Friedelin: Structure, Biosynthesis, Extraction, and Its Potential Health Impact

Pharmaceutical companies are investigating more source matrices for natural bioactive chemicals. Friedelin (friedelan-3-one) is a pentacyclic triterpene isolated from various plant species from different families as well as mosses and lichen. The fundamental compounds of these friedelane triterpenoids are abundantly found in cork tissues and leaf materials of diverse plant genera such as Celastraceae, Asteraceae, Fabaceae, and Myrtaceae. They possess many pharmacological effects, including anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. Friedelin also has an anti-insect effect and the ability to alter the soil microbial ecology, making it vital to agriculture. Ultrasound, microwave, supercritical fluid, ionic liquid, and acid hydrolysis extract friedelin with reduced environmental impact. Recently, the high demand for friedelin has led to the development of CRISPR/Cas9 technology and gene overexpression plasmids to produce friedelin using genetically engineered yeast. Friedelin with low cytotoxicity to normal cells can be the best phytochemical for the drug of choice. The review summarizes the structural interpretation, biosynthesis, physicochemical properties, quantification, and various forms of pharmacological significance.


Introduction
Plants in the form of whole plants, vegetables, fruits, whole grains, and nuts provide various phytochemicals like phenolic compounds, terpenoids, alkaloids, pigments, and other natural antioxidants [1,2].These phytochemicals are nonnutritive substances that possess large health-protective benefits [3].Over 80% of the world's population relies on the traditional medical system to treat their health issues [4].
Initially, the compound was extracted by soaking plant materials in various organic solvents.However, with the advancement of technology, modern extraction and analytical methods for the extraction of friedelin from different plant materials were used.With its great pharmaceutical usage, the amount of friedelin that can be obtained from plant sources is insufficient, whilst the amount that can be obtained through chemical processes is sometimes difficult to achieve, requires intense reaction conditions, and results in the production of unsafe compounds.In 2022, Wang et al. [33] used CRISPR/Cas9 technology and gene overexpression plasmids to produce friedelin using genetically engineered yeast.
According to the information obtained from various kinds of published research, friedelin could be a potential source in preventing various chronic diseases after the extraction and incorporation are completed at the target location.Nevertheless, the production of friedelin involves a number of significant procedures, the most important of which are the identification of the source, the determination of an appropriate quantity, and the execution of an appropriate extraction method.Therefore, this study is a complete presentation addressing the sources, qualities, and applications of friedelin, with a main emphasis on its numerous extraction procedures along with their applicability, limitations, and prospective remedies.

Chemistry and Biosynthesis Pathway of Friedelin
Triterpenes are an essential class of chemicals that are present in both prokaryotes and eukaryotes and are involved in a wide variety of biological processes [77].Triterpenoids and their derivatives have been shown to have a variety of functions, including those of hormones [78], lipid membrane components [79], and defense chemicals [80][81][82].In addition, numerous triterpenoids, or their downstream products, have medical applications [83][84][85].The biosynthesis of triterpenoids begins with the oxidation of 2-3-oxidosqualene, which is followed by protonation, cyclization, and several rearrangements [77].This substance is capable of being transformed into a large variety of structurally distinct backbones, with over 100 of them having been found in plants alone.Members of the oxidosqualene cyclases (OSCs) and squalene-hopene cyclases (SHCs) families of enzymes commonly carry out these changes [77].
Friedelin is a pentacyclic triterpenoid that is derived from perhydropicene [45].There is a substituent of an oxo group at position 3 of the perhydropicene molecule, as well as methyl groups at positions 4, 4a, 6b, 8a, 11, 11, 12b, and 14a [45].It has a pentacyclic structure consisting of five rings with the molecular formula C 30 H 50 O (Figure 1).It is an extremely basic compound with a pKa value of −7.4 and showed high solubility in chloroform, sparing solubility in ethanol, and insolubility in water [40].The molecular weight of friedelin is 426.7 g/mol with a topological surface area of 17.1 Å 2 .It contains one hydrogen bond acceptor, nine defined atom stereocenters, and one covalently bonded unit (details of chemical and physical properties of friedelin are shown in Table S1).
Molecules 2023, 28, x FOR PEER REVIEW 4 of 22 triterpenoids, or their downstream products, have medical applications [83][84][85].The biosynthesis of triterpenoids begins with the oxidation of 2-3-oxidosqualene, which is followed by protonation, cyclization, and several rearrangements [77].This substance is capable of being transformed into a large variety of structurally distinct backbones, with over 100 of them having been found in plants alone.Members of the oxidosqualene cyclases (OSCs) and squalenehopene cyclases (SHCs) families of enzymes commonly carry out these changes [77].

