Abstract
Globally, herbal medicines and their extracts or several herbal constituents have been in use since time immemorial. Nowadays, several developments in the field of technology exist, which involves improvement in use of analytical tools, genome studies, and various engineering-oriented strategies, and advances in microbial culturing, etc., are opening up new opportunities in the field of research regarding herbal medicines. Numerous studies have been carried out on commercial scale for the verification of therapeutic efficacy of the production of plant-based medicines. In this chapter, a brief description will be provided about therapeutic importance of some common natural compounds, viz., garlic, Aloe vera, Smilax, meadow saffron, asparagus, and lily of the valley, and their subjection for clinical trials. Clinical trials have examined and reported beneficial impacts of these natural compounds on conditions like cardiovascular disorders, prevention of cancer, and cure as anti-hyperglycemic and anti-hypercholesterolemic agents for anti-inflammatory and several other diseases. Hence, the prime focus of this chapter is identification and significant study of commonly used Indian medicinal plants that have their origin in India and few neighboring countries based on a complete research investigation of traditional books and number of national and international research articles.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Herbal medicines
- Clinical trials
- Research investigation
- Technology
- Therapeutic properties
- Garlic
- Aloe vera
- Smilax
- Meadow saffron
- Asparagus
- Lily of the valley
1 Introduction
Nature is source of variety of medicinal products from the very ancient time, with numerous varieties of drugs useful for the mankind and directly produced from the plant sources. One particularly strong application of Penicillin’s discovery, together with the fact that many medications come from microorganisms, etc. In the late 1980s, combinatorial chemistry diverted the focus of efforts of drug discovery directly from nature to the bench of laboratories, which was further subjected for clinical trials.
However, natural compounds also face several kinds of challenges in the discovery of new drugs, viz., barriers of technical screening, isolation of new compounds, and characterization and optimization of the same, which has directly contributed to rejection in their quest by the pharmacy industries since the early 1990s till now. Nowadays, several developments in the field of technology exist, which involves improvement in use of analytical tools, genome studies, and various engineering-oriented strategies, and advances in microbial culturing, etc., are opening up new opportunities in the field of research.
New drug discovery with the use of natural products is a very demanding task in the field of research for the designing of new compound leads. It provides description of the bioactive compounds originating from natural resources, analysis on the basis of presence of phytochemicals, and their categorization and investigation on the basis of therapeutic evidence, because this is the base with which any drug is subjected for clinical trials.
This chapter provides a brief description about some common natural products and also reviews clinical trials performed on these natural products. The possible mechanisms of action for the practical impact of the following natural compounds are also described.
1.1 Garlic
Garlic (Allium sativum) is an aromatic yearly herbaceous spice and one of the most seasoned and authenticated herbs that have been used since ancient times. It belongs to Amaryllidaceae family [1, 2]. Garlic is utilized as a remedy for numerous common maladies because of hundreds of phytochemicals present in it [2]. Reportedly it includes sulfur-containing compounds such as ajoenes (E-ajoene, Z-ajoene), thiosulfinates (allicin), vinyldithiins (2-vinyl-(4H)-1,3-dithiin; 3-vinyl-(4H)-1,2-dithiin), sulfides (diallyl disulfide [DADS], diallyl trisulfide [DATS]), and others, which account for 82% of the total garlic sulfur content [3].
Garlic has solid antioxidant properties due to its dietary and phenolic compounds. An orderly survey and meta-analysis of 12 randomized controlled trials (RCTs) uncovered noteworthy increments in serum antioxidant capacity and superoxide dismutase levels and diminished serum malondialdehyde levels as a result of garlic (Allium sativum) supplementation (80–4000 mg/day for 2–24 weeks) [2]. Garlic extract was found to increase the activities of some antioxidant enzymes (e.g., superoxide dismutase [SOD]) and decrease glutathione peroxidase (GSH-Px) in rat liver tissues. Notably, several reports indicated that aged garlic extract (AGE) rich in flavonoids, phenol, and different sulfur compounds, e.g., S-ally-(L)-cysteine (SAC), shows high radical scavenging activity [4]. Although experimental studies have shown a clear hypoglycemic effect of garlic, the effect of garlic on human blood glucose remains controversial. Garlic significantly lowered total cholesterol and low-density lipoprotein (LDL) cholesterol and moderately increased high-density lipoprotein (HDL) cholesterol compared to placebo in diabetic patients [5]. In a double-blind clinical trial (N = 38), a combination of nettle leaves (20% w/w), onion and garlic (20%), fenugreek seeds (20%), walnut leaves (20%), cinnamon bark (10%), and berry leaf (10%) powder effectively controlled type 2 diabetes in human subjects [6]. Aged garlic extract (2400 mg/day orally) reduced volumes of low attenuation but not total fibrous or fibro fatty plaque in the coronary arteries of patients with diabetes mellitus (N = 80) compared with placebo [7]. Crushed raw garlic (100 mg/kg twice daily for 4 weeks) reduced waist circumference, systolic and diastolic blood pressure, triglycerides, and fasting blood glucose, and increased serum HDL cholesterol in patients with metabolic syndrome [8]. In an open-label phase 1 trial, a combination of A. sativum, Aloe vera, Nigella sativa, Plantago psyllium, Silybum marianum, and Trigonella foenum-graecum reduced fasting blood glucose, HbA1, LDL, and triglycerides in patients with hyperlipidemia and hyperglycemia with advanced type 2 diabetes [9].
Garlic and its preparations are widely known as agents for the prevention and treatment of cardiovascular diseases. Extensive scientific literature supports the suggestion that garlic consumption has significant effects on lowering blood pressure, preventing atherosclerosis, reducing cholesterol and triglycerides, inhibiting platelet aggregation, and increasing fibrinolytic activity [25]. In a randomized controlled trial (N = 104), taking aged garlic extract (2400 mg daily for 1 year) slowed the development of coronary artery calcification and progression to coronary atherosclerosis, with a significant decrease in systolic blood pressure, in cardiovascular disease patients [10]; also, aged garlic extract decreased the cardio-ankle vascular index, a measure of endothelial function and arterial stiffness, over a three-month period in subjects with type 2 diabetes mellitus (N = 65) [11]. In a randomized, placebo-controlled study, black garlic, given for 6 months, improved heart function, as measured by walking distance, left ventricular ejection fraction (LVEF), and quality of life, in patients with coronary artery disease [12]. The preventive effect of garlic on atherosclerosis has been attributed to its ability to reduce the lipid content in the arterial membrane. Allicin, S-allyl cysteine, present in aged garlic extract and diallyl disulfide, present in garlic oil, are the active compounds responsible for the anti-atherosclerotic effect [13].
Many in vitro and in vivo studies are done to know the cancer-preventive effects of garlic preparations and their respective components. It is apparent that garlic contains a large number of potent bioactive compounds with anticancer properties, largely derived from allyl sulfide. Different garlic derivatives have been reported to modulate an increasing number of molecular mechanisms in carcinogenesis, such as DNA adduct formation, mutagenesis, free radical scavenging, cell proliferation and differentiation, as well as angiogenesis [14]. A matched case-control study in a hospital was conducted to explore the association between dietary Allium consumption and breast cancer risk among Iranian women and it shows that high consumption of certain Allium vegetables, particularly garlic and leek, can reduce the risk of breast cancer [15]. In rodents, garlic and its components have been reported to inhibit the development of chemically induced tumors in the liver, thus showing tumor cell growth inhibition and chemopreventive effects [16, 17]. It diminishes the tumor cell growth in the prostate, bladder, and stomach [18,19,20].
Extracts of garlic and its related phytochemicals have anti-inflammatory potential also. One study reported that garlic extracts markedly affected liver inflammation and damage caused by Eimeria papillata infections [21], and a meta-analysis of ten trials and one observational study found that garlic intake of 2–2.4 g/day for four weeks or longer decreased levels of the inflammatory mediators tumor necrosis factor-alpha (TNF-α), highly sensitive C-reactive protein (CRP), and interleukin (IL)-6, supporting the use of garlic as an adjuvant treatment for metabolic diseases [22]. The anti-inflammatory activity of garlic is caused by the inhibition of the emigration of neutrophilic granulocytes in the epithelia. Aged black garlic (ABG) has shown potent antioxidant activities and these activities may be responsible for its anti-inflammatory activity [23, 24].
