The Role of Medicinal and Aromatic Plants against Obesity and Arthritis: A Review

Obesity is a significant health concern, as it causes a massive cascade of chronic inflammations and multiple morbidities. Rheumatoid arthritis and osteoarthritis are chronic inflammatory conditions and often manifest as comorbidities of obesity. Adipose tissues serve as a reservoir of energy as well as releasing several inflammatory cytokines (including IL-6, IFN-γ, and TNF-α) that stimulate low-grade chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, diabetes, hypertension, cardiovascular disorders, fatty liver disease, oxidative stress, and chronic kidney diseases. Dietary intake, low physical activity, unhealthy lifestyle, smoking, alcohol consumption, and genetic and environmental factors can influence obesity and arthritis. Current arthritis management using modern medicines produces various adverse reactions. Medicinal plants have been a significant part of traditional medicine, and various plants and phytochemicals have shown effectiveness against arthritis and obesity; however, scientifically, this traditional plant-based treatment option needs validation through proper clinical trials and toxicity tests. In addition, essential oils obtained from aromatic plants are being widely used as for complementary therapy (e.g., aromatherapy, smelling, spicing, and consumption with food) against arthritis and obesity; scientific evidence is necessary to support their effectiveness. This review is an attempt to understand the pathophysiological connections between obesity and arthritis, and describes treatment options derived from medicinal, spice, and aromatic plants.


Introduction
Obesity can be characterized as a body mass index (BMI) of 25 or more in adults, who are classified as overweight, or a BMI of 30 or more, classified as obesity [1]. In 2016, around 1.9 billion adults (aged > 18 years) were overweight, but >650 million people were (e.g., transforming growth factor β 2 ), food antigens, and essential microbiota supplements (e.g., non-sterile breast milk contains long-chain polyunsaturated fatty acids (LCPUFAs), which impede the production of proinflammatory cytokines [24][25][26] (Figure 1). Human milk intake in infancy can also protect children against various pathogens, including but not limited to Bordetella pertussis, Campylobacter, Haemophilus, Salmonella, Streptococcus, Shigella, Vibrio cholerae, and respiratory viruses [23,27,28]. Noticeably, formula-fed children show reduced transforming growth factor β 2 compared to breast milk-fed children; instead, they display higher levels of plasma proinflammatory cytokines (e.g., IL-2 and TNF-α) than breast-fed children [29]. Inadequate intake of LCPUFAs in the body/diet can influence the development of obesity and arthritis (Figure 1). Resistin-an adipokine-along with other senescence-associated secretory phenotype factors, regulates glucose metabolism, oxidative stress, inflammatory responses, and autoimmune diseases. [30,31]. High plasma resistin concentrations can increase the possibility of inflammation, insulin resistance, and the aging process [30]. Resistin possibly interacts with TLR-4 receptors, influences the transcription of proinflammatory genes, inflammatory cytokines, and chemokines, and causes osteoclastogenesis via the NF-κB pathway [30]. Sedentary lifestyle and increased calorie intake are related to the progression of adipocyte hypertrophy and low-grade inflammation via the recruitment of antigen-producing cells in adipose tissues [31,32]. Resistin, adiponectin, TNF-α (released by adipocytes), and proinflammatory cytokines (e.g., IL-1β, IL-6) derived from adipokines increase muscle and bone metabolism [30,32]. This biological pathway is responsible for the generation of several chronic diseases, including obesity, diabetes, and arthritis [32].

