a significant increase in the use of natural and plant-based products to promote synergistic biological health benefits ^[4]^[5]^[6]. This is particularly important in western society where a shift in the modern dietary regimen towards a “Western diet” and an increase in sedentary lifestyles is believed to be, in part, responsible for the substantial increase in the prevalence of cardiovascular complications ^[7]^[8].

Cardiovascular diseases (CVDs) refer to a broad range of conditions affecting the heart and blood vessels ^[9]. They register a global annual death toll of more than 19.1 million and are the most prevalent cause of morbidity and mortality ^[10]. Alarmingly, the World Health Organization estimates that CVDs will contribute to over 22 million deaths in 2030 ^[11]. CVDs encompass a variety of diseases, including hypertension, atherosclerosis, coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI) and stroke ^[9]. Atherosclerosis and hypertension are the leading causes of CVDs and are the most common underlying diatheses for most deaths ^[12]. Independent risk factors for CVDs include hypertension, hyperhomocysteinemia (HHcy), dyslipidemia, type-2 diabetes, and cholesterol ^[12]^[13]^[14]. The pathology of CVDs is complex, and oxidative stress, hyper-inflammation, endothelial dysfunction, and hyperlipidemia have been reported as common phenotypes in the pathogenesis of CVDs and have become the main targets of therapeutic intervention ^[15]^[16]. Conventional therapy commonly used to treat CVDs can be costly and may produce adverse side effects, unwanted drug–drug interactions and life-threatening toxicities ^[17], and thus, alternative approaches have been considered, including physical activity, as well as the use medicinal natural product supplementation, for CVD treatment ^[18]^[19]^[20].

Taurine, a natural product, is a non-toxic, semi-essential sulfur-containing amino acid (Figure 1A) that is abundant in human cardiac and vascular tissues ^[21]^[22]. Although synthesized endogenously from methionine and cysteine ^[23], the majority of taurine is obtained through dietary intake (e.g., seafood, meat, poultry and eggs) ^[21]. It is well-established that taurine has diverse physiological functions in humans and is seen to protect against several pathophysiological conditions ^[22]^[24]^[25]. Most of the effects mediated by taurine are reported in the cardiovascular system and include modulating ion transporters, membrane stabilization, anti-oxidation, anti-hyperlipidemia, anti-platelet, and anti-inflammatory activity, as well as modulation of blood pressure and vascular tone ^[22]^[24]^[25].

Figure 1. Chemical structures of (A) taurine, (B) BCP, (C) α-pinene, (D) β-pinene, (E) limonene, (F) α-humulene and (G) sabinene. Abbreviations: BCP, β-caryophyllene. Black: carbon, gray: hydrogen: blue: nitrogen; red: oxygen, yellow: sulfur Figure designed with Biorender.com.

Piper nigrum, commonly known as black pepper, has been used to treat a variety of conditions ^[26]. The therapeutic value of black pepper is attributed to its constituents, terpenes or terpenoids, which are a diverse class of organic compounds present in essential oils obtained from plants ^[26]^[27]. Terpenes consist of over 30,000 compounds whose functional groups include alcohols, aldehydes, or ketones ^[28]. Abundant terpenes found in black pepper consist of β-caryophyllene (BCP) (Figure 1B), α-pinene (Figure 1C), β-pinene (Figure 1D), limonene (Figure 1E), α-humulene (Figure 1F), and sabinene (Figure 1G) ^[29]. The therapeutic merit of black pepper has been attributed to the ability of BCP to specifically activate cannabinoid 2 receptor (CB₂R), resulting in downstream signaling pathways that mediate anti-inflammatory, anti-atherosclerotic and anti-oxidative properties, which have been correlated with beneficial cardiovascular effects ^[30]. Unlike BCP, studies involving α-pinene ^[31]^[32], β-pinene ^[31]^[32] and α-humulene ^[33] have demonstrated the inability of these terpenes to interact with CB₂R. Several studies have noted the significant cardiovascular-protective effects of black pepper and its terpenes against a range of CVDs, including hypertension, atherosclerosis, CAD, and HF due to their anti-inflammatory, anti-oxidative, anti-hyperlipidemia and blood pressure-lowering abilities ^[34]^[35]. As such, black pepper provides novel therapeutic strategies to target CVD initiation and progression.