1.2 Aloe vera
Aloe barbadensis Miller commonly known as Aloe vera is the most popular natural product in the prevention and ailment of various health problems and maladies. It belongs to the family Asphodelaceae (Liliaceae). It is native to subtropical regions and tropical climates. There are more than 400 species of Aloe belonging to family Liliaceae. The main characteristic of the A. vera plant is its high water content, which ranges between 99 and 99.5% [26]. The remaining 0.5–1.0% solid material contains over 75 different potentially active compounds, including water-soluble and fat-soluble vitamins, minerals, enzymes, simple/complex polysaccharides, phenolic compounds, and organic acids [27]. Distinctive mechanisms have been proposed for the wound-healing effects of Aloe vera. Glucomannan, a polysaccharide rich in mannose, and gibberellin, a growth hormone, interact with growth factor receptors on fibroblasts, stimulating their activity and proliferation, which in turn significantly increases collagen synthesis after topical and oral Aloe vera [28]. A study revealed that Aloe vera-based and chitosan-based hydrogel gels exhibited wound-healing effects and high biocompatibility with seeded mesenchymal stem cells used for healing grade II burns in rats [50]. In a randomized controlled clinical trial, a polyherbal cathartic capsule of Shou Hui Tong Bian, containing Polygonum multiflorum and Aloe vera, improved arthroscopy, replacement efficacy, recovery time, time to postoperative exhaustion of borborygmus, and abdominal distention in postoperative patients (N = 98) after joint replacement arthroscopy compared to conventional treatment [29]. In a meta-analysis (23 studies, N = 4023), the authors conclude that Aloe vera may have beneficial effects in reducing pain scores and the severity of mucocutaneous conditions, such as psoriasis, burns, and wound healing, compared to placebo [30]. Abbasi reported that in a double-blind RCT of 28 patients, use of a topical skin ointment containing Aloe vera, honey, and peppermint as a dressing for skin graft donor sites was superior to petroleum jelly in reducing wound erythema and improved treatment satisfaction [31]. In a clinical study, to verify the effectiveness of A. vera gel compared to silver sulfadiazine 1% cream as a burn dressing for the treatment of superficial and partial burns, burn wound healing was significantly earlier in patients treated with A. vera than patients treated with 1% silver sulfadiazine [32]. Polysaccharides isolated from A. vera induce matrix metallopeptidase (MMP)-3 and metallopeptidase inhibitor-2 gene expression during rat skin wound repair, which directly helps regulate the wound-healing activity of A. vera gel in rats [33]. Aloe vera enhanced the efficacy of topical human vascular endothelial cell transplantation on excised full-thickness skin wounds in diabetic mice in improving angiogenesis in part by improving glycemic control. Oral administration also promoted wound healing through inhibition of MMP-2 and MMP-9 expression [45].
Clinical studies have suggested that A. vera gel may act as a safe anti-hyperglycemic and anti-hypercholesterolemic agent for patients with type 2 diabetes without any significant effects on other normal blood lipid levels or liver or kidney function [34]. A polyherbal formulation, including Aloe vera, was tested in an open-label phase I trial in 30 patients who had hyperlipidemia and hyperglycemia [35]. The formulation was found to be safe and effective in lowering blood glucose and serum lipid levels in patients with type 2 diabetes [9]. In a randomized controlled trial, A. vera gel complex reduced body weight, body fat mass, and insulin resistance in obese prediabetics and untreated early diabetic patients [36]. Jain et al. found that A. vera gel has significant antidiabetic and cardioprotective activity because it significantly reduces oxidative stress in streptozocin-induced diabetic rats and improves antioxidant status [37]. A. vera also showed improvement in the function of isolated rat pancreatic islets in which it increased islet cell survival, their mitochondrial activity, and insulin levels while reducing the production of reactive oxygen species [38].
Aloin, a natural compound anthraquinone and the main component of Aloe vera, has been documented for its momentous potential therapeutic options in cancer, showing chemotherapeutic effects against 1,2-dimethylhydrazine induced by pre-neoplastic lesions within the colon of Wistar rats [39]. In recent studies, a polysaccharide moiety has been shown to inhibit the binding of benzopyrene to primary rat hepatocytes, thereby preventing the formation of potentially carcinogenic benzopyrene-DNA adducts. An induction of glutathione S-transferase and an inhibition of the tumor-promoting effects of phorbol myristic acetate were also reported, suggesting a possible benefit of using Aloe gel in cancer chemoprevention [40, 41].
A. vera leaf extricates have been advanced for digestion and are utilized within the treatment of peptic ulcer for cytoprotective activity whereby A. vera gel expresses antibacterial properties against both susceptible and resistant Helicobacter pylori strains and acts as a novel effective natural agent for combination with antibiotics for the treatment of H. pylori gastric infection [42]. One study illustrated that newly designed Aloe- and myrrh-based gels demonstrated to be effective in the topical application of minor recurrent aphthous stomatitis and was prevalent in diminishing ulcer size, erythema, and exudation; myrrh resulted in greater pain reduction in a randomized, double-blind, vehicle-controlled study [43]. Local application of Aloe vera/Plantago major gel in addition to routine care was evaluated in patients with diabetic foot ulcer. Patients in the experimental group demonstrated significantly reduced ulcer surface and total ulcer score, but not ulcer depth [44]. Acetyl polysaccharides from Aloe vera leaf gel showed antioxidant and anti-inflammatory effects against ulcerative colitis in rat serum and colon tissue by attenuating colon lesions and increasing short-chain fatty acids likely via upregulation of Zonula occludens-1 (ZO-1), occludin, NAD(P)H Quinone Dehydrogenase 1 (NQO1), and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathways [47].
Several studies have been conducted to test the antioxidant property of A. vera. Oral administration of Aloe vera leaf gel showed anti-inflammatory and antimicrobial effects against parasitic cryptosporidiosis in immunocompetent and immunosuppressed mice with dexamethasone by reducing the levels of interferon-gamma (IFN-γ), IL-4, IL-6, and IL-17, and a reduction in Cryptosporidium DNA or oocysts in stool samples compared to nitazoxanide [46]. Oral administration of a proprietary Aloe vera gel formula normalized pro-inflammatory and anti-inflammatory cytokines and increased relative abundance of Bacteroides, Butyricimonas, Ruminococcus, and Mucispirillum in diabetic mice induced by a high-fat diet [48]. Applying Aloe vera gel to experimentally induced penile fractures in rats without closing the sutures reduced the degree of inflammation in the area [49]. Compared with control, a new wound dressing composed of alginate and Aloe vera gel and cross-linked with zinc ions exhibited anti-inflammatory activity, stimulated angiogenesis in the proliferative phase, increased type I collagen fibers, and decreased type III collagen fibers in rats compared to control [51]. Aloe vera gel improved lipid peroxidation and oxidative stress, reduced creatine phosphokinase MB (CK-MB) enzymatic activities and glutathione concentration, increased antioxidant activities, reduced inflammatory cell infiltration, and prevented left ventricular fibrosis in rats with isoprenaline-induced myocardial infarction [52].
In rats exposed to cartap and malathion, pretreatment with aqueous extract of Aloe vera demonstrated marked hepatoprotective effects by reducing the oxidative stress induced by pesticides [53]. Pretreatment with 30 mg/kg Aloe vera attenuated liver injury with ischemia and reperfusion in a small rat study as evidenced by decreased levels of malondialdehyde (MDA) in liver tissue, higher levels of SOD, catalase (CAT), and GSH-Px, and decreased pathological tissue change and immune activity score in the inducible nitric oxide synthase (iNOS) system compared to the control group [54]. Jung et al. found that in a rat model of thioacetamide-induced hepatic retinopathy, aloin suppressed liver damage and swelling of Müller cells through normalization of Kir4.1 and aquaporin-4 channels. The results indicate that aloin may be useful in protecting retinal damage associated with liver failure [55].
1.3 Smilax
Smilax ornata, genus of flowers inside the family Smilacaceae (Liliaceae), commonly called as sarsaparilla, includes approximately 300 species of woody or herbaceous vines, variously called catbriers and greenbriers. It is mainly found in temperate, tropical, and subtropical zones worldwide. The roots of that flora had been used for hundreds of years in Asia and the Americas as a tonic, diuretic, and sudorific. The rhizome, roots, stems, and leaves of sarsaparilla are utilized in traditional medicine [58]. In recent years, interest in the study of the genus Smilax has increased. The study of the genus Smilax has drawn more attention recently. Reviews exist about the antioxidant properties described as a 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenger. The phenolic chemicals stilbenes, flavones, flavanones, flavonols, smilasides, smiglasides, and helionosides are responsible for this affiliation [66].