Extraction Methods and Analysis
The process of phytochemical extraction and purification from plant material is typically influenced by a number of parameters, the most important of which are time, temperature, the concentration of the solvent, and the polarity of the solvent [87].Because it is unlikely that a single solvent could reliably extract all of the phytochemicals present in the plant material, distinct phytochemicals are extracted in solvents of varying polarity according to the chemical nature of the phytochemical.
Friedelin is a pentacyclic triterpenoid non-polar compound.Various extraction methods reported to be used for friedelin extraction are represented in Figure 3. Depending upon the plant parts used, organic solvents such as methanol, ethanol, hexane, dichloromethane, petroleum ether, and chloroform are commonly used to extract friedelin (aforementioned Table 1).Soxhlet has been the most common extraction method of friedelin for a very long time (Table 2).This assertion is supported by the fact that Soxhlet has been a standard technique for more than a century and is currently the standard against which other leaching methods are measured [88].

Extraction Methods and Analysis
The process of phytochemical extraction and purification from plant material is typically influenced by a number of parameters, the most important of which are time, temperature, the concentration of the solvent, and the polarity of the solvent [87].Because it is unlikely that a single solvent could reliably extract all of the phytochemicals present in the plant material, distinct phytochemicals are extracted in solvents of varying polarity according to the chemical nature of the phytochemical.
Friedelin is a pentacyclic triterpenoid non-polar compound.Various extraction methods reported to be used for friedelin extraction are represented in Figure 3. Depending upon the plant parts used, organic solvents such as methanol, ethanol, hexane, dichloromethane, petroleum ether, and chloroform are commonly used to extract friedelin (aforementioned Table 1).Soxhlet has been the most common extraction method of friedelin for a very long time (Table 2).This assertion is supported by the fact that Soxhlet has been a standard technique for more than a century and is currently the standard against which other leaching methods are measured [88].Supercritical fluid extraction (SFE) is an environmentally friendly and selective method to obtain plant extracts [91,92].de Vasconcelos et al. [90] used a modified supercritical fluid extraction-CO 2 method in which plant material was extracted with CO 2 modified with methanol (10% v/v), ethanol (10% v/v), or pentane (10% or 20% v/v).They found that SFE CO 2 modified with 10% methanol and SFE CO 2 modified with 10% ethanol had the highest concentration of friedelin with 6.10 ± 0.75 mg/g plant material and 6.00 ± 0.97 mg/g plant material, respectively, as compared to SFE CO 2 modified with 10% pentane, which had a friedelin yield of 3.00 ± 0.90 mg/g plant material, whereas SFE CO 2 modified with 20% pentane had a friedelin yield of 3.70 ± 0.98 mg/g plant material [90].De Melo et al. [86] used pure and ethanol-modified CO 2 for the extraction of friedelin by the supercritical fluid extraction method.Different particle size (coarse particles to >80 mesh size) and ethanol (CO 2 modifier) content (0-5 wt.%) in a 0.5 L capacity unit, at 300 bar, 50 ºC, and a CO 2 flow rate of 11 g/min was used for the total (η total ) and friedelin (η friedelin ) extraction.In this extraction method, they found that intermediate granulometries (40-60 mesh to 60-80 mesh) and a CO 2 : EtOH ratio 95.0: 5.0 wt% with 300 bar pressure enhance the friedelin selectivity by up to 2.6 times [86].
Vieira et al. [34] used a supercritical fluid extraction method for the extraction of friedelin from Quercus cerris bark.They analyzed two CO 2 :EtOH ratios, 95.0:5.0 wt% and 97.5:2.5 wt%, with Q CO2 5 g/min & 8 g/min and temperature ranges 40-60 • C at a constant pressure of 300 bar.They found that the CO 2 :EtOH ratio of 97.5:2.5 wt%, Q CO2 8 g/min, and temperature 60 • C had the highest extraction yield of 0.48 wt% with a friedelin concentration of 28 wt% [34].Kornpointner et al. [65] used this extraction method with a condition like 2 h (1 h static/1 h dynamic) at 20 MPa and 60 • C from Cannabis sativa roots.The flow was set to 3 mL/min with 10 vol % EtOH as a co-solvent.They found that compared to conventional solvent extraction methods using n-hexane (0.698 ± 0.078 mg/g DW) and ethanol (0.0709 ± 0.036% by wt DW), the supercritical CO 2 combined with ethanol method has significantly less friedelin (0.0548% by wt DW, p < 0.05) yield [65].
Microwaves are non-ionizing electromagnetic (EM) waves in the electromagnetic spectrum between radio-frequency waves and infrared.The frequency 915 MHz is best for industrial applications due to its greater penetration depth, while 2450 MHz is used in domestic microwave ovens and extraction applications with a wide range of commercial applications [93].
Alves et al. [61] used ultrasound-assisted extraction (UAE) and pressurized-liquid extraction (PLE) methods for friedelin extraction from Monteverdia aquifolia leaves extracts and compared them with the conventional Soxhlet extraction (SOX) extraction method.They found the highest yield of 8.3% in SOX with ethanol (360 min and ±78 • C) with 6.6% in UAE (30 min, 50 • C, amplitude 80%, and solvent/biomass ratio 20 mL g −1 ) and 5.3% in PLE (25 min and 60 • C) with the same solvent.However, UAE and PLE produced better extracts with greater TPC and AA than traditional extraction and used less solvent [61].