2. Anti-Inflammatory Effects of Taurine and Terpenes

Acute and chronic inflammation play key roles in the pathogenesis, progression, and severity of CVDs ^[36]. Hypertension, atherosclerosis and CAD are characterized as chronic inflammatory diseases and are clinically associated with increased expression of important pro-inflammatory receptors (e.g., toll-like receptors (TLR) and receptor for advanced glycation end-products (RAGE)) and molecules (e.g., high-mobility group box-1 (HMGB-1), interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), nitric oxide (NO), prostaglandin E₂ (PGE₂), inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2) ^[8]^[37]. Thus, their downregulation and inhibition have been reported in literature as potential therapeutic targets against CVDs ^[38]. Taurine and terpenes contain general anti-inflammatory effects (Table 1), which may be useful in combination therapy as due to their abilities to suppress the expression of pro-inflammatory cytokines and alleviate cell and tissue damage in multiple disease states ^[39]^[40]^[41]^[42]. The two natural compounds significantly mitigate the expression of pro-inflammatory mediators (e.g., IL-1α, IL-1β, IL-6, IL-13, IL-17, TNF-α, interferon-γ, MCP-1, and vascular endothelial growth factor) in order to reverse the severity of inflammation-mediated injury ^[42]^[43]. Administration of taurine (100 mM) in Wistar rats 30 days after coronary artery occlusion-induced ischemia significantly decreased myocardial infarct size and reduced expression of IL-6 and TNF-α, suggesting that taurine provides anti-inflammatory cardio-protective effects ^[44]. Understanding the anti-inflammatory targets of taurine and terpenes may provide further evidence of their therapeutic use for CVDs (Figure 2, Table 1), as well as other conditions such as inflammatory bowel disease ^[45], rheumatoid arthritis ^[45], and traumatic brain injury where inflammation is a well-known critical event ^[43].

Figure 2. The anti-inflammatory abilities of taurine and terpenes through modulating NF-κB signaling. Taurine, its metabolites, and the major terpenes present in black pepper may suppress inflammation through preventing NF-κB-mediated proinflammatory cytokine production. The current literature suggests that this occurs through inhibition of upstream kinase signaling pathways, such as receptors of the immune system (i.e., TLR, RAGE, TNFR and IL-6R), MAPK/p38/ERK/JAK-signaling, release of HMGB-1, NF-κB activation, translocation or reducing NF-κB DNA binding ability. Ɑ-humulene may also inhibit proinflammatory cytokine production through downregulation of AP-1 signaling. Abbreviations: AP-1, activator protein-1; BCP, β-caryophyllene; CB₂R, cannabinoid type 2 receptor; ERK, extracellular signal-regulated kinase; HMGB-1, high-mobility group box-1; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; IκKβ, nuclear factor kappa-B kinase subunit beta; IL-6R, interleukin 6 receptor; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation protein 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, phosphorylation; RAGE, receptor for advanced glycation end products; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor. Figure designed with Biorender.com.

2.1. Inflammatory Signaling Pathways

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a central transcription regulator that plays a critical role in the activation of inflammatory responses by inducing transcription of pro-inflammatory genes ^[46]. During basal conditions, NF-κB is bound to the inhibitory protein nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) within the cytosol ^[47]. Upon stimulation, the inhibitor of NF-κB subunit beta (IκKβ) phosphorylates and degrades IκBα, allowing NF-κB dimers p50 and p65 to translocate towards the nucleus where they upregulate the activation of pro-inflammatory genes ^[48]. The phosphorylation of IκBα is triggered by a diverse range of stimuli, including various ligands for IL-6 receptors, TNF receptor (TNFR), and pattern-recognition receptors (PRRs) (e.g., TLR and RAGE) ^[49]^[50]^[51], which can activate kinase-signaling transduction pathways consisting of p38-mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and Janus kinase (JAK) ^[52].