Smilax glabra showed protective effects against lead-induced renal oxidative stress, inflammation, and apoptosis in weaning rats and human embryonic kidney-293 (HEK-293) cells. Hence, it is a natural antioxidant and anti-inflammatory agent for the treatment of lead-induced nephrotoxicity [56]. Astilbin at 5.3 mg/kg reduced joint damage in the hind paw of complete Freund’s adjuvant (CFA)-induced arthritic rats. Astilbin exhibited remarkable inhibitory effects on TNF-α, IL-1β, and IL-6 mRNA expressions and these effects showed inhibition of cytokine production and inflammatory response in test mice close to anti-rheumatic drug, leflunomide [61]. The methanol extract of Smilax 400 mg/kg claimed to produce anti-inflammatory activity in the bradykinin-prompted and prostaglandin-induced edema models [65].
Kwon et al. suggested a novel molecular mechanism for water extract of Gleditsia sinensis thorns (WESGR)-mediated anti-prostate cancer effects at particular steps such as with migration and adhesion to collagen, and it could provide the possibility of therapeutic utilization of WESGR against prostate cancer progression [57]. She et al. observed that the supernatant of water-soluble extract from Smilax glabra Roxb. (SGR) should enhance adhesion, inhibit migration and invasion of HepG2, M.D. Anderson - Metastatic Breast 231 (MDA-MB-231), and T24 cells in vitro, as well as diminish metastasis of MDA-MB-231 cells in vivo. Outcomes of F-actin and vinculin dual staining showed the improved focal adhesion in SW-dealt-with cells. Microarray evaluation indicated a repression of transforming growth factor-beta (TGF-β1) signaling by means of SW remedy, which became verified by real-time reverse transcription-polymerase chain reaction (RT-PCR) of TGF-β1-associated genes and immunoblotting of transforming growth factor beta receptor I (TGFBR1) protein [60]. Song et al. observed the growth inhibitory action of Smilax by treatment of its water-soluble extract 3.5 μg/μL on multiple cancer cells in vitro and in vivo, and redox-dependent persistent activation of extracellular signal-regulated kinase 1 (ERK1/2) [62]. Another study revealed that SGR inhibited growth of human breast cancer mobile line Michigan Cancer Foundation-7 (MCF7), colon carcinoma mobile line human colorectal adenocarcinoma cell line (HT-29), and gastric cancer cellular line human gastric cancer cell line (BGC-823) in a dose-structured way [63].
Huang et al. obtained total flavonoids (which include four marker compounds) of S. glabra, and the full content became as much as 55.6%. The consequences recommended that total flavonoids of S. glabra (TFSG) has huge effect on reducing uric acid in hyperuricemic mice by means of inhibiting the xanthine oxidase (XOD) sports and upregulating the expression of renal organic anion transporter 1 (OAT1) and organic cation transporter novel family member 2 (OCTN2) and their mRNA in kidney tissue of hyperuricemic mice [59].
A study revealed that SGR extract inhibited the HepG2 and Hep3B cell growth by causing cell-cycle arrest at either S phase or S/G2 transition and induced apoptosis, evidenced by a DNA fragmentation assay [64]. In vitro assay demonstrated the antioxidant potential of Smilax. The Smilax triggered a big reduction of the formalin-evoked flinches in rats, an effect reversed through opioid antagonist naloxone [66]. Rafatullah et al. studied the effect of ethanol extract of sarsaparilla 100 mg/kg/day for 90 days on carbon tetrachloride (CCl4)-induced hepatocellular damage in rats [67].
Nithyamala et al. investigated analgesic interest of root powder of Smilax by means of hot plate technique and acetic acid prompted writhing technique in albino mice. The oral administration of root substantially expanded the response time in a dose-based manner in warm plate technique. The basis powder also induced inhibitory impact on writhing triggered by using acetic acid [68]. Methanolic extract of Smilax roots examined for its immunomodulatory interest by means of nitro blue tetrazolium chloride (NBT) reduction test and anti-arthritic test by in vitro protein denaturation and in vivo complete Freund’s adjuvant (CFA) precipitated arthritis. Extract at 200 mg/kg and 400 mg/kg showed statistically significant inhibition (p < 0.05) of the edema formation in CFA model [69].
Leaf and fruit extracts of Smilax were shown to exhibit antimicrobial and antioxidant activities, which may be attributed to the presence of secondary metabolites such as alkaloids, flavonoids, tannins, triterpenoids, and sterols [73]. In vitro antioxidant activities of leaf and stem extracts of Smilax were performed, which revealed the reducing power of leaf and stem extracts of Smilax [70]. Another study revealed marked reducing activity of methanolic extract of stem when compared to aqueous extract of stem [71]. Muthu et al. investigated the evaluation of in vivo antioxidant activity of ethanolic extract of root on aluminum-chloride-induced apoptosis suppressing antioxidative stress in Wistar rats and found that Smilax can be used as an antioxidant that is beneficial in preventing the progress of various oxidative stresses [72].
1.4 Meadow Saffron
Meadow saffron, Colchicum autumnale, belonging to family Liliaceae is a flowering species. It is native to mountains in wet grasslands – Turkey and Balkans [81]. It is also known as autumn crocus [74]. Meadow saffron is claimed to have many therapeutic uses such as anti-inflammatory, antitumoral, possible inhibition of viral replication, inhibitory effect on coagulation activation, and antifibrotic. It is useful in treatment of gout and Behçet’s disease. The therapeutic activity of this plant is attributed to the presence of alkaloids or, in other words, colchicinoids such as colchicine and demecolcine [74,75,76,78]. Colchicine’s benefits in the treatment of cirrhosis, psoriasis, and amyloidosis have been made evident by researchers [79]. Bioactive phenolic compounds such as lignans, flavonoids, phenolic acids, and tannins are also distributed in meadow saffron [80].
A randomized, multicenter, controlled, open-label parallel group (2:1 ratio), phase III clinical trial demonstrated that early administration of colchicine has clinical effectiveness in reducing the complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a population highly susceptible, and may mitigate the health crisis and prevent the collapse of the health system in the successive waves of the coronavirus pandemic [83, 84].
Colchicine has been known as a treatment for gout for several millennia. Aggravation in gout is intervened by a combination of neutrophil and macrophage activation, leukocyte adhesion molecules, inflammasome actuation, and IL-1β production. It is reported that all of these pathways are influenced by colchicine [85]. Mikkelsen et al. prepared a crystalline alkaloid, desacetyl-methyl-colchicine, from bulbs of C. autumnale for the clinical trial in certain hematologic disorders and acute gout in a 51-year-old patient with history of recurrent acute episodes of arthritis [82]. In a randomized placebo-controlled trial evaluating the efficacy and toxicity of colchicine in acute gout, patients were treated with an initial dose of 1 mg followed by sequential doses of 0.5 mg every two hours until either significant symptomatic relief or intolerance. Patients treated with colchicine were observed to experience pain relief within 48 hours as compared to placebo [86]. The AGREE—Acute Gout Flare Receiving Colchicine Evaluation—trial was the first randomized, placebo-controlled trial to compare low- and high-dose colchicine and it was observed that there is a comparable response rate in the low-dose group versus high-dose group [76]. Also, high-dose group showed more side effects like diarrhea and nausea [76]. A placebo-controlled randomized trial evaluating colchicine for flare prophylaxis in patients with chronic gout initiating allopurinol found that subjects treated with colchicine had fewer and less severe flares [87].
In a randomized controlled clinical trial, two groups were divided: the patients in the intervention and control groups were treated with Rhazes tablet + Ibuprofen pearl (400 mg) PRN (pro re nata) and placebo tablet + Ibuprofen pearl (400 mg) PRN, respectively. It was concluded that Rhazes tablet can be used as a pharmacological intervention to reduce pain in patients with lower back pain [83].
Since 1974, colchicine is the treatment of choice for Familial Mediterranean Fever (FMF). It is evident through a randomized controlled trial in which patients were treated with colchicine and fewer attacks were observed [88]. A randomized cohort study showed favorable efficacy of colchicine in treatment of secondary amyloidosis [89]. Colchicine was found more effective than melphalan and prednisone in increasing the survival rate of patients [89].
Colchicine was reported to be used in Behçet’s syndrome; 7–12 patients were reported to show improvement in symptoms when treated with colchicine 0.5 mg twice a day [90]. A double-blind controlled trial wherein 116 sufferers with Behçet’s syndrome were randomized to get hold of either colchicine or placebo for 2 years showed enormous reductions in the occurrence of genital ulcers, erythema nodosum, and arthritis in woman patients, in addition to a decrease in the incidence of arthritic signs in men [91, 92].
