Crude extract of Ficus deltoidea Jack (FD) as a natural biological therapy

Aim: This study shows how important it is to coordinate research on Ficus deltoidea Jack (FD) so that results from different sources can be compared directly and a scientific conclusion can be made. Methods: The author looked for research papers on Ficus (F.) deltoidea on Google Scholar, Science Direct, Google.com, Wiley, PubMed, Hindawi, Springer, and other related databases. This analysis excludes data that cannot be trusted, thesis papers, and review articles about F. deltoidea. Results: In traditional medicine, the plant’s leaves and syconia are used to cure a wide variety of ailments, including itchiness, diarrhoea, cancer, sexual dysfunction, age-related issues, malaria, cancer, anxiety, pain, constipation, fever, diabetes, tooth pain, and tooth decay. In vitro and in vivo studies showed the effectiveness of the leaves against cancer cell lines. Conclusions: Based on the existing research on the health benefits of FD, it is critical to focus on its more active constituents and their identification, determination, further development, and, most importantly, standardization of the leaves for the management and treatment of cancer and its related cases. More research is needed before it can be considered a promising herbal source of novel medication candidates for treating various disorders.

the separation of this species into two subspecies: F. deltoidea subsp. motleyana and F. deltoidea subsp. deltoidea [12]. There are two kinds of F. deltoidea plants: male and female. The difference between a male plant and a female plant is that the male plant has longer leaves, while the female plant has big, round, and long leaves [13]. The evergreen little tree or shrub can grow to 7-10 meters in its natural habitat [8]. The local people cultivate FD as a houseplant for aesthetic and medical advantages [14].

Traditional uses
The plant is well-known among the Malay people and is utilised in treating diabetes, headaches, sore throats, and colds [7]. Traditional medicine uses various sections of the plant to cure various conditions [15]. In traditional medicine, hyperlipidemia, hypertension, and diabetes are all treated with F. deltoidea [7,12]. This plant plays a significant role in traditional medicine, with its fruit used to treat a wide range of ailments, from headaches and toothaches to wounds (roots and leaves) [8,15]. The consumption of fruit is a common method for alleviating pain associated with toothache and migraine, root and leaf remedies for cuts and scrapes [8]. After giving birth, women drank a decoction of the leaves to help tighten the uterine and vaginal muscles [8,15]. It has been theorized that drinking a concoction made from the leaves can increase blood flow, have aphrodisiac effects, and even can fight diabetes [13]. Traditional uses for the extract include treating wounds, rheumatism, and ulcers; it is also effective as an antidiabetic medicine and a tonic for usage after giving birth [16].

Antioxidants activity
An antioxidant defence system is in place to counteract the oxidative stress caused by the body's normal physiological process of radical and reactive oxygen species (ROS) formation [17]. ROS are made when oxidative stress and the antioxidative defence system are out of balance. ROS can damage lipids, carbohydrates, proteins, and DNA, leading to many diseases [17]. Because of antioxidants' ability to protect the body from harmful free radicals and ROS, many chronic diseases can be avoided and even reversed. Different parts of F. deltoidea were evaluated for antioxidant potential (Table 1). Antioxidant activities of F. deltoidea have been documented in several investigations, but the portion of the plant utilized in the vast majority of the studies was the leaf [18]. The removal of ROS by the hydrolysed protein fractions was superior to that by the unhydrolyzed protein fractions [19]. Based on a one-way analysis of variance, only the protein hydrolysates of 30 and 100 kDa indicated significant differences in radical scavenging capacities [19]. Methanolic leaf extract had the highest antioxidants for ferric reducing antioxidant power (FRAP) (6-9 mmol Fe 2+ /g), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (2-3 mmol TE/g), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) (EC50:200-410 μg/mL) [12]. The methanol extract of F. deltoidea was the most effective at scavenging free radicals at 400 µg/mL (85.41%). Lacklustre radical scavenging activity was observed in butanol extract [1]. The findings of this study revealed that solvent extracts play a critical role in demonstrating biological activities. It was discovered that antioxidant and total phenolic content (TPC) depend on the polarity of the solvent in the case of antioxidant activity [1]. Eighty-five per cent of the antioxidant activity of the FD extract was attributed to flavan-3-ol monomers and proanthocyanidins [20]. Based on these results, it is plausible that the leaves of F. deltoidea could be employed as a natural antioxidant. These enzymes' activity and protein levels were elevated after exposure to F. deltoidea extract, suggesting that this compound may be responsible for reducing ROS production by acting on these enzymes. As a result, the extract directly scavenges ROS and indirectly stimulates the production of antioxidant enzymes ( Figure 2). The main antioxidant defence system consists of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Anti-ageing is partially achieved by SOD's ability to scavenge the superoxide anion formed in the early stages of oxidative stress. With the help of SOD, superoxide can be converted into harmless hydrogen peroxide and dioxygen. To quickly catalyse the decomposition of hydrogen peroxide, cells frequently use CAT and GPx (Figure 2).