Taurine and terpenes both exert anti-inflammatory effects through inhibition of NF-κB and kinase-signaling pathways ^[53]^[54]^[55]. An increase in taurine metabolites, chloro-taurine (TauCl) and taurine-bromamine (TauBr) have been shown to modulate the myeloid-differentiation factor-88 (MyD88)-dependent TLR/NF-κB inflammatory signaling pathway in both human and mouse macrophages to disrupt the phosphorylation and degradation of IκBα ^[56]^[57], as well as prevent the activation and subsequent translocation of NF-κB ^[56]^[58]. Additionally, taurine can significantly reduce the expression signal transducer and activator of transcription 3 (STAT) 3 in the JAK-STAT signaling pathway ^[44], which is shown to play a vital role in cardio-protection, as inflammation associated with myocardial ischemia is mitigated through inhibition of JAK-STAT3-signaling pathways ^[44]. Black pepper terpenes have also been shown to attenuate pro-inflammatory cytokine expression through downregulation of kinase signaling pathways and inhibition of IκBα phosphorylation ^[44]^[59]. Limonene blocks the phosphorylation of IκBα and NF-κB to suppress lipopolysaccharide (LPS)-induced inflammation in acute lung injury ^[59]. α-pinene has been shown to inhibit IκKβ activation and prevent NF-κB translocation ^[60]. In human chondrocytes, α-pinene (200 µg/mL) suppressed IL-1β-induced inflammation through suppression of NO, iNOS, matrix metallopeptidase (MMP)-1, and IL-13 pro-inflammatory mediators ^[61]. This anti-inflammatory effect was produced by the inhibition of c-Jun N-terminal kinase (JNK) phosphorylation. Additionally, α-pinene has also been shown to attenuate MAPK and NF-κB activation, resulting in the decreased expression of pro-inflammatory factors IL-6, TNF-α, NO, iNOS, and COX-2 ^[44]. The terpenes BCP, α-humulene, and α-pinene have been shown to inhibit the expression of NO synthase and COX-2 through inhibition of MAPK action through IKK-B inhibition ^[38], while limonene was shown to mitigate pro-inflammatory cytokines secretion as well as rescue iNOS, MMP-1, and MMP-3 gene transcription through inhibition of MAPK/JNK-dependent NF-κB activation pathways ^[62]. Pre-treatment with limonene (25, 50 and 75 mg/kg) inhibited release of pro-inflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) and prevented phosphorylation of p38-MAPK, IκBα, NF-κB p65, JNK and ERK in mice with lipopolysaccharide (LPS)-induced acute lung injury ^[59]. Likewise, both α-pinene and β-pinene reduce the expression of genes associated with LPS-induced inflammation ^[63], suggesting that terpenes may mediate anti-inflammatory effects through regulation of kinase and NF-κB gene signaling.

BCP has been identified as a CB₂R agonist ^[64], which is primarily expressed in immune tissues and is known to modulate immune cell function to provide anti-inflammatory effects ^[65]. Exogenous administration of CB₂R agonists is observed to inhibit inflammation by reducing the production of pro-inflammatory cytokines and attenuating oxidative stress in various inflammatory diseases ^[66]^[67]. BCP has been observed to inhibit the activation of NF-κB, thus attenuating the production of inflammatory mediators. Furthermore, this effect disappears with CB₂R^−/− knockout expression, suggesting that BCP exerts its anti-inflammatory responses through activation of CB₂R ^[68]. The cardioprotective effects of BCP on isoproterenol (ISO)-induced myocardial injury in Wister rats through activation of the CB₂R has been observed. BCP modulated MAPK/ERK/JNK/NF-κB signaling to significantly suppress the expression of IL-1β, IL-6, TNF-α, iNOS, and COX-2 ^[69]. Additionally, this comprehensive study reported that BCP also attenuated mitochondrial dysfunction and improved the atherogenic index via a CB₂R-independent reduction in dyslipidemia ^[69]. BCP has been shown to inhibit the expression of vascular cell adhesion molecule-1 ^[70], which is known to promote the adhesion of macrophages to the vascular endothelium in the development of atherogenic plaque ^[71]. These studies suggest that both taurine and terpene extracts present in black pepper may combine to exert effective anti-inflammatory responses and thereby provide beneficial cardioprotective effects in CVDs.

The nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome is a critical component of the innate immune system and is responsible for the production of pro-inflammatory cytokines in response to cellular damage ^[72]. Recently, NLRP3 has been shown to play an indispensable role in the development of vascular diseases, including hypertension, atherosclerosis, and CAD, as well as diabetes and neurological disorders ^[73]. Increasing evidence supports NLRP3 as a new target to inhibit inflammatory diseases ^[74]. NLRP3 is regulated by NF-κB signaling pathways; therefore, taurine and terpenes have the ability to inhibit NF-κB as researchers have previously highlighted a pathway for preventing NLRP3 activation. Although taurine has been shown to attenuate in vitro and ex vivo inflammation through inhibition of NF-κB-dependent NLRP3 activation ^[75]^[76], studies on the isolated effect of black pepper terpenes on inflammasome inhibition are limited. A study conducted on the essential oil of pomelo peel, in which limonene (55.92%) was the most abundant compound, found that it significantly inhibited inflammation mediated by NLRP3 activation in rats ^[77]. Additionally, Makauy leaf ethanol extract consisting of limonene (5.6%) and BCP (4.9%) inhibited the in vitro expression of NLRP3 in J774A.1 mouse macrophage cells stimulated with LPS-induced inflammation ^[78]. Lastly, CB₂R agonist JWH-133 has been shown to produce cardioprotective effects against MI in rats by suppressing NLPR3-related mechanisms, suggesting that BCP, a CB₂R agonist, may also suppress inflammation through NLPR2 inhibition ^[79].

Collectively, these studies highlight the effects that taurine and black pepper terpenes have on inhibiting NF-κB, kinase- and inflammasome-signaling pathways and suppressing the expression of pro-inflammatory mediators. The potential combined use of taurine and terpenes may have synergistic effects in exerting effective anti-inflammatory responses, potentially providing effective treatment of CVDs.

2.2. High-Mobility Group Box-1

HMGB-1 is an evolutionarily preserved, architectural, non-histone chromosome binding peptide that is found abundantly within the nucleus bound to DNA ^[80]^[81]. HMGB-1 facilities nuclear homeostasis by coordinating important nuclear functions, such as maintaining stability of the genome, acting as a chaperone for DNA, and regulating DNA transcription, replication, recombination, and repair ^[80]^[81]. Outside the nucleus, HMGB-1 drives cell stress responses by acting as a dynamic alarmin signal (which can also be referred to as a danger associated molecular pattern (DAMP)) that engages with PRRs of the immune system (e.g., TLR1/2/6, TLR4 and RAGE) to promote inflammation through the canonical NF-κB signaling pathway (discussed above) ^[81]^[82]^[83]^[84]. Elevated levels of HMGB-1 have been demonstrated in animal models of atherosclerosis, hypertension, CAD, MI, and HF ^[84]. Clinical studies have also reported increased HMGB-1 serum levels in patients with CAD ^[85]^[86], peripheral artery ^[87] and HHcy ^[88], suggesting that HMGB-1 has a critical pathogenic role during development and progression of CVDs. While the correlation between taurine and HMGB-1 has yet to be investigated in the literature, a study involving patients with bladder cancer noted elevated levels of taurine upregulate gene 1 (TUG1; long non-coding RNA transcripts that require taurine for gene upregulation) and the reversal of TUG1 knockdown by overexpression of HMGB-1 ^[89], thus suggesting a possible unknown mechanism between taurine, TUG1 and HMGB-1. The role that taurine and BCP have in attenuating HMGB-1-mediated inflammation and dysfunction remains elusive; however, there is evidence to suggest that there may be an unknown interlinking mechanism between taurine and HMGB-1 ^[90]. In mice with HMGB-1 deletion in intestinal epithelial cells, a diet high in fat, cholesterol and fructose increased taurine concentration in serum collected from portal blood samples when compared with wild type controls ^[90].