All parts of the plant, especially the bulbs, are highly toxic. If taken in abundance it can be highly toxic and can be fatal. Cramping, vomiting, diarrhea, increased blood pressure, and respiratory failure are the poison symptoms [93]. Formerly, poisoning occurred when people used homemade preparations. Due to this, many deaths have been reported [94].
1.5 Asparagus
Asparagus officinalis is a medicinal plant belonging to family Liliaceae. It is native to temperate Himalayas and includes about 300 species around the world. It is beneficial in treating leprosy, dysuria, epilepsy, night blindness, jaundice, disorders of the kidney and liver, as well as being anticancer, antidiabetic, anti-inflammatory, diuretic, increase fertility, lessen menstrual cramps, and laxative [95, 96]. The main bioactive constituents of asparagus are a group of steroidal saponins. This plant also contains vitamins A, B1, B2, C, and E, as well as Mg, P, Ca, Fe, and folic acid. Other primary chemical constituents of asparagus are essential oils, asparagine, arginine, tyrosine, flavonoids (kaempferol, quercetin, and rutin), resin, and tannin [97, 98]. Saponins have a wide range of biological activities, including those of antioxidants, immunostimulants, antihepatotoxic, antibacterial, beneficial for diabetic retinopathy, anticarcinogenic, antimicrobials, that inhibit molds, antidiarrheal, and antiulcerogenic agents [97, 99].
The hypoglycemic effects of asparagus extracts were evaluated by streptozotocin (STZ)-induced diabetic rats, which had the same efficacy at a dose of 500 mg/kg as the antidiabetic drug glibenclamide (5 mg/kg rat body weight) [100]. Asparagus juice (CAJ) from asparagus old stem was used in type I diabetic rat model, and results showed that CAJ reduced the blood glucose level along with lipid level in diabetic rats by decreasing the content of serum glucose, total cholesterol, and MDA, and improved level of serum insulin [101]. Hypoglycemic activity of asparagus old stem was also reported by Zhao (2010). He reported the presence of flavonoids, polyphenols, saponins, and polysaccharides, which showed remarkable hypoglycemic effects at 1.43, 5.58, 1.82, and 4.24 mg/g dry weight, respectively [102]. The extract of A. officinalis in the diabetic rats showed potent antioxidant activity and improvement in β-cell function both at 250 mg/kg and 500 mg/kg. The insulin–glucose ratio was reported to increase at both doses [103].
A. officinalis also shows antitumorigenic and antimetastatic effects. In a transgenic mouse model of high-grade serous ovarian cancer, asparagus was reported to decrease the cellular viability and caused cell-cycle G1 phase arrest. It inhibited tumor growth and increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in the ovarian tumor tissues [104]. The inedible bottom part of asparagus was utilized as a supplement and the saponins from old stem of asparagus suppressed the cell viability of breast, colon, and pancreatic cancers. The extract inhibited the tumor cell motility [105]. The popular vegetable dish of asparagus, i.e., the shoots of white asparagus, was reported to possess antioxidant, anti-inflammatory, and antitumor activities. The Wistar rats with induced colon carcinogenesis were treated with asparagus for seven weeks and the rats exhibited a 50% reduction in the amount of pre-neoplastic lesions and promoted normal cellular homeostasis [106]. Xiang et al. also reported the anticancer effects of asparagus. Deproteinized asparagus polysaccharide exhibited widespread anticancer activity in opposition to hepatocellular carcinoma cells and sensitized the tumoricidal consequences of mitomycin, indicating that asparagus is a chemosensitizer for liver cancer therapy [107]. Mechanistic studies revealed the inhibition of migration, invasion, and angiogenesis of cancer cells [108].
Asparagus showed antioxidant, anti-inflammatory, and antihepatotoxic properties in the 40 Wistar rats that were given 400 mg/kg of the extract. Asparagus extract increased the total antioxidative capability and improved function of liver and kidney tissues. According to the researchers, it has a potential protective action against oxidative stress, and liver and kidney damage [109]. Also, asparagus seed extract additionally accelerated general antioxidant reputation at a dose of 500 mg/kg in streptozotocin-induced diabetic rats [100]. Ku et al. (2017) reported the high binding capacity of soluble polyphenols of asparagus to human serum albumin and it also showed the protective effects against bisphenol-A-induced toxicity [110].
Asparagus has potential against bile acids, which are the important excretory pathways for cholesterol metabolism. Asparagus effect was studied on cholesterol as it reduced the simulating gastrointestinal digestion and measured binding capacity of the food and bile acid [98]. Another study indicated the cholesterol-lowering activity of asparagus in hyperlipidemia mouse model; polysaccharides present on asparagus lowered the lipoprotein cholesterol [111, 112]. Asparagus also showed the positive results in lowering the blood pressure from human clinical trials and therefore can be used as an antihypertensive agent [113].
There are various other therapeutic as well as physiological effects of asparagus. The instant powder of asparagus increased the sleep time in insomnia patients, and also shortened the sleep time through the food test that was performed on 60 volunteers [114]. Jager et al. (2005) proved the antiepileptic activity of asparagus instant powder [115] and Miura et al. (2016) discovered the stress-relieving property [116].
1.6 Lily of the Valley
Lily of the valley is a common name of Convallaria majalis. This plant belongs to Liliaceae family. The plant contains numerous steroidal glycosides, cardiac glycosides, flavonoids, chelidonic acid, choline, and azetidine-2-carbonic acid. In rhizomes and roots of the plant, steroidal saponins are predominant [115,116,117,120]. From ancient times, lily of the valley is used for the treatment of various cardiovascular ailments including congestive heart failure, cardiomyopathy, irregular heartbeat, urinary tract infections (UTIs), kidney stones, epilepsy, edema, and various eye infections. It is also used in the treatment of leprosy [121]. An ointment made from the roots is used in the treatment of burns and to prevent scar tissue. However, owing of the plant’s potential toxicity, it should never be used without first consulting a professional [131].
Cardiac glycosides, also known as cardenolides, are a type of steroid that has long been known to have a positive ionotropic impact on the heart. All cardiac glycosides increase intracellular sodium by affecting ion transport across cardiac muscle cell membranes via effects on Na(+)/K(+)-ATPase enzymes. As a result, intracellular calcium levels rise, improving heart contractility. Atrial flutter and fibrillation are also converted to steady sinus rhythm with cardiac glycosides [123, 124].
Convallaria majalis has been demonstrated in animal trials to raise K+ in the atria and atrial stroke volume. Despite the fact that convallatoxin is a vasoconstrictor, the sum of all cardiac glycosides and other ingredients may have a greater vasotonic effect, improving circulation and coronary flow [125, 126].
A study was done for the determination of whether convallatoxin present in the plant as a cardiac glycoside induces the expression of tissue factor and leads to hypercoagulable state. The findings indicate that the convallatoxin induces the tissue factor expression in endothelial cells and also induces hypercoagulable state [122].
Convallaria majalis is a homoeopathic medicine that has a beneficial effect on the heart and also acts as a diuretic. Lateef et al. (2010) evaluated the effect of lily of the valley on kidney function by investigating the effect of plant extract on serum uric acid and creatinine on rabbits for 14 days. After the completion, animals were sacrificed to collect blood sample. It was concluded that the alcoholic extract at 10 mg/kg acts as a significant hypouricemic agent [127].
Another study indicated the effect of convallamaroside, i.e., the steroidal saponin present in Convallaria majalis. Isolated extract was injected to the mice and evaluated by intradermal test. Convallamaroside medication to mice reduced the number of new vasculatures produced by sarcoma mouse cells (p = 0.001) [128].
For a single ingredient, convallatoxol, the dose that killed 50% of a sample population (LD50) in cats was 0.14 mg/kg given intraperitoneally [130]. This herb’s human dose is 0.6 g powdered herb or 5–10 drops tincture, split daily. A case report detailed a dog that died abruptly after consuming lily of the valley in its enclosed yard [129].
The essential oil of lily of the valley is used in aromatherapy to treat headaches, depression, and melancholy. Memory loss, apoplexy, and epilepsy can all be treated with it. It is utilized to help brain cells grow stronger and to boost cognitive functions. UTI is treated with a tincture made from lily of the valley flowers, which clears blockages from the urethra. Because of its purgative and laxative properties, this herb is commonly used as a substitute for aloes. This, in turn, keeps the digestive system running smoothly.
The lily of the valley also has the following advantages:
-
Kidney stones are broken down.
-
Prevents the body from retaining water.
-
Pain associated with joint tissues such as gout and rheumatism are reduced.