Anti-inflammation activity
The process through which the body reacts to cellular damage is called inflammation [42]. It is a chain of events that can be set off by various stimuli, resulting in a predictable behavioural signature [42]. Results showed that FD aqueous extract (FDA) had significant anti-inflammatory effects in all assays at (P < 0.05) [11], and the paw oedema and formalin tests showed dose-response effects. In conclusion, the F. deltoidea leaf can reduce short-term and long-term inflammation and pain-related inflammation [11]. The findings, therefore, demonstrated the presence of pharmacologically active compounds with antinociceptive activity in the aqueous extract of F. deltoidea leaves [15]. Because of this, it is frequently applied in medicine to treat ailments that cause pain [15]. The fact that the FDA suppressed carrageenan-induced rat paw oedema for 5 h beginning 0.5 h after administration of the phlogistic drug implies that the extract's mode of action entailed suppressing the cyclooxygenase (COX)-dependent response [42]. The lipopolysaccharides (LPS) stimulated microglial cells at a maximal dose (100 μg/mL), and the extract significantly decreased the production of ROS, nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 ( Table 1). The extract of F. deltoidea considerably decreased the ultraviolet (UV)-induced production of TNF-α, IL-1, IL-6, and COX-2. The F. deltoidea extract may block proinflammatory cytokines, making it a potent remedy for skin conditions ( Table 2). Numerous compounds that inhibit the immune response have been identified in plants. The first large class of plant chemicals, phenolic compounds, are crucial to many plant functions. Depending on environmental conditions, phenolic chemicals can accumulate in various plant tissues and cells during ontogenesis. It has been shown through research that, phenolic chemicals, many of which are found in the cell walls, vacuoles, and nuclei of cells, have anti-inflammatory and anti-septic characteristics ( Table 2). Action mechanisms because of exposure to inflammatory substances, cells secrete arachidonic acid and inflammatory mediators like cytokines, serotonin, histamine, prostaglandins, leukotrienes, and vascular permeability and leukocyte recruitment are increased ( Figure 3). The UV-induced expression of TNF-α, IL-1, IL-6, and COX-2 was significantly reduced when the extract of F. deltoidea was used. Pro-inflammatory cytokines may be inhibited by the F. deltoidea extract, which may be an effective skin disease treatment [45] 5 In vivo 200 and 400 mg/kg The dose-dependent down-regulation of pro-inflammatory nuclear factor-kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and IL-6 mRNA levels by the FD extract considerably at P < 0.05 alleviated these bone microstructural and biomarker alterations. In this OP/osteoarthritis (OA) preclinical model, the FD extract showed good anti-osteoporotic characteristics by increasing bone formation and reducing bone resorption via anti-inflammatory pathways [46] 6 Aqueous, ethanolic Leaves Biomarkers related to endothelial activation and inflammation were inhibited by FD at the highest levels, whereas FD reduced monocyte binding at the second-highest level (17.3%) [47]

Effects on microorganisms