Moreover, BCP and CB₂R activation may lower HMGB-1, contributing to a reduction in inflammation. CB₂R knockout mice challenged with LPS to induce sepsis displayed reduced survival rate and significantly elevated serum IL-6, TNF-α and HMGB-1 levels when compared with CB₂R expressing littermates ^[91]. Furthermore, treatment with GW405833 (10 mg/kg, a CB₂R agonist) was able to significantly reduce serum levels of TNF-α, IL-6, and HMGB-1 6 h after LPS injection (5 mg/kg) ^[91]. Furthermore, activation of CB₂R with GW405833 has been shown to induce intracellular HMGB-1 degradation via the autophagy-lysosome pathway in macrophages without modulating HMGB-1 mRNA expression ^[92], thus potentially preventing its release into the extracellular milieu where it can engage with immune system receptors and activate pro-inflammatory downstream signalling pathways. BCP’s anti-inflammatory properties may also be due to its ability to reduce HMGB-1 and its endogenous receptors as BCP was able to attenuate increased serum levels of HMGB-1 and suppressed protein expression of TLR4 and RAGE and their downstream inflammatory molecules (i.e., ERK, p38 and JNK phosphorylation, NF-κB, early growth response protein-1, and macrophage inflammatory protein-2 protein) in Kupffer cells from mice with galactosamine and LPS-induced hepatic injury ^[93].

Although the relationship between taurine, terpenes and HMGB1 remains elusive, these findings suggest that targeting HMGB-1-mediated inflammation through a combination of taurine and black pepper terpenes may be a potential mechanism to reduce inflammation associated with CVDs.

2.3. Toll-like Receptors

TLRs are integral to immunity as they provide host surveillance by detecting molecular signatures present on pathogens (referred to as pathogen-associated molecular patterns) and launch mechanisms of inflammation to neutralize and eliminate infection ^[94]. Importantly, TLRs also provide protection against tissue injury in the absence of pathogenic infiltration by identifying DAMPs (e.g., HMGB-1) secreted by damaged, injured, and dying cells ^[94]^[95]. However, unregulated TLR activation results in a vicious cycle of unresolving inflammation and has been demonstrated to be fundamental in the development of CVDs. Thus, they have become a target to attenuate disease development ^[95]^[96]. Specifically, taurine has been shown to suppress inflammation via modulation of the TLR2 and TLR4 ^[97]^[98]^[99] signaling pathways. TLR2 and 4 are able to recognize bacterial cell wall components (e.g., lipopeptides, peptidoglycan and LPS), and stimulation of TLR4 causes receptor homodimerization of the MyD88- and Toll/IL-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-dependent signaling cascade, whereas TLR2 activation requires recruitment of TLR1 or 6 for normal receptor function via the MyD88-dependent pathway ^[100]^[101]. Male Sprague-Dawley rats challenged with LPS (25 mg/kg; TLR4 activating ligand) to induce acute lung injury showed that those which were pre-treated with taurine supplemented drinking water had decreased infiltration and activation of neutrophils and macrophages. Further, they lowered levels of TLR4, MyD88, NF-κB and p65, reduced pro-inflammatory cytokines (IL-6, IL-18) and increased anti-inflammatory cytokines (IL-4, IL-10) in serum and lung tissues of the treated rats ^[97]. Similarly, taurine provides hepatic protection by targeting the TLR4/MyD88/NF-κB pathway in rat models of chronic alcohol-fed ^[98] and thioacetamide-induced ^[99] liver injury, resulting in decreased lymphocyte infiltration and reduced inflammation (TLR4, MyD88, IκB, NF-κB, iNOS, IL-6, IL-1β, and TNF-α). Regarding TLR2, taurine has been shown to reduce neutrophil activation of MAPK signaling following Streptococcus uberis (TLR2 activating ligand) infection ^[102]. A supporting study also showed that pre-treatment of taurine in rat models with Streptococcus uberis mastitis had significantly decreased expression of iNOS and TNF-α, which was associated with the downregulation of TLR2 and NF-κB mRNA expression, as well as inhibition of the DNA binding activity of NF-κB ^[103].