Quantification of Friedelin
Pharmaceutical researchers have studied friedelin extensively.Analytical quantification of friedelin is increasingly dependent on diverse methods.GC-MS and GC-FID, which enable new technology, are the main analytical methods.
Friedelin isolated from the cork of Quercus suber L. and cork byproduct was quantified by gas chromatography-mass spectroscopy (GC-MS) [95,96].The chromatographic conditions were as follows: isothermal temperature 80 • C for 5 min followed by 285 • C for 15 min; 250 • C injector temperature; 285 • C transfer line temperature; 1:50 split ratio.The MS obtained data at 1 scan s−1 over m/z 33-800 in electron impact mode with 70 eV electron impact energy and the ion source were 200 • C. GC-MS quantification showed cork byproduct friedelin yields up to 1.4-5.0g/kg [95] and Quercus suber cork yield friedelin of 2.47 g/kg dry weight [96].
Gas chromatography with flame ionization detection (GC-FID) was used for the quantification of friedelin extracted from Maytenus ilicifolia [97].In this technique, 0.44 mg L −1 friedelin was quantified with the condition split mode (1:90) injected 1.0 L of samples in a 280 • C injector and 320 • C FID detector, with the column set at 300 • C isothermal mode, and the carrier gas was 1.5 mL/min helium [97].

Biological and Pharmacological Properties
Herbal therapies for the treatment of various diseases like diabetes, cancer, and liver problems are growing worldwide.Ayurvedic medicine uses herbal plant extracts to reduce the harmful side effects of medicines and improve efficacy.Numerous studies have demonstrated that Friedelin displays a diverse array of biological and pharmacological characteristics, encompassing hepatoprotective, antioxidant, anti-inflammatory, anticancer, anti-ulcerogenic, and neuroprotective properties.