-
Conjunctivitis is treated with this medication.
-
Paralysis, shock, and speech loss are all treated using essential oils.
-
Aids in the treatment of leprosy and edema.
-
Poisoning and drunkenness are treated by producing vomiting.
2 Conclusions
Natural products act as very potential products for new drug discovery and have the ability to generate new drug leads that will be further subjected for clinical trials. In the present study, several advances in the field of technology of natural products were discussed and how they are subjected for clinical trials were described in detail. In this chapter, several conclusive points were also discussed on the basis of analyzed data and therapeutic-evidence-based studies, which provide a very strong basis for the conduction of natural-products-based-drug clinical trials to continue for making major contributions toward change in human health and maintenance of longevity without any serious adverse effects. There is also a requirement for further studies to provide more powerful evidence of the adverse effects concerned with the drugs discussed above. In addition, the safety of consumption of aforementioned compounds in definite conditions and diseases should also be noted down. Furthermore, after considering all the evidence-based facts and conditions, it seems that natural products can be utilized to provide various health-promoting properties.
References
Lindstedt S, Wlosinska M, Nilsson AC, Hlebowicz J, Fakhro M, Sheikh R (2021) Successful improved peripheral tissue perfusion was seen in patients with atherosclerosis after 12 months of treatment with aged garlic extract. Int Wound J 18(5):681–691. https://doi.org/10.1111/iwj.13570
Askari M, Mozaffari H, Mofrad MD, Jafari A, Surkan PJ, Amini MR, Azadbakht L (2021) Effects of garlic supplementation on oxidative stress and antioxidative capacity biomarkers: a systematic review and meta-analysis of randomized controlled trials. Nat Library Med 35(6):3032–3045. https://doi.org/10.1002/ptr.7021
Al-Snafi A (2013) Pharmacological effects of Allium species grown in Iraq. An overview. Int J Pharmacol Health Care Res 1:132–147
Jang HJ, Lee HJ, Yoon DK, Kim JH, Ji DS, Lee CH (2018) Antioxidant and antimicrobial activities of fresh garlic and aged garlic by-products extracted with different solvents. Food Sci Biotechnol 27(1):219–225. https://doi.org/10.1007/s10068-017-0246-4
Ashraf R, Amir K, Shaikh AR, Ahmed T (2005) Effects of garlic on dyslipidemia in patients with type 2 diabetes mellitus. J Ayub Med Coll, Abbottabad 17(3):60–64
Parham M, Begherzadeh M, Asghari M, Akbari H, Hosseini Z, Rafiee M, Vafaeimanesh J (2020) Evaluating the effect of a heb on the control of blood glucose and insulin- resistance in patients with advanced type 2 diabetes (a double-blind clinical trial). Caspian J Intern Med 11(1):12–20. https://doi.org/10.22088/cjim.11.1.12
Shaikh K, Kinniger A, Cherukuri L, Birudaraju D, Nakanishi R, Almeida S, Jayawardena E, Shekar C, Flores F, Hamal S, Sheikh MS, Johanis A, Cu B, Budoff MJ (2020) Aged garlic extract reduces low attenuation plaque in coronary arteries of patients with diabetes: a randomized, double-blind, placebo-controlled study. Nat Library Med 19(2):1457–1461. https://doi.org/10.3892/etm.2019.8371
Choudhary PR, Jani RD, Sharma MS (2018) Effect of raw crushed garlic (Allium sativum) on components of metabolic syndrome. J Diet Suppl 15(4):499–506. https://doi.org/10.1080/19390211.2017.1358233
Zarvandi M, Rakhshandeh H, Abazari M, Nick RS, Ghorbani A (2017) Safety and efficacy of a polyherbal formulation for the management of dyslipidemia and hyperglycemia in patients with advanced-stage of type-2 diabetes. Biomed Pharmacother 89:69–75. https://doi.org/10.1016/j.biopha.2017.02.016
Wlosinka M, Nilson AC, Hlebowicz J, Hauggaard A, Kjellin M, Fakhro M, Lindstedt S (2020) The effect of aged garlic extract on the atherosclerotic process-a randomized double-blind placebo-controlled trial. BMC Compl Med Ther 20(1):132. https://doi.org/10.1186/s12906-020-02932-5
Hamal S, Cherukuri L, Birudaraju D, Matsumoto S, Kinninger A, Chaganti BT, Flores F, Shaikh K, Roy SK, Budoff MJ (2020) Short-term impact of aged garlic extracts on endothelial function in diabetes: a randomized, double-blind, placebo-controlled trial. Exp Ther Med 19(2):1485–1489. https://doi.org/10.3892/etm.2019.8377
Liu J, Zhang G, Cong X, Wen C (2018) Black garlic improves heart function in patients with coronary heart disease by improving circulating antioxidant levels. Front Physiol 9:1435. https://doi.org/10.3389/fphys.2018.01435
Gebhardt R, Beck H (1996) Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures. Lipids 31(12):1269–1276. https://doi.org/10.1007/bf02587912
Capasso A (2013) Antioxidant action and therapeutic efficacy of Allium sativum L. Molecules 18(1):690–700
Pourzand A, Tajaddini A, Pirouzpanah S, Jafarabadi MA, Samadi N, Ostadrahimi AR, Sanaat Z (2016) Associations between dietary Allium vegetables and risk of breast cancer: a hospital-based matched case-control study. J Breast Cancer 19(3):292–300. https://doi.org/10.4048/jbc.2016.19.3.292
Kweon S, Park KA, Choi H (2003) Chemopreventive effect of garlic powder diet in diethylnitrosamine induced rat hepatocarcinogenesis. Life Sci 73(19):2515–2526
Knowles LM, Milner JA (2003) Diallyl disulfide induces ERK phosphorylation and alsters gene expression profiles in human colon tumor cells. J Nutr 133(9):2901–2906. https://doi.org/10.1093/jn/133.9.2901
Hsing AW, Chokkalingam AP, Gao YT, Madigan MP, Deng J, Gridley G, Fraumeni JF (2002) Allium vegetables and risk of prostate cancer: a population-based study. J Natl Cancer Inst 94(21):1648–1651. https://doi.org/10.1093/jnci/94.21.1648
Lau BH, Woolley JL, Marsh CL, Barker GR, Koobs DH, Torrey RR (1986) Superiority of intralesional immunotherapy with Corynebacterium parvum and Allium sativum in control of murine transitional cell carcinoma. J Urol 136(3):701–705
Wattenberg LW, Sparnis VL, Barany G (1989) Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer Res 49(10):2689–2692
Ahmad TA, Sayed BA, Sayed LH (2016) Development of immunization trials against Eimeria spp. Trials Vaccinol 5:38–47. https://doi.org/10.1016/j.trivac.2016.02.001
Koushki M, Dashatan NA, Pourfarjam Y, Doustimotlagh AH (2021) Effect of garlic intake on inflammatory mediaors: a systematic review and meta-analysis of randomized controlled trials. Postgrad Med J 97(1145):156–163. https://doi.org/10.1136/postgradmedj-2019-137267
Hobauer R, Frass M, Gmeiner B, Kaye AD, Frost EA (2000) Garli extract (allium sativum) reduces migration of neutrophils through endothelial cell monolayers. Middle East J Anaesthesiol 15(6):649–658
Gu X, Wu H, Fu P (2013) Allicin attenuates inflammation and suppresses HLA-B27 protein expression in ankylosing spondylitis mice. Biomed Res Int:171573. https://doi.org/10.1155/2013/171573
Chan JY, Yuen AC, Chan RY, Chan SW (2013) A review of the cardiovascular benefits and antioxidant properties of allicin. Phytoher Res 27(5):637–646
Hamman JH (2008) Composition and application of Aloe vera leaf gel. Molecules 13:1599–1616. https://doi.org/10.3390/molecules13081599
Maharjan HR, Nampoothiri PL (2015) Evaluation of biological properties and clinical effectiveness of Aloe vera: a systematic review. J Tradit Complement Med 5(1):21–26. https://doi.org/10.1016/j.jtcme.2014.10.006