Osteoarthritis and Inflammation
There are various types of arthritis, and these are multifactorial, with the common features of chronic intense pain and inflammation [33]. Osteoarthritis (OA) is a chronic painful disorder that increases with age and is common in adults aged over 55 years [34]. The mechanisms of OA are not completely understood, but its clinical features include irreversible age-related damage to the joint cartilage, pain, and low-grade inflammation over a period of many years [35]. The pathogenesis of OA can also be caused by cellular stress produced by the activation of endogenous cytosolic proteins such as nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome [36][37][38][39][40], proinflammatory cytokines released by macrophages [41][42][43], or the production of proinflammatory cytokines induced by uric-acid-crystal-induced inflammasome assembly [40]. There is a positive correlation between osteoarthritis (OA) severity, uric acid levels (in synovial fluid), and proinflammatory cytokines (e.g., IL-18, IL-1β) [38,44]. Monosodium uric acid (MSU) can accumulate in joints as crystals when its plasma concentrations exceed its solubility (≥70 mg/L) [45], stimulating the synthesis of different inflammatory cytokines [46]. The inflammatory processes are also triggered by chemokines, proteases, and oxidative materials that cause osteoporosis, cartilage degradation, and inflammation in the synovial joints [44,47]. This process is further exaggerated when toll-like receptors recognize MSU (monosodium urate crystals), and when lymphocytes and macrophages in synovial fluids uptake MSU. These interactions ultimately release various inflammatory cytokines (especially IL-1β, IL-6, TNF-α, and IL-18) via nucleotide-binding domain and the leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome [36][37][38][39][40]. OA is also influenced by calcium-oxalate-containing crystals that stimulate the production of IL-1β, causing cartilage damage [48]. OA is also caused by mutations of genes encoding collagens (e.g., types II, IV, V, and VI) [33,49]. The pathogenesis of OA can cause neuronal damage in joint tissues, causing intense pain, limited mobility, depression, and anxiety in elderly people ( Figure 2) [50,51]. People experiencing OA also often have multiple comorbidities, such as obesity [52][53][54], diabetes [4], cardiovascular diseases [3], cancers [5], and musculoskeletal disorders [2]. Currently, analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to manage OA, but these drugs have no effect on the prevention of OA's pathogenesis, and they are mainly for symptomatic management. In addition, these drugs have adverse effects on the gut, liver, kidneys, and heart [55][56][57][58]. Long-term use of NSAIDs to manage arthritis provides poor pain relief, major discomfort for patients, and can lead to invasive procedures, such as surgeries [59][60][61] (Figure 3). A clinical study showed that paracetamol alone provided insufficient analgesia in OA, but an NSAID such as diclofenac (0.15 g daily) showed noticeable efficacy in OA management [62]. It is also important to note the adverse effects of diclofenac, including gastrointestinal toxicity, liver toxicity, and renal impairment ( Figure 3). Another study reported that celecoxib (an NSAID) caused lower cardiovascular, renal, and gastrointestinal adverse reactions than ibuprofen or naproxen (NSAIDs), which was similar in patients experiencing OA or RA [63]. It is understood that there are significant variations between drugs within a group of drugs (e.g., NSAIDs), and the efficacy of a particular drug may depend on its molecular structure, formulation, route of administration, dosage, and duration of treatment [64]. The bioactivity and efficacy of a drug also depend on its metabolic capabilities (e.g., hepatic or renal impairment, aging-related) and bioavailability at the target site. Importantly, chronic treatment with NSAIDs for OA can result in adverse outcomes and cause adverse events in older adults [65,66]. Opioids are not recommended to manage OA [51,67], but these drugs are widely used in OA-related chronic pain management for older adults, despite their potential adverse effects-such as addiction, dependence, analgesic tolerance, respiratory depression, and behavioral disorders over long-term usages ( Figure 3) [66,[68][69][70][71]. Routes of administration of commonly used drugs for the treatment of OA, and some adverse effects associated with these drugs. Abbreviations-NSAIDs: non-steroidal anti-inflammatory drugs (NSAIDs); mAb: monoclonal antibody. This figure was made with www.biorender.com (accessed on 25 January 2022).

RA and Inflammation
Despite differences in the initiation and progression mechanisms between OA and RA-the latter of which is another type of arthritis that is multifactorial, and whose root causes remain to be elucidated-long-term low-grade inflammation is the common ground in the pathogenesis of obesity, OA, and RA [52][53][54]72]. As with the pathogenesis of OA, RA manifests with increased secretion of proinflammatory cytokines (e.g., IL-1, IL-6, IL-12, IL-17, IL-18, and TNF-α). In parallel, secretion of immunomodulatory cytokines (e.g., IL-10, IL-11, and IL-13) is reduced in the blood, along with stiffness, swollen joints, and impaired movement of the affected person [73][74][75][76] (Figure 1). Defensive cells, such as T helper 1 (Th1) and T helper 17 (Th17) cells, produce an inflammatory response via IL-17A, IFN-γ, and TNF-α, leading to the pathogenesis of RA [77,78]. Toll-like receptors (TLRs) regulate the functions of the nuclear factor kappa B ligand (NF-κB), osteoclastogenesis, and generation of proinflammatory cytokines [79][80][81]. As a result, joint pain, inflamed joints, and damage to cartilage can be seen during clinical symptoms of RA [82]. Inflammatory cytokines such as IL-17 or TNF-α can influence the upregulation of matrix metalloproteinase (MMP) enzymes, which irreversibly damage the extracellular matrix and the cartilage of joints [74,83] (Figure 1). Apart from inflammatory or genetic mechanisms, fat-rich food intake, smoking, and periodontal infections also affect the generation and progression of RA [84,85]. Women are more prone to RA than men. Citrullination of proteins in lung macrophages, along with neuropathic pain and osteoporosis, can potentially influence the pathogenesis of RA [84,[86][87][88].