By measuring the minimum inhibitory concentrations (MICs) and the diameter of the zone of inhibition, the antimicrobial activity against bacteria and fungi was tested ( Table 3). The utility of F. deltoidea extracts against Gram-positive and Gram-negative bacteria are extensively known (Table 3). According to scientific research on F. deltoidea, these plants have garnered increasing interest in recent years. At a concentration of 31.26 mg/L, the plant extract did not stimulate the growth of the bacteria Edwardsiella tarda, Escherichia (E.) coli, Flavobacterium sp., Pseudomonas aeruginosa, or Vibrio cholera (Table 3). An extract from the plant prevented the growth of Aeromonas hydrophila, Klebsiella sp., Salmonella sp., and Vibrio alginolyticus when administered at a dosage of 62.5 mg/L. At a concentration of 125 mg/L, the plant extract inhibits the expansion of the pathogen Vibrio parahaemolyticus [10]. A 10-12 mm inhibition was found against the tested bacterial strain [50]. All bacteria tested were inhibited by the extract; however, Bacillus (B.) subtilis showed the greatest inhibition at 12 mm [51]. When tested against Staphylococcus (S.) aureus, the plant extract exhibited an inhibitory zone of 15.67 mm and a MIC of 3.125 mg/mL. The smallest reported sensitivity to chloroform extract was 6.33 mm, while the largest MIC was 25 mg/mL, both for B. subtilis [52]. Except for chloroform and aqueous extracts of B. subtilis, E. coli, and P. aeroginosa, all extracts demonstrated inhibitory effects on the fungi, Gram-positive and Gram-negative bacteria [5]. Results showed that the methanol extract was effective against the bacteria and the fungi used in the tests. The methanol extract showed the lowest MIC value (3.125 mg/mL) and the widest inhibition zone (15.67 mm) against the growth of S. aureus. B. subtilis had the highest MIC value (25 mg/mL) and the lowest sensitivity (6.33 mm) to the chloroform extract [5]. At 50 and 100 mg/mL, the MIC and minimum fungicidal concentration (MFC) for Candida albicans were both achieved with the studied extracts. The extract had a 69.5% inhibitory effect on biofilm formation by Candida [53]. All test organisms showed that the extracts had a strong antimicrobial effect ( Table 3). The qualitative and quantitative variability in the antifungal characteristics of the extracts is the root cause of the diversity in the inhibitory impact of plant extracts. The antimicrobial properties of these species may have come from the alkaloids, flavonoids, and cardiac glycosides found in these species' leaves. Based on our findings, F. deltoidea extracts may be a viable alternative to antibiotics for managing drug-resistant bacterial and fungal strains. Apparently, the secondary metabolites in this plant are responsible for the extract's extensive antibacterial activity. Various phytochemical substances have been reported to give F. deltoidea its medicinal benefits [1]. Species of the fig tree, F., are excellent resources for polyphenolic chemicals. The enhanced efficacy of the extracts is considered due to the synergistic effects of the various bioactive compounds present in F. deltoidea. In particular, the released chemicals attach easily to the negatively charged cell wall and break it, causing protein denaturation and cell death in microorganisms ( Figure 4), ultimately leading to its rupture and denaturation of its proteins and the death of the cell.    Effects on the endocrine system About 1.9 billion persons globally are overweight, and about 600 million are clinically obese [65]. This makes obesity the largest public health problem in the world today [65]. Fat accumulation in the cytoplasm of adipocytes defines the increased adipose cell size characteristic of obesity [66]. Several enzymes, including fatty acid synthase, lipoprotein lipase, and adipocyte fatty acid-binding protein, control this metabolic shift in adipocytes [66]. People have used traditional medicinal plants and their active phyto constituents to