Chithra P, Sjithlal GB, Chandrakasen G (1998) Influence of Aloe vera on collagen characteristics in healing dermal wounds in rats. Mol Cell Biochem 181(1–2):71–76. https://doi.org/10.1023/a:1006813510959
Huang S, Xie Y, Huang Z, Zhang G, Chen G, Yuan J, Wang J, Xiangyang L, Zhou Y (2021) Effect of observation of Shou Hui Tong Bian Capsule (Polygonum Multiflorum and Aloe-Based Herbal Capsule for Cathartic Effect) in rapid rehabilitation of joint surgery. Evi Based Compl Alternat Med:2268464. https://doi.org/10.1155/2021/2268464
Metin ZG, Helvaci A, Eren MG (2021) Effects of Aloe vera in adults with mucocutaneous problems: a systematic review and meta-analysis. J Adv Nurs 77(3):1105–1126. https://doi.org/10.1111/jan.14653
Abbasi MS, Rahmati J, Ehsani AH, Takzare A, Partoazar A, Takzaree N (2020) Efficacy of a natural topical skin ointment for managing Split-thickness skin graft donor sites: a pilot double-blind randomized controlled trial. Adv Skin Wound Care 33(7):1–5. https://doi.org/10.1097/01.asw.0000666916.00983.64
Shahzad MN, Ahmed N (2013) Effectiveness of Aloe vera gel compared with 1% silver sulphadiazine cream as burn wound dressing in second degree burns. J Pak Med Assoc 63:225–230
Tabandeh MR, Oryan A, Mohammadalipour A (2014) Polysaccharides of Aloe vera induve MMP-3 and TIMP-2 gene expression during the skin wound repair of rat. Int J Biol Macromol 65:424–430
Huseini HF, Kianbakht S, Hajiaghaee R, Dabaghian FH (2012) Anti-hyperglycemiac and anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. Planta Med 78:311–316
Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C (2008) Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 371:117–125. https://doi.org/10.1016/S0140-6736(08)60104-X
Devaraj S, Jialal R, Jialal I, Rockwood R (2008) A pilot randomized placebo-controlled trial of 2 Aloe vera supplements in patients with pre-diabetes/metabolic syndrome. Planta Med p. 74–77
Jain N, Vijayaraghavan R, Pant SC, Lomash V, Ali m. (2010) Aloe vera gel alleviates cardiotoxicity in streptozocin-induced diabetes in rats. J Pharm Pharmacol 62:115–123
Rahimifard M, Nigjeh MN, Mahroui N (2013) Improvement in the function of isolated rat pancreatic islets through reduction of oxidative stress using traditional Iranian medicine. Cell J:147–163
Hamiza OO, Rehman MU, Khan R (2014) Chemopreventive effects of aloin against 1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats. Hum Exp Toxicol 33:148–163. https://doi.org/10.1177/0960327113493307
Kim HS, Lee BM (1997) Inhibiting of benzo[a]pyrene-DNA adduct formation by Aloe barbadensis miller. Carcinogenesis 18(4):771–776
Kim hs, Kacew S, Lee BM. (1999) In vitro chemopreventive effects of plant polysaccharides (Aloe barbadensis miller, Lentinus edodes, Ganoderma lucidum and Coriolus versicolor). Carcinogenesis 20(8):1637–1640
Babaee N, Zabihi E, Mohseni S, Moghadamnia AA (2012) Evaluation of the therapeutic effects of Aloe vera gel on minor recurrent aphthous stomatitis. Dent Res J 9:381–385
Mansour G, Ouda S, Shaker A, Abdallah HM (2014) Clinical efficacy of new Aloe vera-myrrh-based oral mucoadhesive gels in the management of minor recurrent aphthous stomatitis: a randomized, double-blind, vehicle-controlled study. J Oral Pathol Med 43:405–409
Najafian Y, Khorasani ZM, Njafi MN, Hamedi SS, Mhjour M, Feyzabadi Z (2019) Efficacy of Aloe vera/Plantago major gel in diabetic foot ulcer: a randomized double-blind clinical trial. Curr Drug Discov Technol 16(2):223–231. https://doi.org/10.2174/1570163815666180115093007
Kaewsrisung S, Sukpat S, Issarasena N, Patumraj S, Somboonwong J (2021) The effects of oral Aloe vera on the efficacy of transported human endothelial cells and the expression of matrix metalloproteinases in diabetic wound healing. Heliyon 7(12):e08533. https://doi.org/10.1016/j.heliyon.2021.e08533
Farid A, Tawfik A, Elsioufy B, Safwat G (2021) In vitro and in vivo anti-cryptosporidium and anti-inflammatory effects of Aloe vera gel in dexamethasone immunosuppressed mice. Int J Parasitol Drugs Drug Resis:156–167. https://doi.org/10.1016/j.ijpddr.2021.09.002
Liu C, Hua H, Zhu H, Cheng Y, Guo Y, Yao W, Qian H (2021) Aloe polysaccharides ameliorate acute colitis in mice via Nrf2/HO-1 signaling pathway and short-chain fatty acids metabolism. Int J Biol Macromol 185:804–812. https://doi.org/10.1016/j.ijbiomac.2021.07.007
An J, Lee H, Lee S, Song Y, Kim J, Park IH, Kong H, Kim K (2021) Modulation of pro-inflammatory and anti-inflammatory cytokines in the fat by an aloe gel-based formula, QDMC, is correlated with altered gut microbiota. Immune Netw 21(2):e15. https://doi.org/10.4110/in.2021.21.e15
Akgul KT, Dogantekin E, Ozer E, Kotanoglu M, Gokkurt Y, Hucumenoglu S (2021) Histopathological effects of aloe vera on wound healing: an experimental study. Turk J Med Sci 51(4):2193–2197. https://doi.org/10.3906/sag-2102-224
Sharifi E, Chehelgerdi M, Kelishadrokhi AF, Nafchi FY, Dehkordi KA (2021) Composition of therapeutic effects of encapsulated Mesenchymal stem cells in Aloe vera gel and Chitosan-based gel in healing of grade-II burn injuries. Regen Ther 18:30–37. https://doi.org/10.1016/j.reth.2021.02.007
Koga AY, Felix JC, Silvestre RGM, Lipinski LC, Carletto B, Kawahara FA, Pereira AV (2020) Evaluation of wound healing effect of alginate film containing Aloe vera gel and cross-linked with zinc chloride. Acta Cir Bras 35(5):e202000507. https://doi.org/10.1590/s0102-865020200050000007
Sumi FA, Sikder B, Rahman MM, Lubna SR, Ula A, Hossain MH, Jahan IA, Alam MA, Subhan N (2019) Phenolic content analysis of Aloe vera gel and evaluation of the effect of aloe gel supplementation on oxidative stress and fibrosis in isoprenaline-administered cardiac damage in rats. Prev Nutr Food Sci 24(3):254–264. https://doi.org/10.3746/pnf.2019.24.3.254
Gupta VK, Siddiqi NJ, Ojha AK, Sharma B (2019) Hepatoprotective effect of Aloe vera against cartap- and malathion-induced toxicity in Wistar rats. J Cell Physiol 234(10):18329–18343. https://doi.org/10.1002/jcp.28466
Sehitoglu MH, Karaboga I, Kiraz A, Kiraz HA (2018) The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats. North Clin Istanb 6(3):203–209. https://doi.org/10.14744/nci.2018.82957
Jung E, Kim J (2018) Aloin inhibits muller cells swelling in a rat model of thioacetamide-induced hepatic retinopathy. Molecules 23(11):2806. https://doi.org/10.3390/molecules23112806
Shi Y, Tian C, Yu X, Fang Y, Zhao X, Xia D (2020) Protective effects of Smilax glabra Roxb. Against Lead-induced renal oxidative stress, inflammation and apoptosis in weaning rats and HEK-293 cells. Front Pharmacol. https://doi.org/10.3389/fphar.2020.556248
Kwon OY, Ryu S, Choi JK, Lee SH (2020) Smilax glabra Roxb. Inhibits collagen induced adhesion and migration of PC3 and LNCaP prostate cancer cells through the inhibition of Beta 1 integrin expression. Molecules 25(13):3006. https://doi.org/10.3390/molecules25133006
Saleem SA, Lakshmi B, Kumar JNS (2021) Review article on traditional out look of Smilax zeylanica. Res J Pharmacol Pharmacodyn. https://doi.org/10.52711/2321-5836.2021.00014
Huang L, Deng J, Chen G, Zhou M, Liang J, Yan B, Shu J, Liang Y, Huang H (2019) The anti-hyperuricemic effect of four astilbin stereoisomers in S.glabra on hyperuricemic mice. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2019.03.004
She T, Zhao C, Feng J, Wang L, Qu L, Fang K, Cai S, Shou C (2015) Sarsaparilla (Smilax glabra Rhizome) extract inhibits migration and invasion of cancer cells by suppressing TGF-β1 pathway. PLoS One 10(3):e0118287. https://doi.org/10.1371/journal.pone.0118287