RA, Gut Dysbiosis, and Inflammation
RA also manifests as a result of excess inflammatory cytokines, with the influence of major changes in the microbial population of the gut. For example, Faecalibacterium spp. are a part of the healthy gut microbiota that is responsible for butyrate production [89][90][91], and helps in the secretion of mucin-a natural lubricator of gut epithelial cells. If the abundance of Faecalibacterium spp. decreases, other opportunistic bacteria such as Collinsella, Eggerthella, Haemophilus, Prevotella, and Streptococcus can grow and produce inflammatory cytokines and/or cause citrullination of proteins, leading to RA [90,92].
Prevotella copri (P. copri) is a part of our normal gut microbiota and oral cavity, and can grow massively with the influence of change in diet, stress, lack of oral hygiene, and microbial infection [85,[93][94][95]. As a result, P. copri can cause increased production of T helper cells (e.g., Th1, Th17) and inflammatory cytokines (e.g., IL-1β, IL-6, IL-17, and IL-23), leading to an inflammatory response in the gut, and can possibly migrate to inflammatory joint tissues [96,97] (Figure 1). Prevotella spp. can produce increased prostaglandin E2 in joint tissues, and has been observed in RA, causing joint pain, inflammation, and bone degradation [98,99] (Figure 1). The simultaneous growth of Porphyromonas gingivalis in the mouth and P. copri in the intestine are noticed in RA patients [100]. P. gingivalis possibly translocates to synovial joints via phagocytosis, causes citrullination of proteins in joints, and increases inflammatory cytokine production [101,102]. Proper management and restoration of healthy gut microbiota by using probiotic supplements as food can reduce the population of Prevotella spp. and increase the gut population of Lactobacillus spp. [95].

Relationships between Obesity and Arthritis
OA and RA are both prevalent in older adults (>55 years), and especially in the elderly with frailty syndromes (e.g., falls, immobility, delirium, incontinence, and adverse effects of medications) [72,103]. Obesity is also a common comorbidity of this population cohort for various reasons, including inactivity, diet, diabetes, and aging [104,105]. Tumor necrosis factor α (TNF-α)-a proinflammatory cytokine-from the adipose tissues of obese animals can cause low-grade inflammation in adipocytes [52,106]. Adipose tissues mainly produce inflammatory biomarkers such as TNF-α, and macrophages and other immune cells are partially responsible for oxidative damage and low-grade inflammation in the body [52,106,107]. NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3)-a polyprotein complex inflammasome found in macrophages-is also responsible for releasing proinflammatory cytokines. NLRP3 is stimulated by the activation of NF-κB (nuclear factor kappa B, which TNF-α stimulates), and causes the secretion of the proinflammatory cytokines pro-IL-1β and pro-IL-18 [108] ( Figure 4). NLRP3 is matured by PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) or lipopolysaccharides. NLRP3 maturation stimulates the release of cytokines (e.g., IL (interleukin)-1β, IL-6, and IL-18) and low-grade inflammation in multiple organs, including joints ( Figure 4) [109]. Clinical studies show strong positive connections between obesity, osteoarthritis, and rheumatoid arthritis [52,53,[110][111][112] (Figure 4). People with a body mass index of >30 kg/m 2 show higher incidence of knee OA than people of normal weight, and it is recommended to reduce weight in order to improve clinical symptoms of OA in obese patients [113,114]. A clinical study showed that obesity was present (33.4%) in RA patients (n = 11,406) at a significantly higher rate than obesity (31.6%) in the control group (n = 54,701) [112]. Obesity causes inflammation and autoimmune conditions in RA patients [112]. Obese RA patients experience more tender joints and swelling in joints than non-obese RA patients [115]. Obesity is a common comorbidity of RA patients, and it also reduces the efficacy of drugs working against TNF-α, but losing body weight improves the success of treatment with these drugs [111]. Importantly, no association with BMI was found in this review with drugs other than anti-TNF-α drugs, such as biologics that act against IL-6, CD4, or CD20 [111]. Studies have reported that the RA patients experience lower grip strength and fatigue (40-80%), and these decrease their strength and their interest in being involved in various physical activities [116,117]. Similarly, a later study showed that patients who also experienced RA displayed fatigue (40%) and anxiety/depression (52%) as comorbidities [118]. Obese RA patients experienced less remission (improvement of symptoms and pain relief) and lower disease activity scores than non-obese (control) RA patients [110]. Van Beers-Tas et al. mentioned that reduced smoking increased arthritis remission, but obesity increased arthritis progression and delayed its remission [119]. Another study on a small number (n = 19) of obese RA patients (aged 55 years on average; range: 34-71) observed that reduction in dietary energy intake and moderate physical exercise led to a 9% reduction in fat mass and improved physical fitness of the participants [120]. Conversely, another study with a comparatively large number (n = 192) of participants (aged 64.5 years on average, range: 50-78) in a similar weightreduction program did not improve structural joint damage, muscle strength, or knee joint alignment, but achieved some benefits in terms of overall health improvement [121]. Noticeably, age was an important factor in the performance of the participants, and there were differences in the measurements of performance, as the previous study measured outcomes such as the capability to ride a bicycle, whereas the later study investigated using MRI and radiographs [120,121]. Collectively, management of obesity may improve the clinical symptoms of obese OA and RA patients.