treat obesity and the problems that come with it. There is much-untapped potential in natural products for treating obesity, and they could be a great substitute for developing safe and effective anti-obesity medications. After therapy with F. deltoidea at 500 and 1,000 mg/kg/day, insulin resistance, obesity index, TC, triglycerides, low-density lipoprotein (LDL) cholesterol, MDA, testosterone, and follicle-stimulating hormone (FSH) were decreased to nearly normal levels in polycystic ovary syndrome (PCOS) rats ( Table 4). The capacity of F. deltoidea leaf extracts to prevent the development of mature adipocytes suggests that they may have anti-obesity capabilities [67]. The findings showed that F. deltoidea is a viable medicinal plant for creating novel functional foods, herbal medicines, and contemporary drugs with enormous potential for treating obesity. It has been demonstrated through scientific research that F. deltoidea can lower hyperglycaemia in a variety of prandial situations (Table 4). Different studies have claimed that F. deltoidea has antidiabetic and antioxidant properties, but most of these investigations have only employed the leaf. Researchers have found a link between the phenolic content of plants and their ability to combat diabetes [18]. Increased protein content and lower glucosidase activity in treated F. deltoidea samples provide compelling evidence for the critical role of proteins in demonstrating the beneficial antidiabetic effect [18]. Some research has suggested that F. deltoidea antihyperglycemic effects are mediated by the plant's ability to increase insulin secretion from pancreatic cells, boost adipocyte glucose uptake, and boost adiponectin release from adipocytes [68]. Particularly, flavonoids and isoflavonoids are because of the high levels of antioxidant activity found in the extract, which benefits in awarding against illnesses caused by oxidative damage [25]. The findings suggested that the extracts may be a viable antibiotic option for regulating the growth of various bacterial strains. Pure substances or crude extracts may work through the production of inflammatory cytokines, leading to the death of microphages in the circulation and the release of secretory insulin. On the other hand, stimulating dendritic cells in the brain, where Hypoglycemia is present, will indicate insulin release. By inhibiting the connection between the insulin receptor in the cells and insulin release, the presence of fat that covers the insulin receptor likely contributes to insulin resistance and diabetes mellitus. The condition depicted in Figure 5 highlights complications associated with diabetes mellitus: The neurological system is harmed by nephropathy, retinopathy, and neuropathy (damage to nephrons).

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There were dose-dependent inhibitory effects on the activity of yeast and rats in the gut but no effect on porcine pancreatic -amylase. In terms of α-glucosidase inhibition, the water fraction had the highest protein content at 73.33 µg/mg fraction [18] 17

Antihypertensive activity
There is a strong association between hypertension and the development of cardiovascular disease [92]. Over 1 billion people throughout the world are afflicted with it. Hypertension is more common in the elderly than in the young [92]. People over 60 have a prevalence of 65.5% of hypertension. Insulin resistance, obesity, glucose intolerance, concomitance, haemagglutinin, excessive uric acidemia, atherosclerosis, and cardiovascular illnesses are just a few of the chronic diseases and difficulties connected to hypertension [92].