Antioxidant and Hepatoprotective Activity
Under physiological conditions, the body maintains a balance between the production and elimination of free radicals.Excessive free radicals damage cellular proteins, membrane lipids, and nucleic acids, causing lipid peroxidation [98].The antioxidant and hepatopro-tective activity of friedelin is shown in Figure 4. Friedelin isolated from Azima tetracantha Lam.leaves sowed a free radical scavenging effect on 2,2-diphenyl-picrylhydrazyl (DPPH), nitric oxide, hydroxyl, and superoxide radical with IC 50 values of 21.1 mM, 22.1 mM, 19.8 mM, and 21.9 mM, respectively [99].Friedelin (25 µg/mL) isolated from Holothuria scabra showed 90.22 ± 0.15% DPPH free radical scavenging activity with an effective concentration (EC 50 ) value that was found to be 14.63 ± 0.01µg/mL [19].Friedelin isolated from the ethyl acetate extract of the stem of Tapinanthus bangwensis showed 73.69% free radical scavenging activities comparable to 93.96% by ascorbic acid [20].
Molecules 2023, 28, x FOR PEER REVIEW 9 of 22 membrane lipids, and nucleic acids, causing lipid peroxidation [98].The antioxidant and hepatoprotective activity of friedelin is shown in Figure 4. Friedelin isolated from Azima tetracantha Lam.leaves sowed a free radical scavenging effect on 2,2-diphenyl-picrylhydrazyl (DPPH), nitric oxide, hydroxyl, and superoxide radical with IC50 values of 21.1 mM, 22.1 mM, 19.8 mM, and 21.9 mM, respectively [99].Friedelin (25 μg/mL) isolated from Holothuria scabra showed 90.22 ± 0.15% DPPH free radical scavenging activity with an effective concentration (EC50) value that was found to be 14.63 ± 0.01μg/mL [19].Friedelin isolated from the ethyl acetate extract of the stem of Tapinanthus bangwensis showed 73.69% free radical scavenging activities comparable to 93.96% by ascorbic acid [20].Sunil et al. in 2021 [21] evaluated the hepatoprotective effects of friedelin in CCl4-induced oxidative stressed rats by administering a dose of 40 mg/kg for a period of 7 days.The results showed that friedelin was able to restore this hepatic enzyme to normal levels and exhibited similar hepatoprotective effects to silymarin (25 mg/kg), indicating its significant antioxidant and hepatoprotective properties [21,99].Friedelin fulfilled Lipinski's rule of five and showed better bioactivity than Silibinin.The findings of this investigation indicated that the bioactivity score of friedelin is superior to that of Silibinin, a potent hepatoprotective medication [100].
By comprehending network theory and systems biology, network pharmacology is the future drug discovery paradigm.Shi et al. [102] were able to identify the top 10 targets coming from the protein-protein interaction network by molecular docking of friedelin with ulcerative colitis (UC) receptors (Figure S1).Further, they demonstrated that 42 mg/kg/d intra-peritoneal friedelin (i.p) alleviated the effects of colitis by lowering inflammatory cytokines (IL-1β and IL-6), increased anti-inflammatory cytokines (IL-10), restored colon mucosa, and improved symptoms and bodily function in a mice model induced by dextran sulfate sodium [102].[21] evaluated the hepatoprotective effects of friedelin in CCl 4induced oxidative stressed rats by administering a dose of 40 mg/kg for a period of 7 days.The results showed that friedelin was able to restore this hepatic enzyme to normal levels and exhibited similar hepatoprotective effects to silymarin (25 mg/kg), indicating its significant antioxidant and hepatoprotective properties [21,99].Friedelin fulfilled Lipinski's rule of five and showed better bioactivity than Silibinin.The findings of this investigation indicated that the bioactivity score of friedelin is superior to that of Silibinin, a potent hepatoprotective medication [100].
By comprehending network theory and systems biology, network pharmacology is the future drug discovery paradigm.Shi et al. [102] were able to identify the top 10 targets coming from the protein-protein interaction network by molecular docking of friedelin with ulcerative colitis (UC) receptors (Figure S1).Further, they demonstrated that 42 mg/kg/d intra-peritoneal friedelin (i.p) alleviated the effects of colitis by lowering inflammatory cytokines (IL-1β and IL-6), increased anti-inflammatory cytokines (IL-10), restored colon mucosa, and improved symptoms and bodily function in a mice model induced by dextran sulfate sodium [102].