Current Drugs for the Management of Obesity and Arthritis
A few anti-obesity drugs have now been approved for human use, and most of these show various side effects. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the United States Food and Drug Administration (USFDA) has so far approved five drugs-namely, orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide-to treat obesity [122]. Importantly, the European Medicines Agency (EMA) has approved three drugs to fight symptoms of obesity: orlistat, bupropion/naltrexone, and liraglutide [123]. Orlistat reduces intestinal absorption of fat content from food, as it is a pancreatic lipase inhibitor; side effects of this drug include diarrhea, oily stools, abdominal pain and, less frequently, cholelithiasis, cholestatic hepatitis, and subacute hepatitis [124]. People feel less hungry when using the drug combination phentermine/topiramate, as phentermine decreases one's appetite, while topiramate reduces seizures and migraine headaches. Noticeably, this drug combination can cause serious side effects, including dysgeusia (taste alteration), paresthesia (burning sensation in hands and feet), hypoesthesia (loss of sensation of a body part), attention deficiency, dizziness, constipation, and dry mouth [125]. There are serious safety concerns with respect to the long-term efficacy of anti-obesity medications; the European Medicines Agency refused the approval of phentermine/topiramate, while for lorcaserin, authorization was previously withdrawn for a low overall benefit/risk ratio [126]. Lorcaserin (for the risk of cancer), rimonabant, and sibutramine have been withdrawn from the US market for safety concerns [126,127]. Mitral regurgitation is a serious side effect of lorcaserin, and may lead to other complications, such as increased risk of cardiovascular complications [127,128]. The naltrexone/bupropion drug combination has little effect against obesity individually. Longterm opioid treatment causes various behavioral adverse effects, addiction, and tolerance, but naltrexone-as an opioid antagonist-shows efficacy against dependency on opioids and alcoholic beverages [64,69,122,129]. Patient management using these analgesics should also consider the reduced metabolic capability of people such as the elderly, or people suffering from chronic kidney or liver diseases [70,[130][131][132][133]. Bupropion is used for treating depression and for help with giving up smoking. Individually, these drugs have no or little effect on obesity; used in combination, they form a safe anti-obesity polypharmacy drug with no serious side effects except for nausea [134,135].
Liraglutide-an anti-diabetic drug-works as an anti-obesity drug as well, and shows side-effects such as nausea, diarrhea, abdominal pain, and constipation. Acute pancreatitis and rare thyroid tumors are severe adverse effects that may arise from the use of liraglutide [136].
Rheumatoid arthritis (RA) is currently treated with disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, non-steroidal anti-inflammatory drugs (such as paracetamol, ibuprofen, naproxen, diclofenac, indomethacin, ketoprofen, and meloxicam), Janus kinase (JAK) inhibitors (e.g., baricitinib and upadacitinib), anti-malarial drugs (e.g., hydroxychloroquine and chloroquine), TNF-α inhibitors, and glucocorticoids (e.g., prednisone, hydrocortisone, and dexamethasone). All of these drug types produce severe adverse effects ( Figure 5), limiting their efficacy, and scientists are looking for safe alternative drugs or food supplements for the prevention or cure of RA [95,[137][138][139]. Overall, anti-obesity drugs are effective in reducing body weight, but in consideration of their adverse effect profiles, the only possible alternative to these drugs is bariatric surgery, which also increases the risk of developing alcohol use disorders [140]. Thus, scientists, naturopaths, and traditional medicinal practitioners are investigating some suitable plants that have the ability to reduce weight. A single plant may contain hundreds of secondary metabolites, a few of which may be effective against obesity. Plants are readily available from nature; many plants can be cultivated and extracted to isolate active ingredients for various purposes.