High blood pressure in spontaneously hypertensive rats (SHR) can be reduced by administering an ethanol and water extract of FD. The renin-angiotensin-aldosterone system (RAAS) pathway, antioxidants, and the endothelial system may all play a role in this [93]. Rats treated with FD extract and losartan had significantly reduced blood pressure, heart rate, and heart weight compared to the controls ( Table 5). The systolic blood pressure (SBP) of rats treated with FD plus losartan for four weeks was significantly lower than that of rats not treated with FD. Urine spectral analysis revealed 24 putative biomarkers with significance estimates greater than 0.5 (Table 1). Results from this study show that F. deltoidea has strong antihypertensive efficacy and shows promise for further research and development as an antihypertensive drug. The ethanol and water extract of FDK lowers blood pressure in SHR. This could be due to RAAS, antioxidant, and endothelial systems [93] 2 In vivo Ethanol-water 800 or 1,000 mg/kg/day When FDA and losartan were used to treat rats, the rats' blood pressure, heart rate, and heart weight were all much lower than the controls [94] 3 In vivo 1,000 mg/kg/day After four weeks of treatment with FD, the SBP of rats treated with FD and losartan was much lower than that of rats that were not treated. An analysis of the spectra of urine showed that there were 24 possible biomarkers with variable importance projections above 0.5 [95] 4 1,000 mg/kg Compared to the control group, rats treated with 1,000 mg/kg of FD and losartan demonstrated a significant decrease in blood pressure. Rats treated with FDK had decreased serum concentrations of angiotensin II and aldosterone compared to controls and rats treated with losartan. There were no variations between serum and urine electrolytes [96] Aphrodisiac activity Disturbances in a man's sex drive might manifest as erectile dysfunction, ejaculatory dysfunction, or even an orgasmic condition [97]. Sexual activity is necessary for all humans and has been shown to increase the link between husband and wife, making it a good indicator of marital satisfaction. Psychological discomfort, infertility, and even suicide have all been linked to sexual dysfunction. Male mice benefit from an ethanolic extract from the leaves because it increases fertility and reproductive hormones (Table 1). Testosterone levels, sperm counts, and rat mobility improved after administering an aqueous and an ethanolic extract of FD leaves (Table 6). These treatments also substantially impacted the lowering of blood glucose levels, the number of abnormal sperm, and the frequency with which blood clots formed. Alloxan monohydrate's negative effects on blood clotting, sperm quality, and testosterone level in male rats can be mitigated by administering an oral dose of an aqueous and ethanolic extract of FD leaves [98]. The sperm count, LDH-C 4 activity, and testosterone concentration of rats with diabetes were all enhanced after oral administration of an aqueous and ethanolic extract of FD leaves. These treatments had a major effect on blood glucose levels and sperm abnormalities [99]. Studies have demonstrated that plant polysaccharides help prevent testicular injury and encourage the renewal of testicular architecture. This study's findings suggest that F. deltoidea extracts enhance general sexual performance and may also be useful in treating erectile dysfunction. The results support traditional medical claims that these plants have aphrodisiac properties and could improve sexual performance. These findings support the legitimacy of traditional Indian medicine's recommendation for these plants.  When rats were given an aqueous, and an ethanolic extract of F. deltoidea leaves, their testosterone level, sperm count, and mobility improved. Moreover, these treatments greatly reduced the blood glucose levels, the number of abnormal sperm, and the rate at which the blood clots. In conclusion, giving male rats an oral dose of the aqueous and ethanolic extract of F. deltoidea leaves may reverse the effects of alloxan monohydrate on blood clotting, sperm quality, and testosterone levels [98] Wound healing activity Major causes of physical incapacity include wounds [103]. A wound is a tissue disturbance brought on by physical, chemical, microbial, or functional losses [103]. Numerous factors, including bacterial infection, necrotic tissue, obstruction of the blood supply, lymphatic blockage, and diabetes mellitus, cause the wound healing process to be delayed (or reduced). Generally speaking, if any agent could change the aforementioned factors, the healing rate would be increased [104]. In Ayurveda, many plants play a crucial part in