Dong L, Zhu J, Du H, Nong H, He X, Chen X (2017) Astilbin from Smilax glabra Roxb. Attenuates inflammatory responses in complete freund’s adjuvant-induced arthritis rats. Evid Based Complement Alternat Med:8246420. https://doi.org/10.1155/2017/8246420
Song G, She T, Feng J, Lian S, Li R, Zhao C, Luo J, Dawuti R, Cai S, Qu L, Shou C (2017) Sarsaparilla (Smilax glabra rhizome) extract activates redox-dependent ATM/ATR pathway to inhibit cancer cell growth by Sphase arrest, apoptosis and autophagy. Nutr Cancer 69(8):1281–1289. https://doi.org/10.1080/01635581.2017.1362447
Gao Y, Su Y, Qu L, Xu S, Meng L, Cai SQ, Shou C (2011) Mitochondrial apoptosis contributes to the anti-cancer effect of Smilax glabra Roxb. Toxicol Lett 207(2):112–120. https://doi.org/10.1016/j.toxlet.2011.08.024
Sa F, Gao JL, Fung KP, Zheng Y, Lee SMY, Wang YT (2008) Anti-proliferative and pro-apoptotic effect of Smilax glabra Roxb. Extract on hepatoma cell lines. Chem Biol Interact 171(1):1–14. https://doi.org/10.1016/j.cbi.2007.08.012
Khan A, Singh PD, Reese PB, Howden J, Golding M, Thomas TT (2020) Investigation of the preliminary mechanism of action for the acute anti-inflammatory activity of the methanol extract of Smilax ornate Lem. J Ethanopharmacol 248:112360. https://doi.org/10.1016/j.jep.2019.112360
Hirota BCK, Paula CDS, Oliveira VBD, Cunha JMD, Schreiber AK, Ocampos FMM, Barison A, Miguel OG, Miguel MD (2016) Phyochemical and antinociceptive, anti-inflammatory and anti-oxidant studies of Smilax larvata(Smilacaceae). Evi Based Comp Alt Med. https://doi.org/10.1155/2016/9894610
Rafatullah S, Mossa JS, Ageel AM, Yahya MAA (2008) Hepatoprotective and safety evaluation studies on sarsaparilla. Pharm Biol 29(4):296–301. https://doi.org/10.3109/13880209109082901
Nithyamala I, Ayyasamy S, Pitchiahkumar M, Kumar A, Velapandian V (2013) Evaluation of analgesic and antiinflammatory activity of siddha drug Karuvilanchiverchoornam (root powder of Smilax zeylanica Linn) in rodents. IOSR J Pharm Biol Sci 6(1):6–11
Babu PV, Ashwini T, Krishna MV, Raju MG (2017) Immunomodulatory and antiarthritic activities of smilax zeylanica. Int J Phytomed 9(1). https://doi.org/10.5138/09750185.1963
Uddin MN, Ahmed T, Pathan S, Al-Amin MM, Rana MS (2015) Antioxidant and cytotoxic activity of stems of Smilax zeylanica in vitro. J Basic Clin Physiol Pharmacol 26(5):453–463
Thirugnanasampandan R, Mutharaiah VN, Bai NV (2009) In vitro propagation and free radical studies of Smilax zeylanica vent. Afr J Biotechnol 8(3):395–400
Muthu AK, Senthil BS, Kalaichelvan VK (2018) In vivo antioxidant activity of ethanolic extract from root of smilax on aluminium chloride induced oxidative stress in wistar rats. J Drug Delivery Therapeutics 8(6). https://doi.org/10.22270/jddt.v8i6-s.2078
Shree VSD, Arbin A, Noorain GKS, Sahana BK, Kekuda TRP (2018) Preliminary phytochemical analysis, antimicrobial and antioxidant activity of Smilax. J Drug Delivery Therapeutics. 8(4). https://doi.org/10.22270/jddt.v8i4.1779
Toplan GG, Gurer C, Mat A (2016) Importance of colchicum species in modern therapy and its significance in Turkey. J Fac Pharm 46:129–144
Alali FQ, Tawaha K, El-Elimat T (2007) Determination of (−)-demecolcine and (−)-colchicine content in selected Jordanian Colchicum species. Pharmazie 62(10):739–742
Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (2010) High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 62(4):1060–1068. https://doi.org/10.1002/art.27327
Sakane T, Takeno M (2000) Novel approaches to Behcet’s disease. Expert Opin Investig Drugs 9(9):1993–2005
Cifuentes M, Schilling B, Ravindra R, Winter J, Janik ME (2006) Synthesis and biological evaluation of B-ring modified colchicine isocolchicineanalogs. Bioorg Med Chem Lett 16(10):2761–2764. https://doi.org/10.1016/j.bmcl.2006.02.010
Cocco G, Chu DC, Pandolfi S (2010) Colchicine in clinical medicine. A guide for internists. Eur J Intern Med 21(6):503–508. https://doi.org/10.1016/j.ejim.2010.09.010
Ondra P, Valka I, Sutlupinar N, Simanek V (1995) Chromatographic determination of constituents of the genus colchicum (Liliaceae). J Chromatogr A 704:351–356
Akram M, Alam O, Khan U, Naveed A, Asif HM (2012) Colchicum autumnale:a review. Acad J 6:8. https://doi.org/10.5897/JMPR.9000370
Mikkelsen WM, Salin RW, Duff IF (1956) Alopecia totalis after desacetylmethylcolchicine therapy of acute gout-report of a case. N Engl J Med 255:769–770
Estebanez EB, Alconero LL, Fernandez BJ, Marguello MG, Caro JCL, Vallejo JD, Sampedro MF, Cacho PM, Espiga CR, Saiz MMG (2021) The effectiveness of early colchicine administration in patients over 60 years old with high risk of developing severe pulmonary complications associated with coronavirus pneumonia SARS-CoV-2 (COVID-19): study protocol for an investigator-driven randomized controlled clinical trial in primary health care—COLCHICOVID study. Trials 22:590–592
Malek VG, Parvari S, Jafari F, Rouhani Y, Rahimi R, Abbassian A (2019) Efficacy of a traditional herbal formula based on Colchicum autumnale L. (Rhazes tablet) in low back pain: a randomized controlled clinical trial. Int J Ayurvedic Med 10(1). https://doi.org/10.47552/ijam.v10i1.1178
Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S (2015) Colchicine: old and new. Am J Med 128(5):461–470. https://doi.org/10.1016/j.amjmed.2014.12.010
Ahem MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M (1987) Does colchicine work? The results of the first controlled study in acute gout. Aust NZ J Med 17(3):301–304. https://doi.org/10.1111/j.1445-5994.1987.tb01232.x
Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA (2004) Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 31(12):2429–2432
Dinarello CA, Wolff SM, Goldfinger SE, Dale DC, Alling DW (1974) Colchicine therapy for familial Mediterranean fever. A double-blind trial. N Engl J Med 291(18):934–937. https://doi.org/10.1056/nejm197410312911804
Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM (1997) A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone and melphalan, prednisone and colchicine. N Engl J Med 336(17):1202–1207. https://doi.org/10.1056/nejm199704243361702
Matsumura N, Mizushima Y (1975) Leucocyte movement and colchicine treatment in Behcet’s disease. Lancet 2(7939):813. https://doi.org/10.1016/s0140-6736(75)80031-6
Komlodi-Pasztor E, Sackett DL, Fojo AT (2012) Inhibitors targeting mitosis: tales of how great drugs against a promosing target were brought down by a flawed rationale. Clin Cancer Res 18(1):51–63. https://doi.org/10.1158/1078-0432.ccr-11-0999
Yurdakul S, Mat C, Tuzun Y, Ozyazgen Y, Hamuryudan V, Uysal O, Senocak M, Yazici H (2001) A double-blind trial of colchicine in Behcet’s syndrome. Arthritis Rheum 44(11):2686–2692. https://doi.org/10.1002/1529-0131(200111)44:11<2686::aid-art448>3.0.co;2-h
Poutaraud A, Girardin P (2002) Alkaloids in Meadow Saffron, Colchicum autumnalel. J Herbs Spices Med Plants 9(2):63–79. https://doi.org/10.1300/J044v09n01_08
Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL (2019) Colchicine: an ancient drug with novel applications. Br J Dermatol 178(2):350–356. https://doi.org/10.1111/bjd.15896
Gaur RD (1999) The flora of the district Garhwal North West Himalaya. TransMedia, Srinagar, Garhwal, p 170
Kirtikar KR, Basu BD (1984) Indian medicinal plants. New Connaught Place, Dehradun India, p 2499