Research Methodology
To select the information on medicinal or aromatic plants for use against obesity and rheumatoid arthritis (RA) for this review, data from recent literature (no time limit used) were gathered from the PubMed, Scopus, and Google Scholar databases. The keywords used for the literature research included the terms obesity, anti-obesity, rheumatoid arthritis, RA, medicinal plant, essential oils, and preclinical and clinical studies.  (Table 1). Curcuma longa has shown anti-inflammatory and anti-arthritic effects in various clinical and preclinical studies. The rhizome of Curcuma longa is traditionally used as a spice in Indian cuisine and for medicines in Ayurveda. The rhizome of this plant is known to be effective against asthma, allergies, rheumatism, liver disorders, and inflammation in Ayurvedic medicines. A recent clinical trial demonstrated that 0.5 g twice daily consumption of Curcuma longa extract (composition: 80% wt/wt aqueous-based extract standardized to turmerosaccharides, and 20% wt/wt curcuminoids) over 12-week period improved symptoms (such as knee pain using both the visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain values) of patients experiencing symptomatic knee osteoarthritis and knee effusion synovitis [151].
Boswellia serrata is known as an Ayurvedic medicine used against rheumatic pain and inflammatory diseases. In recent years, several randomized clinical trials found that the extracts of Boswellia serrata provided relief from arthritis-related pain and stiffness from knee osteoarthritis [155], reduced inflammatory cytokines, and improved Western Ontario and McMaster Universities Osteoarthritis Index and visual analog scale scores [157]. Supplementation of 100 mg of Boswellia serrata extract with 300 mg of hyaluronic acid (1 tab/day for 20 days) improved arthritis-pain-related visual analogue scales (e.g., the American Knee Society Score (AKSS) and visual analogue scale (VAS) for pain) [167]. Curcuma longa (350 mg extract) and Boswellia serrata extract (150 mg) twice daily for 12 weeks also improved OA pain in patients with moderate knee OA using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and visual analogue scale (VAS) [168].  [166] Ginger (rhizomes of Zingiber officinale) improved RA by increasing expression of the forkhead-box-P3 (FoxP3) gene, and by reducing the expression of retinoic-acid-receptorrelated orphan nuclear receptor gamma (RORγt) and T-bet genes [165] (Figure 6). FoxP3 is an essential transcription factor of regulatory T (T-reg) cells, and expression of this factor helps the development and function of T-reg cells [169]. Activation of T-reg cells produces the immunomodulatory cytokines transforming growth factor (TGF)-β and interleukin-10 (IL-10), and reduces inflammation [169]. The transcription factor RORγt is considered to be a major regulator of the differentiation of T helper 17 cells (Th17 cells) and the production of IL-17 family cytokines, which play an essential role in the development of a number of autoimmune disorders, including arthritis. T-bet is an immune cell transcription factor; in dendritic cells, T-bet reportedly regulates the production of the proinflammatory cytokine IL-1α [170]. Cumulatively, the decrease in the expression of these two transcription factor genes can be helpful in ameliorating RA ( Figure 6) [171]. In another study with knee OA patients, 12 weeks of treatment with ginger (750 mg capsule) and ginger supplemented with diclofenac (750 mg capsule with a 50 mg diclofenac tablet) improved OA [163]. Noticeably, no severe adverse effects were recorded in these studies. Importantly, a Tinospora cordifolia-, Zingiber officinale-, and Semecarpus anacardiumcontaining Ayurvedic drug reportedly improved the symptoms of OA [158]. Furthermore, another clinical study over a period of 24 weeks with co-treatment with an Ayurvedic formulation containing mixed extracts of Tinospora cordifolia, Boswellia serrata, Emblica officinalis, and Zingiber officinale, along with glucosamine sulphate (2 g/day) and celecoxib (0.2 g/day), reduced symptoms of knee OA [160]. A three-month treatment with a herbal formulation containing mixtures of powders of Withania somnifera (roots), Boswellia serrata (stem), Curcuma longa (rhizomes), and zinc produced better pain relief and reduced the disability scores of patients with knee OA [172]. Commiphora species of plants have been used in traditional medicine as painkillers and anti-inflammatory agents. In a recent clinical trial, a TCM medicinal formulation containing extracts of Commiphora myrrha (gum resin) and Paeonia lactiflora (root) showed pain relief and no severe adverse effects when given over a period of 12 weeks in people experiencing knee OA [161].
Piper nigrum is traditionally used in many Ayurvedic formulations [166]. The main alkaloid of fruits of this plant is piperine. Daily treatment twice for 4 weeks with herbal capsules containing curcumin (300 mg), gingerols (7.5 mg), and piperine (3.75 mg) reduced the prostaglandin E2 levels in people experiencing chronic knee OA [166]. Another plant-Typhonium trilobatum (L.) Schott (Ghatkul, Ghetkun)-is known to have antiarthritic and anti-rheumatic effects (leaf and whole plant, respectively). A preclinical study confirmed that the plant showed anti-inflammatory and analgesic effects, but the study needs further evidence from actual clinical trials [173,174]. It can be concluded that various trials have shown the efficacy of a number of Ayurvedic and other traditional medicinal formulations in the treatment of arthritis; however, more clinical trials are necessary, as there are various discrepancies between the settings of clinical trials, such as the population sizes, types of patients, methodologies, and duration of treatment. Using modern formulations, such as implementation of nanotechnology-based formulations, would increase the bioavailability of some of these phytochemicals (such as curcumin), as shown in experimental studies [175,176].