Antidiabetic Activity
Different mechanisms of antidiabetic effects of friedelin are shown in Figure 6.Susanti et al. [27] investigated the antidiabetic properties of friedelin isolated from twigs of Garcinia prainiana in insulin sensitivity 3T3-L1 adipocytes.The study observed that the intracellular fat accumulation was increased by 2.02-fold in the presence of friedelin when treated with an adipogenic cocktail (0.5 mM 3-isobutyl-1-methyl-xanthine (IBMX), 0.25 mM dexamethasone, 1 µg/mL insulin) compared to the cells treated with the vehicle.Adipocyte insulin sensitivity was tested using a deoxyglucose uptake assay.Compared to insulin-treated cells, friedelin increased glucose absorption by 1.8-fold [27].

Antidiabetic Activity
Different mechanisms of antidiabetic effects of friedelin are shown in Figure 6.Susanti et al. [27] investigated the antidiabetic properties of friedelin isolated from twigs of Garcinia prainiana in insulin sensitivity 3T3-L1 adipocytes.The study observed that the intracellular fat accumulation was increased by 2.02-fold in the presence of friedelin when treated with an adipogenic cocktail (0.5 mM 3-isobutyl-1-methyl-xanthine (IBMX), 0.25 mM dexamethasone, 1 μg/mL insulin) compared to the cells treated with the vehicle.Adipocyte insulin sensitivity was tested using a deoxyglucose uptake assay.Compared to insulin-treated cells, friedelin increased glucose absorption by 1.8-fold [27].

Antidiabetic Activity
Different mechanisms of antidiabetic effects of friedelin are shown in Figure 6.Susanti et al. [27] investigated the antidiabetic properties of friedelin isolated from twigs of Garcinia prainiana in insulin sensitivity 3T3-L1 adipocytes.The study observed that the intracellular fat accumulation was increased by 2.02-fold in the presence of friedelin when treated with an adipogenic cocktail (0.5 mM 3-isobutyl-1-methyl-xanthine (IBMX), 0.25 mM dexamethasone, 1 μg/mL insulin) compared to the cells treated with the vehicle.Adipocyte insulin sensitivity was tested using a deoxyglucose uptake assay.Compared to insulin-treated cells, friedelin increased glucose absorption by 1.8-fold [27].Sunil et al. [21] used STZ-induced diabetic Wistar rats to show the antidiabetic mechanism of isolated friedelin from A. tetracantha.Diabetic rats had decreased protein expression of liver PI3K, p-Akt, GLUT2 and AMPK, and skeletal muscle GLUT4.GLUT2, PI3K, AMPK, p-Akt, and GLUT4 protein expressions decreased in diabetic rats.They found that Sunil et al. [21] used STZ-induced diabetic Wistar rats to show the antidiabetic mechanism of isolated friedelin from A. tetracantha.Diabetic rats had decreased protein expression of liver PI3K, p-Akt, GLUT2 and AMPK, and skeletal muscle GLUT4.GLUT2, PI3K, AMPK, p-Akt, and GLUT4 protein expressions decreased in diabetic rats.They found that 40 mg/kg friedelin increased PI3K, p-Akt, GLUT2, and AMPK protein expression in STZ-induced diabetic rats [21].
A computational approach to uncover the interaction between molecules extracted from Syzygium cumini and antidiabetic targets was done by Smruthi et al. [103].Twenty-two phytoconstituents were docked with carbohydrate metabolism enzyme α-amylase using Autodock software (https://autodock.scripps.edu/accessed on 19 November 2023) and the Lamarckian genetic algorithm.Friedelin had a significantly lower binding energy of −9.54 kcal/mol than the synthetic medication acarbose, which had a binding energy of −2.43 kcal/mol [103].

Anticancer Activity
Several clinical trials have shown that herbal remedies have anticancer properties [104].Herbal medication was combined with conventional chemotherapy in anticancer therapy studies to improve therapeutic benefit, quality of life (QoL), and adverse effects [105].Friedelin demonstrated anti-proliferative properties against various cancer cell lines [106].The anticancer activity of friedelin is shown in Figure 7, and IC 50 values are listed in Table 3.
A computational approach to uncover the interaction between molecules extracted from Syzygium cumini and antidiabetic targets was done by Smruthi et al. [103].Twentytwo phytoconstituents were docked with carbohydrate metabolism enzyme α-amylase using Autodock software (https://autodock.scripps.edu/accessed on 19 November 2023) and the Lamarckian genetic algorithm.Friedelin had a significantly lower binding energy of −9.54 kcal/mol than the synthetic medication acarbose, which had a binding energy of −2.43 kcal/mol [103].