the recovery from injury. Plants are superior medicines because they work by stimulating the body's natural mending processes [105]. Healing time is reduced, and aesthetics are preserved with plant-based therapy [106]. Animal products comprise less than 10% of wound-healing pharmaceuticals, whereas plants account for over 70%. Antiseptic coagulants and wound washes made from plant-based ingredients are utilized in emergencies [106]. Compared to wounds treated with sterile deionized water or dressed with a blank placebo, wounds treated with a placebo containing 5%, 10% F. deltoidea extract, or intrasite gel dramatically accelerated the healing rate [107]. A dose-dependent increase in cell proliferation can be achieved with leaf extract. In scratch testing, F. deltoidea leaf extract sped up wound healing compared to ascorbic acid-treated and untreated cells [108]. The 20% methanolic extract of leaves has been shown to speed up the healing process of wounds (Table 7). In terms of DNA and hydroxyl proline content, mice given an extract concentration of 80% showed the highest levels ( Table 7). The extract's wound-healing efficacy is proportional to its concentration (Table 7). FD extract is an effective treatment for wound healing since it can activate the body's natural repair processes. The mechanism of F. deltoidea extract's activity on the healing of wounds still must be understood. Wounds treated with F. deltoidea extract containing 5 or 10% of the total extract considerably expedited the healing process compared to wounds treated with sterile deionized water [107]  Leaves 10-1,000 μg/mL Inhibition of human liver glucuronidation activity was found in the range from 34.69 μg/mL to 398.10 μg/mL [110] 5 In vivo Hot aqueous

Leaves
The liver and kidneys were unaffected by the extract. Rats treated with the extract gained weight, improved depressed behaviour, and had fewer pyknotic and dark-stained neurons in their hippocampus [111] Anticancer activity There has been much focus on plant-based biological products for quite some time. The potential for finding novel biomolecules with future applications motivates the investigation of these priceless by-products. Natural plant products are becoming increasingly popular for use in both the prevention and treatment of disease. The traditional use of medicinal plants as a treatment method is the basis for contemporary medicine [112]. The success rate of treating cancer with allopathic medicine or chemotherapy drugs like cisplatin has increased over time [16]. However, this course of treatment is commonly cited as having dangerous side effects because of the toxicity of chemotherapeutic drugs. Additionally, chemoresistance is to blame for 90% of drug failures in patients with metastatic cancer [16]. Researchers have tried to find alternative treatment approaches to treat cancer, some of which involve using natural products. Drugs used in chemotherapy to treat cancer are typically based on chemicals first identified in plants or synthetic versions of these molecules [112]. Unfortunately, despite many efforts, cancer is still a major cause of death worldwide. Because of this, researchers are constantly looking for new, cost-effective treatments for cancer. Growing evidence suggests that compounds produced from plants may be able to inhibit several steps in carcinogenic and inflammation-related processes, making these products increasingly important in cancer prevention and treatment. Both 48.2 and 62.7 g/mL had IC 50 values that suppressed microvascular proliferation (Table 8).
Mice infected with azoxymethane/dextran sodium sulfate (AOM/DSS) had lower levels of alpha-catenin in their colons, which was inhibited by the FD ethanol extract. Human colon cancer (HCT 116) was also inhibited by the FD ethanol extract [113]. Nuclear DNA fragmentation showed that the extracts produced apoptosis, a form of cell death (P < 0.05). In PC3 and L ymph N ode Ca rcinoma of the P rostate (LNCaP) cell lines, there was also a substantial increase in mitochondrial membrane potential (MMP) depolarization (P < 0.05) and caspase 3 and 7 activations (P < 0.05) ( Table 8). The IC 50 values were calculated to be 224.39 µg/mL for the aqueous extract and 143.03 g/mL for the ethanolic extract. However, only the ethanolic extract (1,000 µg/mL) caused DNA fragmentation, while the water-based extract had no effect. The breaking caused a loss of about 200 kbp of DNA. Morphological testing revealed apoptotic bodies appeared in both extracts at concentrations of 1,000 µg/mL [114]. When tested for cytotoxic effects on the HL-60 cell line, it was discovered that the FD leaf extract was far more potent than the fruit extract [115]. The FD extract