Essential Oils for Use against Arthritis and Obesity
Apart from the intake of traditional medicines, massages and complementary therapies using essential oils are also claimed by traditional medicinal practitioners (TMPs) to improve the symptoms of various diseases-especially from arthritis or chronic pain. These beliefs stem from the practices and customs learned in various human societies over hundreds or thousands of years, and oral passage of the knowledge gained from generation to generation before the arrival of writing and record keeping on clay tablets, papyrus, or paper [353]. Essential oils are volatile aromatic oils isolated from flowers, barks, leaves, and other parts of specific plants. Many of these oils have antimicrobial, emollient, palatable, and lipophilic permeability through the skin. Essential oils give people a good feeling at spiritual, physical (via massaging), and olfactory levels. The efficacy of these oils against chronic arthritic pain is yet to be established. Some preliminary clinical trials with a few essential oils have shown some benefits against arthritis, but their efficacy over a long period of time is unknown (Table 3). In our search of the PubMed search engine, we found four randomized clinical trials (Table 3) of essential oil therapy. Out of these four trials, aromatherapy with essential oils was used in two studies, whereas oral or gargling administrations were used in the other two trials [354][355][356][357]. A recent systematic review reported that essential oils have been used to treat RA, mainly with a small number of subjects for a short duration of observation (2-12 weeks), and mostly with women (60-100%) [358]. The typical oil used for aromatherapy to treat RA was lavender, ginger, or rosemary oil, and a single study showed efficacy against RA [358]. Table 3. Essential oils used to treat RA in randomized clinical trials (RCTs).

Oil Type Key Findings Reference
Evening primrose oil Patients with RA (n = 40 total) and NSAID-induced GI lesions treated with γ-linolenic acid 540 mg/day (evening primrose oil 6 g/day) for 3 months slightly improved RA-related morning stiffness. [355] Lavender oil Aromatherapy with lavender oil improved arthritic pain (against placebo) in patients (n = 30 each group) with knee osteoarthritis, but no proof of its long-term efficacy. [356] Lavender oil Aromatherapy with lavender oil improved daily routine activities of patients (n = 30 each group) with knee osteoarthritis (against placebo), but no proof of its long-term efficacy. [357] Mouthwash with essential oils and curcumin Gargling with mouthwash containing essential oils and curcumin (MEC) over 6 weeks reduced periodontal disease and RA-related parameters (n = 15 each group) [354] The efficacy of essential oils in anti-obesity trials has been mostly based on in vitro experimental and preclinical studies (Table 4). Essential oils from various plants, flowers, leaves, and roots have been experimentally proven to be effective against obesity based on their anti-inflammatory effects in mice or rats via a common mechanism sharing the pathogenesis of obesity, OA, and RA (Figures 1 and 2). Oral consumption of ginger or garlic oils, inhalation of certain species of lavender oil, or injections of certain citrus essential oils have been shown to result in reductions in body weight, lipid profile, fatty liver disease, and arthritis (Table 4 and references therein). Table 4. Essential oils used to treat obesity and arthritis in preclinical trials.

Essential Oil Key Findings Reference
Garlic essential oil Daily consumption of garlic essential oil (25, 50, and 100 mg/kg) or diallyl disulfide (10 and 20 mg/kg) for 12 weeks in C57BL/6J mice prevented the development of non-alcoholic fatty liver disease. The oil and its major compound also significantly prevented the release of proinflammatory cytokines from murine livers. [359] Ginger essential oil Ginger essential oil (28 mg/kg/day i.p. for 4 weeks) treatment improved joint inflammation caused by streptococcal cell-wall-induced arthritis in female Lewis rats. [351] Pogostemon cablin Benth. or patchouli essential oil Inhalation of the oil reduced food intake, systolic blood pressure, and plasma low-density lipoprotein cholesterol levels in SD rats. [360] Rhaponticum acaule (L.) DC.