Anticancer Activity
Several clinical trials have shown that herbal remedies have anticancer properties [104].Herbal medication was combined with conventional chemotherapy in anticancer therapy studies to improve therapeutic benefit, quality of life (QoL), and adverse effects [105].Friedelin demonstrated anti-proliferative properties against various cancer cell lines [106].The anticancer activity of friedelin is shown in Figure 7, and IC50 values are listed in Table 3.    Malignant breast cancer affects 18% of the world's population and is the second leading cause of mortality for women [15,76].An upregulation of estrogen receptors has been observed in several instances of breast cancer.Friedelin extracted from Hopea odorata demonstrated a −4.710 docking score with estrogen receptor alpha (ER-α) [76].An in vitro cytotoxicity study of friedelin in human breast cancer cells (MCF-7) showed dose-as well as time-dependent inhibition of breast cancer proliferation [15].Friedelin had an IC 50 value of 0.51 µg/mL after 48 h for MCF-7 without causing any cytotoxicity in Vero and V79 cells.Friedelin caused DNA damage with significantly increased ROS levels.After 48 h of 1.2 µM friedelin treatment, Cdkn1a, pRb2, p53, Nrf2, and caspase-3 were upregulated, while Bcl-2, mdm2, and PCNA were downregulated, confirming apoptosis [15].
Prostate cancer is the second most common cancer in men and the fifth leading cause of death [109].It has been reported that drugs targeting CYP17A1, a cytochrome P450c17 inhibitor, slow prostate cancer progression.The first approved CYP17A1 inhibitor was abiraterone acetate.However, successful drugs have side effects and therapeutic resistance in prostate cancer [110].Friedelin derived from Cassia tora has been identified as the most optimal inhibitor of CYP17A1.Friedelin exhibits a stable binding pattern to the conserved binding pocket of CYP17A1, with a higher binding affinity compared to the control compound Orteronel.Friedelin's IC 50 was 72.025 and 81.766 µg/mL in hormonesensitive (22Rv1-a human prostate carcinoma epithelial cell lines) as well as insensitive (DU145-a human prostate cancer cell lines) cell lines, respectively.The histopathological study confirmed that in animal trials, friedelin reduced prostate weight, blood PSA, prostate index, and testosterone [17].
Friedelin suppressed human leukemia cells (AML-196) while exhibiting minimal impact on healthy cells.The induction of apoptosis by friedelin was found to be associated with an increase in the expression of cleaved caspase-3, -8, and -9, as well as cleaved PARP.The levels of Bax protein were observed to be elevated, while those of Bcl-2 were found to be reduced.Friedelin inhibited AML-196 leukemia cell migration and invasion in transwell tests.Furthermore, Friedelin exhibited a dose-dependent inhibition of the MEK/ERK and PI3K/AT signaling pathways [16].
Using in silico molecular docking as well as molecular dynamics simulation, a total of 52 bioactive secondary metabolites from Wedelia trilobata were found to bind to the antiapoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure.Friedelin's binding energy against Bcl-2 protein was 10.1 kcal/mol compared to 8.4 kcal/mol for Obatoclax's.In general, friedelin exhibits superior predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties compared to obatoclax.Friedelin derived from W. trilobata exhibits potential as an inhibitor of the Bcl-2 protein, which is known to be involved in cancer cell survival as well as resistance [18].
Friedelin exhibited in vitro anticancer properties against glioblastoma multiforme (U87MG-GBM) cells.MTT assay indicates that FRI exhibited greater cytotoxicity towards U87MG cells in comparison to PRCC cells, as evidenced by IC 50 values of 46.38 and 1271.77µg/mL, respectively [11].