Like taurine, terpenes may also exert anti-inflammatory effects by modulation of the TLR signaling cascade. In LPS activated RBL-2H3 cells (derived from a basophilic leukemia cell line), α-pinene, β-pinene and limonene displayed anti-inflammatory abilities by reducing the expression of genes associated with LPS-mediated inflammation ^[63]. Likewise, α-pinene attenuated activation of the MAPK and NF-κB pathways and reduced production of IL-6, TNF-α, NO, iNOS and COX-2 following LPS stimulated mouse intraperitoneal macrophages ^[104]. However, in human chondrocytes, α-pinene elicited a more potent inhibition of IL-1β-induced inflammation, NF-κB and JNK activation and expression of iNOS compared with β-pinene and limonene ^[61]. Importantly, BCP has been shown to ameliorate ISO-induced (85 mg/kg) MI through modulation of the heat shock protein-60/TLR2/4/MyD88/NF-κB pathway. BCP treatment was able to markedly reduce infarct size, normalized electrocardiogram and blood pressure parameters and significantly reduced protein expression of MyD88, TLR2, TLR4, and TIR-domain-containing adaptor-inducing interferon-β (accessory molecule of TLR signal transduction) and levels of inflammatory markers (i.e., IL-1β and TNF-α) ^[105]. These findings suggest a direct relationship between the anti-inflammatory abilities of terpenes and TLR-mediated pathways involved in CVDs.

These results suggest that combination therapy of taurine and black pepper terpenes may hold therapeutic cardiovascular-protective value for attenuating inflammation through modulation of TLR2 and 4 signaling pathways, which play a significant role in the development of CVDs.

Table 1. Summary of anti-inflammatory effects of taurine and terpenes in cell and animal models.

Compound	Dosage	Experimental Model	Outcome	Ref
α-humulene	50 mg/kg	In vivo LPS-induced inflammation in the paw of Wistar rats	↓ neutrophil migration, ↓ IL-5 ↓ NF-κB DNA binding ↓ IL-1β and TNF-α expression.	^[106]
α-humulene	50 mg/kg, 22 days	In vivo female BALB/c mice	↓ Eosinophil recruitment ↓ NF-κB and activator protein-1 activation	^[107]
α-pinene	50 mg/kg, 7 days	In vivo ISO-induced myocardial inflammation in Wistar albino rats	↓ cardiac injury biomarkers ↓ NF-κB signaling ↓ IL-6 and TNF-α expression	^[108]
BCP	50–200 µg/mL	In vitro Mouse RAW267.4 macrophages	↓ ERK/p38-MAPK signaling ↓ COX-1 and COX-2	^[109]
BCP	(0.2–25 µM)	In vitro LPS-induced inflammation in C57BL/6 mouse microglial cells	↓ IL-1β, TNF-α, PGE2, iNOS expression ↓ ROS inflammatory biomarkers	^[110]
BCP	10 mg/kg	In vivo cisplatin-induced nephropathy in C57BL/6J mice	CB₂R-dependant decrease in MCP-1, IL-1β, TNF-α, ICAM-1, neutrophil and macrophage infiltration	^[111]
Limonene	50 mg/kg, 21 days	In vivo ISO-induced inflammation in male Wister rats	↓ MAPK/JNK/ERK/NF-κB signaling ↓ IL-1β, IL-6, and TNF-α expression	^[112]
Limonene	20, 50, and 100 mg/kg	In vivo gastritis-induced male Sprague-Dawley rats	↓ NF-κB nuclear translocation ↓ intracellular Ca²⁺, IL-1β, IL-6, TNF	^[113]
Sabinene	0.32–1.25 µL/mL, 1 h	In vitro LPS-induced inflammation in mouse Raw 264.7 leukemic macrophage cell line	Strong anti-inflammatory activity through potent NO scavenging and inhibition of iNOS	^[114]
Taurine	100 mM, 30 days	In vivo myocardial ischemia-induced male albino Wister rats	↓ myocardial infarct size ↑ superoxide dismutase ↓ IL-6 and TNF-α expression	^[44]
Taurine	3000 mg/day, 8 weeks	Clinical study of 50 patients with type-2 diabetes	↓ TNF-α ↑ superoxide dismutase ↑ catalase	^[115]

Abbreviations: BCP, β-caryophyllene; Ca²⁺, calcium; CB₂R, cannabinoid 2 receptor; COX, cyclooxygenase; ERK, extracellular signal-regulated kinase; ICAM-1, intercellular adhesion molecule 1; IκKβ, nuclear factor kappa-B kinase subunit beta; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor kappa-light chain enhancer of activated B cells; NO, nitric oxide; PGE2, prostaglandin 2; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; ↑, increase; ↓, decrease.

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