Medicinal Plants Used to Treat Obesity and Arthritis
Various plant materials produced better results in terms of anti-obesity and antiinflammatory properties compared to their respective placebo or control groups, as observed in various clinical studies. All of these plants are indispensable parts of different traditional and complementary medicines, and recently, in various randomized clinical trials, they have shown some promising results against obesity and/or arthritis (Table 5).

Material Key Findings Reference
Nigella sativa oil Daily consumption of capsules with oil (2 mg/day over a period of 8 weeks) improved HDL-C and lowered LDL-C and TC/HDL-C ratio compared to placebo in obese and overweight women. [367] Nigella sativa oil Patients were given a low-calorie diet supplemented with Nigella sativa oil (3 g/day for 8 weeks) (n = 45 each group), which reduced TNF-α and hepatic C-reactive protein levels, but no changes were observed in plasma IL-6 levels in obese (BMI: 30-35 kg/m 2 ) women aged 25-50 years old. [368] Opuntia ficus-indica Natural fiber complex (litramine) was 3 g/day with a low-calorie diet for 12 weeks, which reduced body weight compared to placebo in obese women (total n = 133) [369] Camellia sinensis Green tea (n = 32; 1 g of dry green tea extract in capsule/day) reduced total cholesterol (TC) and LDL-C after 12 weeks of treatment in non-diabetic obese women. [370]

Crocus sativus
Saffron reduced hyperglycaemia and hyperlipidaemia and improved liver function in patients with type 2 diabetes in an 8-week randomized clinical trial. [371] Laminaria digitata (brown seaweed) Treatment with sodium alginate from Laminaria digitata over a period of 10 days showed no effects in an anti-obesity related trial. [372] Lycium barbarum (fruit juice) A single-day bolus drink increased metabolic rate; 120 mL of fruit juice per day for 2 weeks reduced waist circumference in overweight men and women (n = 15, BMI = 29, age = 34 years). [373]

Allium sativum
Consumption of 1.6 g of garlic powder (4 × 400 mg tablets daily, for 12 weeks) produced significant decreases in waist circumference and body fat percentage in patients with non-alcoholic fatty liver disease (n = 45). [374] Allium cepa Onion powder (9 g per day for 12 weeks) did not cause any major changes between groups. [375]

Persea americana
Avocados are a natural source of lutein. Daily oral consumption of 300 mg/day of ASU-E (Avocado-Soybean Unsaponifiables, Expanscience-a formula with a 1:3 ratio of avocado: soybean oil) for 3 years did not cause any changes in joint space width loss compared to the placebo group. [376]

Momordica charantia
Oral consumption of Momordica charantia (3 × 500 mg per capsule daily for 3 months) taken thrice daily reduced body weight, body mass index, fasting blood glucose levels, and Knee Injury and Osteoarthritis Outcome scores. [377]
Metabolic syndrome (MetS) is a combination of obesity along with high blood pressure and diabetes; obesity can be a driving factor behind the occurrence of MetS. It is said that around one-quarter of the world's adult population now suffers from MetS. There are conventional drugs for the treatment of obesity, such as orlistat or semaglutide, but these drugs either have adverse effects or are not affordable to the general obese people of low-income countries (LICs) and low-middle-income countries (LMICs) [398]. To reduce obesity, the common, illiterate people, with less means to afford expensive conventional drugs, mostly rely on TMPs, who treat obesity, cardiovascular disorders, and diabetes with medicinal plants. A recent survey lists 16 plants/plant parts used in South Africa for weight loss [398]. These plants include leaves of Aloe vera Mill., Rosmarinus officinalis L., and Moringa oleifera Lam.
Over 20 plants used to reduce obesity were listed in a review published in 2013; the authors concluded that among the significant anti-obesity plants were Cissus quandrangularis L., Asparagus officinalis L., and Zingiber officinale Roscoe [399]. Another review listed Curcuma longa L. rhizomes (active ingredient curcumin) and leaves of Salvia officinalis L. (active ingredient: carnosic acid) as anti-obesity plant parts [400]. Obesity as a disorder has been recognized in Ayurveda-the ancient medical treatise of India-where it is described as "meda". Some Ayurvedic plants/plant parts used to treat obesity in India include the fruits of Garcinia cambogia L. (active ingredient: (-)-hydroxycitric acid), Cyperus rotundus L. rhizomes (active ingredient: cyperine), the roots of Embelia ribes Burm.f., whole plants of Boerhaavia diffusa L., seeds of Achyranthes aspera L., and roots of Withania somnifera (L.) Dunal. [401]. Table 6. Role of flavonoids against obesity and arthritis (preclinical and clinical studies).