positively impacted tumour development. When the FD extract was used, the incidence of oral squamous cell cancer (OSCC) decreased from 100% to 14.3% in the high-dose groups [116]. At the end of the treatment period, there was a significant decrease in testosterone, FSH, and luteinizing hormone (LH) levels at P < 0.05 but a significant increase in progesterone and estrogen levels at P < 0.05 in extract treated groups compared to the control group [117]. We found that F. deltoidea extract significantly slowed the growth of established tumours, indicating that it possessed potent anticancer properties (Table 8). Flavonoids abundant in F. deltoidea include isovitexin, gallocatechin, ellagic acid, coumaroylquinic acid, catechin, gallic acid, quercetin (Figure 6), and naringenin. The anticancer benefits of the plant are due to these compounds [8]. F. deltoidea has high levels of polyphenolics, flavonoids (such as genistin), alkaloids (such as antofine), and tannins [118,119]. Flavonoids like epigallocatechin have been proven to inhibit the growth of prostate cancer cells in vitro [120]. Vitexin has a cytotoxic effect on breast, ovary, and prostate cancer cells by upregulating BCL2-associated X protein (Bax) and downregulating BCL2 and causing the breakage of the poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP) protein [121]. By decreasing the BCL2/Bax ratio and activating caspases, vitexin inhibits tumour growth and spread by killing cancer cells [122]. Naturally occurring antioxidant ellagic acid has been demonstrated to have antiproliferative and pro differentiation actions on prostate cancer cells via suppressing eicosanoid synthesis and the heme oxygenase system [123]. Murine leukaemia cells and the human lung cancer cell line have both been shown to undergo apoptosis when treated with the antioxidants rutin and quercetin, respectively, which have been linked to having anticancer characteristics. Plant polyphenols have long been recognized for their antioxidative effects against oxidative stress, which has been associated with cancer [119]. The flavonoids in F. deltoidea have therapeutic potential as a treatment for prostate cancer [122]. The possible mechanism of action of F. deltoidea as a tumour suppressor and its crude extract or pure components is shown in Figure 7. It also depicts the anti-tumorigenic activities induced by signal transducing components by crude extracts or pure chemicals and the tumour cascade pathways initiated in cancerous cells by various growth factors in Figure 7. The expression of the tumour-inducing pathways phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), natriuretic peptide type B (NP-B), mitogen-activated protein kinase (MAPK), and ROS is downregulated at the infection site by crude extract or pure chemical in a conjugated form. Pure substance or crude extract interrupts the cycle, prevents the synthesis of p21 and p27 cyclin-dependent kinase inhibitors, and prevents the mitotic effects. These activities are all connected to cancer cell development, dissemination, and proliferation. F. deltoidea killed multiple tumour cell lines; however, the effectiveness was dose-and time-dependent. This analysis verified the results of ethnobotanical studies that reveal the medicinal potential of F. deltoidea used in traditional medicine. Based on our findings, F. deltoidea extracts or pure compounds have great potential as an anticancer drug.

Toxicity evaluation
Despite their efficacy in treating specific diseases, the widespread use of some medicinal plant species is associated with serious adverse effects. Many pharmaceuticals owe their existence to the discovery of a chemical in a plant that has biological activity and has subsequently been used to treat medical conditions. The natural chemical compounds in plants give them pharmacological and therapeutic properties, and their potential toxicity must be evaluated to ensure that the product is safe for human consumption (Table 9). Compared to the control group, no appreciable variations in the number of micro-nucleated cells were seen. At concentrations up to 5,000 g/plate, the extract was not found to increase the number of revertant colonies in any strains tested. In conclusion, more studies using animal models are necessary to confirm non-geno-harmful effects [128]. Uterine abnormalities in bisphenol A (BPA)-exposed rats improved significantly after six weeks of concurrent therapy with F. deltoidea. The histology of the myometrium and glandular epithelium appeared normal, and mitotic patterns were visible in the interstitial gaps between the stromal cells [129]. In an acute toxicity assay, the extract's median lethal dose (LD 50 ) was greater than at the