Mader TL, Brumm MC (1987) Effect of feeding Sarsaponin in cattle and swine diets. J Anim Sci 65(1):9–15. https://doi.org/10.2527/jas1987.6519
Kahlon TS, Chapman MH, Smith GE (2007) In vitro binding of bile acids by okra, beets, asparagus, eggplant, turnips, green beans, carrots, and cauliflower. Food Chem 103:676–680. https://doi.org/10.1016/j.foodchem.2006.07.056
Wang NF, Zhang XJ, Wang SW, Guo QB, Li ZJ, Liu HH (2020) Structural characterisation and immunomodulatory activity of polysaccharides from white asparagus skin. Carbohydr Polym 227:115314. https://doi.org/10.1016/j.carbpol.2019.115314
Wang S, Zhu F (2016) Antidiabetic dietary materials and animal models. Food Res Int 85:315–331. https://doi.org/10.1016/j.foodres.2016.04.028
Zhao JJ, Zhao HJ, Zhao D, Wang JQ, Qu WJ (2012) Hypoglycemic activity of clarified asparagus juice in streptozotocin induced diabetic rats. Nat Product Res Develop 24:460–464
Zhao HJ (2010) Study on functional components and biological activities of old stem extracts from Asparagus officinalis L. East China Normal University, China
Hafizur RM, Kabir N, Chishti S (2012) Asparagus officinalis extract controls blood glucose by improving insulin secretionβ-cell function in streptozotocin-induced type 2 diabetic rats. Br J Nutr 108(9):1586–1595
Xu G, Kong W, Fang Z, Fan Y, Yin Y, Sullivan SA, Tran AQ, Clark LH, Sun W, Hao T, Zhao L, Zhou C, Jump VL (2021) Asparagus officinalis exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer. Front Oncol. https://doi.org/10.3389/fonc.2021.688461
Wang J, Zhao J, Liu Y, Pang X (2013) Saponins extracted from by-product of Asparagus officinalis L. suppress tumour cell migration and invasion through targeting rho GTPase signalling pathway. J Sci Food Agric 93(6):1492–1498. https://doi.org/10.1002/jsfa.5922
Bousserouel S, Grandois JL, Gosse F, Werner D, Barth SW, Marchioni E, Marescaux J, Raul F (2013) Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model. Int J Oncol 43(2):394–404. https://doi.org/10.3892/ijo.2013.1976
Xiang J, Xiang Y, Lin S, Xin D, Liu X, Weng L, Chen T, Zhang M (2014) Anticamcer effects of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo. Tumour Biol 35(4):3517–3524. https://doi.org/10.1007/s13277-013-1464-x
Cheng W, Cheng Z, Xing D, Zhang M (2019) Asparagus polysaccharide suppresses the migration, invasion, and angiogenesis of hepatocellular carcinoma cells partly by targeting the HIF-1 alpha/VEGF signalling pathway in vitro. Evid Based Complement Alternat Med. https://doi.org/10.1155/2019/3769879
Poormoosavi SM, Najafzadehvarzi H, Behmanesh MA, Amirgholami R (2018) Protective effects of Asparagus officinalis extract against Bisphenol A- induced toxicity in Wistar rats. Toxiol Rep 5:427–433. https://doi.org/10.1016/j.toxrep.2018.02.010
Ku YG, Bae JH, Ayala M, Vearasilp S, Namiesnik J, Pasko P (2017) Efficient three-dimensional fluorescence measurements for characterization of binding properties in some plants. Sensors Actuators B Chem 248:777–778. https://doi.org/10.1016/j.snb.2017.04.050
Middelbeek RJW, Chambers MA, Tantiwong P, Treebak JT, An D, Hirshman MF, Musi N, Goodyear LJ (2013) Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle. Nutrition Diabetes 3:6–9. https://doi.org/10.1038/nutd.2013.13
Li J ( 2011) Study on extraction, purification, and lipid lower in related activity of old stem polysaccharide from Asparagus officinalis L. East China Normal University, China
Chrubasik S, Droste C, Dragano N, Glimm E, Black A (2006) Effectiveness and tolerability of the herbal mixture asparagus P on blood pressure in treatment-requiring antihypertensives. Phytomedicine 13:740–742. https://doi.org/10.1016/j.phymed.2006.01.009
Huang YX (2017) Effect of instant asparagus powder on sleeping improvement. J Anhui Agric Sci 45(11):80–82
Jager AK, Mohoto SP, Heerden FRV, Viljoen AM (2005) Activity of a traditional south African epilepsy remedy in the GABA-benzodiazepine receptor assay. J Ethnopharmacol 96:603–606. https://doi.org/10.1016/j.jep.2004.10.005
Miura T, Yasueda A, Sakaue M, Maeda K, Hayashi N, Ohno S (2016) SUN-LB271: a double-blind randomized controlled trial regarding the safety and efficacy of enzyme-treated asparagus extract intake in healthy human subjects. Clin Nutr 35:S145. https://doi.org/10.1016/S0261-5614(16)30627-6
Chwedorzewska KJ, Galera H, Kosiński I (2008) Plantations of Convallaria majalis L. as a threat to the natural stands of the species: genetic variability of the cultivated plants and natural populations. Biol Conserv 141:2619–2624. https://doi.org/10.1016/j.biocon.2008.07.025
Erdogan OI, Gokbulut A (2017) Adonis sp., Convallaria sp., Strophanthus sp., Thevetia sp., and Leonurus sp.—cardiotonic plants with known traditional use and a few preclinical and clinical studies. Curr Pharm Des 23:1051–1059
Higano T, Kuroda M, Jitsuno M, Mimaki Y (2007) Polyhydroxylated steroidal saponins from the rhizomes of Convallaria majalis. Nat Prod Commun 2:531–536. https://doi.org/10.1177/1934578X0700200504
Higano T, Kuroda M, Sakagami H, Mimaki Y (2007) Convallasaponin A, a new 5β-spirostanoltriglycoside from the rhizomes of Convallaria majalis. Chem Pharm Bull 55:337–339. https://doi.org/10.1248/cpb.55.337
Stansbury J, Saunders P, Winston D, Zampieron ER (2012) The use of convallaria and Crataegus in the treatment of cardiac dysfunction. J Restro Med 1(1):107–111. https://doi.org/10.14200/jrm.2012.1.1012
Morimoto M, Tatsumi K, Yuui K, Terazawa I, Kudo R, Kasuda S (2021) Convallotoxin, the primary cardiac glycoside in lily of the valley induces tissue factor expression in endothelial cells. Vet Med Sci 7(6):2440–2444. https://doi.org/10.1002/vms3.614
Khundmiri SJ (2014) Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules. J Endocrinol 222(1):R11–R24
Jelliffe RW (2014) The role of digitalis pharmacokinetics in converting atrial fibrillation and flutter to regular sinus rhythm. Clin Pharmacokinet 53(5):397–407
Choi DH, Kang DG, Cui X (2006) The positive inotropic effect of the aqueous extract of convallaria keiskeiin beating rabbit artia. Life Sci 79(12):1178–1185
Lehmann HD (1984) Effect of plant glycosides on resistance and capacitance vessels. Arzneimittelforschung 34(4):423–429
Lateef T, Rukash H, Bibi F, Azmi M, Qureshi S (2010) Effect of convallaria majalison kidney function. J Dow Univ Health Sci 4(3):94–97
Nartowska J, Sommer E, Pastewka K, Sommer S, Rozewska ES (2004) Anti-angiogenic activity of convallamaroside, the steroidal saponin isolated from the rhizomes and roots of Convallaria majalis L. Med Chem 61(4):279–282
Moxley RA, Schneider NR (1989) Apparent toxicosis associated with lily-of-the-valley (Convallaria majalis) ingestion in a dog. J Am Vet Med Assoc 195:485–487
Fitzgerald KT (2010) Lily toxicity in the cat. Top Companion Anim Med 25(4):213–217. https://doi.org/10.1053/j.tcam.2010.09.006
Launert E (1981) Covers plants in Europe. A drawing of each plant, quite a bit of interesting information. Edible and Medicinal Plants. Hamlyn
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Vatsa, E., Aggarwal, M. (2023). Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials. In: Arunachalam, K., Yang, X., Puthanpura Sasidharan, S. (eds) Bioprospecting of Tropical Medicinal Plants. Springer, Cham. https://doi.org/10.1007/978-3-031-28780-0_63
Download citation
DOI: https://doi.org/10.1007/978-3-031-28780-0_63
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-28779-4
Online ISBN: 978-3-031-28780-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)