Flavonoid's Name Role against Obesity or Arthritis Reference
Apigenin RA was induced by 0.1 mL Freund's complete adjuvant (FCA) injections in the palmar surface of paws of Sprague-Dawley (SD) rats. Apigenin suppressed the expressions of P2X7/NF-κB signaling and associated RA-related inflammatory reactions (e.g., reduced IL-1β, Il-6 and TNF-α) [388] Apigenin RA was induced in a murine collagen-induced arthritis (CIA) model. Apigenin inhibited CIA by repressing synovial hyperplasia (by reducing the multiplication of fibroblast-like synoviocytes), causing the growth of new blood vessels and osteoclastogenesis. [389]

Cyanidin
The effects of cyanidin-3-O-glucoside were investigated in a murine high-fat-diet-induced non-alcoholic fatty liver disease (NAFLD) model. Treatment with this flavone reduced NLRP3 inflammasome activation, oxidative stress, and steatosis in mice.

Flavonoid's Name Role against Obesity or Arthritis Reference
Over a period of 3 days, 300 mg of EGCG drink increased postprandial fat oxidation in obese men similarly to 200 mg of caffeine, but the effect was not observed with 600 mg of EGCG drink. Limitation: total n = 10, pilot study. [391] (-)-Epigallocatechin-3-O-gallate (EGCG) Consumption of EGCG and resveratrol (282 mg and 80 mg/day over a period of 12-week accordingly) increased oxidative capacity in permeabilized muscle fibers, but showed reduced plasma triacylglycerol concentration in a high-fat mixed-meal assay in obese men (n = 18). [392] Genistein Consumption of 15 g of genistein for 3 months (5 days of daily administration per week plus 2 days without treatment) in adult patients (53% men) reduced blood glucose and malondialdehyde levels, but did not impact on lipid profile. [393] Kaempferol Treatment with 200 mg/kg of kaempferol (over eight weeks) with a high-fat diet in C57BL/6 mice reduced the increases in body and liver weight, serum cholesterol, and triglyceride levels [394] Luteolin Luteolin increased the expression of liver X receptor (LXR)-α (in vitro). Luteolin (0.05% w/w in high fat diet) reduced plasma cholesterol and lowand very-low-density lipoprotein cholesterols in male C57BL/6 mice. [395] Puerarin Obese women with polycystic ovary syndrome (PCOS) took 150 mg/d of puerarin tablets for 3 months in addition to their standard treatment, and showed decreased total cholesterol and systolic blood pressure compared with their pre-treatment levels. [396] Quercetin Quercetin (500 mg/day for 8 weeks) reduced RA symptoms (based on an assessment questionnaire) and high-sensitivity tumor necrosis factor α (hs-TNF-α) in women with RA. [397]

Conclusions
Some natural anti-obesity agents have been described from dietary sources. These include flavonoids from Citrus depressa Hayata, anthocyanins from Vaccinium ashei Rehder and Morus australis Poir., and gingerol, paradol, and shogaol from Zingiber officinale Roscoe [402]. It is evident from several clinical and preclinical trials that essential oils or extracts from aromatic and medicinal plants demonstrate potential therapeutic value against obesity and arthritis (Tables 1-5). These plants and phytochemicals should be considered as functional foods rather than therapeutics, and warrant further extensive clinical studies for dosage and safety determinations for chronic conditions. Importantly, traditional medicines have been used as medicines and foods since prehistoric times. A number of these plant materials (e.g., flavonoids) are used almost every day as a part of our foods, drinks, or spices, and their consumption as medications or therapeutic supplements can help people to avoid the severity of obesity or arthritis ( Table 6). The famous Greek physician Hippocrates in 440 BC stated "Let food be thy medicine, and let medicine be thy food", which is still applicable today. Whether knowingly or unknowingly, human beings do consume at least some bioactive compounds with their daily diet. Traditional medicinal doctors and even scientists recommend that certain foods are beneficial during certain dis-eases. Although the daily intake of plants containing requisite phytochemicals for a given disorder is also recommended by the authors (Tables 1, 3, 5 and 6), we would like to point out that such intake should have scientific evidence behind it, including determination of dosage, frequency of eating, toxicity, and any adverse reactions when taken alone or with other foods. We need to take a closer look at the dietary factors that influence obesity and other inflammatory diseases, obesity and the development of metabolic syndrome, and obesity itself. From this viewpoint, flavonoids such as quercetin, genistein, apigenin, and cyanidin deserve a closer look [403].