concentration of 5,000 mg/kg. The sub-chronic toxicity study findings were shown to have no impact on food consumption, BW, organ weight, mortality, clinical chemistry, haematological, gross pathology, or histology (Table 1). All extracts had a higher than 2,000 mg/kg BW and LD 50 , and the acute toxicity test showed no signs of morbidity or mortality. Histopathological analyses of the kidneys and liver showed no abnormalities [84] despite the non-reportage of any toxic part of F. deltoidea. Additional testing is required using various cell lines in a range of sample dilutions. The medication is then tested in rodents and other animals, particularly mice and rats, before being administered to human patients.  Leaves 1,000 mg/BW This group did not affect glycaemia variables, although total and LDL cholesterol values were dramatically reduced. Vital signs and safety lab tests were within normal ranges at baseline and after 8 weeks of intervention, there were no significant differences between groups or attributable to the intervention [130] 10 Brine shrimp lethality assay and in vivo Aqueous Leaves According to the research, the extracts had no harmful effects on brine shrimp (up to 4,000 μg/mL) or rats (up to 0.2 per cent BW) [89] 11 In vivo Ethanolic Leaves The LD 50 of the extract was found to be more than 5,000 mg/kg in an acute toxicity assay. Food consumption, BW, organ weight, mortality, clinical chemistry, haematological, gross pathology, and histopathology were all unaffected by the sub-chronic toxicity study results [131] 12 In vivo Leaves 1,000 mg/kg It was shown that up to 1,000 mg/kg of F. deltoidea leaf extract was not harmful [124] 13 In vivo Aqueous Leaves 100 mg/kg/day Uterine abnormalities in the BPA-exposed rats significantly improved after six weeks of concomitant therapy with F. deltoidea. The myometrium and glandular epithelium histology seemed normal, and mitotic patterns were present in the interstitial gaps between the stromal cells [129] 14   50 of the extracts for all kinds was higher than 2,000 mg/kg BW, and the acute toxicity test revealed no symptoms of morbidity or mortality. The kidneys and liver's histopathological evaluation revealed no abnormalities [84] 17 In vivo Fruits According to the testing data, the tensile strength of carbon nanotube (CNT)-filled composites increased by 7.73% compared to the control unfilled hybrid composites. For the CNT-filled composites, the flexural characteristics decreased by 49.37% compared to the control, which had no CNTs [133] 18 In vivo Methanol: distilled water (60:40 % v/v) Leaves 300, 2,000, and 4,000 mg/kg Some important organs underwent haematological and histological examination. Mortality was not recorded at any point during the study in either the acute or sub chronic toxicity groups Encapsulated plant extracts (600 and 1,000 mg/kg) increased serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels significantly, and histological assessment of the liver, kidneys, and spleen showed normal tissue limits [134] 19 Viability assay Methanol

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Viability was only shown to be hazardous at 500 and 1,000 μg/mL (P < 0.001) [76] 20 In vivo Ethanol Leaves 125, 250, 500, and 1,000 mg/kg BW The absence of toxic symptoms and death at a 2,000 mg/kg BW dose suggests that the LD 50 was higher. Throughout this time, no changes in the mouse's behaviour, substantial weight changes, haematological parameters, or serum biochemistry were noticed [135]

Discussion
The therapeutic properties of FD have been recognized for centuries, and the elderly have found several uses. Scientific research was conducted to confirm its effects, particularly in pharmaceutical applications, as it gained increasing attention. Its biological efficacy was documented in the current study. These findings provide solid evidence for the considerable and positive benefits of F. deltoidea extract on the rate of wound healing, cancer, fever, diabetes, blood pressure, bacterial infection, fungal infection, and many other diseases due to the presence of phenolic and flavonoid bioactive compounds. However, additional research into the bioactive components that may be responsible for its anticancer activity is necessary. Further studies must determine the appropriate dosage for treating and controlling cancer and related disorders globally. This study may serve as a solid foundation for creating herbal medicines or active compounds with tremendous potential for use in the treatment and prevention of cancer and its related future.

Author contributions
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Conflicts of interest
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