Neuroprotective Activity
Cognitive dysfunction is a major health issue in the 21st century, and many neuropsychiatric and neurodegenerative disorders, such as schizophrenia, Alzheimer's disease dementia, seizure disorders, cerebrovascular impairment, and Parkinsonism, can severely debilitate [113].Medicinal plant phytochemicals regulate the key inhibitory neurotransmitter receptors to maintain brain chemical homeostasis.Several plants cure cognitive problems in traditional medicine [114].Chang et al. (2013) examined the neuroprotective effects of 176 phytochemicals on primary cortical neurons after oxygen-glucose deprivation.Friedelin showed similar cell viability after oxygen-glucose deprivation (OGD) insult, which was 0.97 ± 0.003 at 1 µM and 1.00 ± 0.009 at 10 µM, compared to the untreated control group at 1.00 [22].After OGD insult, friedelin exhibited neuroprotective effects, as shown in Figure 8.
Oxidative stress (OS) along with c-Jun N-terminal kinase (JNK) have been significant factors involved in neuroinflammatory signaling pathways as well as their associated neurodegenerative disorders.Sandhu et al. [23] tested the friedelin neuroprotection effect.Friedelin exhibited a protective effect against scopolamine-induced oxidative stress, neuroinflammation, glial cell activation, and p-JNK as well as NF-κB and their downstream signaling molecules.Friedelin was found to enhance neuronal synapse and improve memory deficits induced by scopolamine through the inhibition of β-secretase enzyme (BACE-1) and amyloidogenic pathways [23] as shown in Figure 8.

Antimicrobial and Antiparasitic Activity
With the rise of microbe resistance toward various antimicrobial drugs, novel antimicrobial medicines developed from natural bioactive substances were sought [115].Friedelin has been extensively researched for its potential health advantages and various biological properties, such as its ability to inhibit the growth of microorganisms.Friedelin extracted from Pterocarpus erinaceous [25], Azima tetracantha [24], Jatropha tanjorensis [26], Calophyllum inophyllum, Maytenus undata [74], Calophyllum brasiliense [73], Garcinia smeathmannii [72], and Cola lateritia K. Schum [116] have been reported to have antimicrobial properties against bacterial and fungal pathogens, as shown in Table 4.The antibacterial and resistance-modifying activities of friedelin isolated from the methanol extract of Paullinia pinnata L. roots were evaluated in vitro against Staphylococcus aureus strains SA1199B, RN4220, and XU212.These strains possess the Tet (K), Nor (A), and Msr (A) transporters, which confer resistance to tetracycline, norfloxacin, and macrolides, respectively [71].Friedelin had moderate antibacterial activity against three resistant S. aureus strains with MICs between 128 and 256µg/mL.At a concentration of 10µg/mL, friedelin did not exhibit any antibacterial activity.However, when combined with tetracycline, erythromycin, and norfloxacin, friedelin demonstrated a two-fold increase in potency [71].

Conclusions
This work presents detailed information on the various kinds of plant species that have been explored for the isolation of friedelin.Supercritical fluid extraction (SFE), ultrasoundassisted extraction (UAE), microwave-assisted extraction (MAE), and pressurized-liquid extraction (PLE) have been used to maximize friedelin extraction from plant sources.In this review, convincing evidence has been presented for the potent antioxidant activity of friedelin in several assay systems.Friedelin also suppresses inflammation in the brain tissues and regulates different cell signaling pathways.This review summarized that friedelin possesses potential as a valuable adjunctive therapy in the prevention and management of neurodegenerative disorders, cancer, diabetes, and inflammatory disease due to its natural origin.Nevertheless, it is important to note that the majority of the cited findings in this study are derived from experiments conducted in laboratory settings and animal models, which may not accurately reflect the impact on human subjects.Therefore, further investigation is required to explore the various pharmacokinetic parameters, potentially involving human participants, in order to ascertain the suitability of this substance as a prescribed medication in the future.High demand for friedelin has led to the development of CRISPR/Cas9 technology and gene overexpression plasmids to make it in genetically altered yeast.To efficiently acquire friedelin in large quantities, different plasmids must be studied.

Figure 3 .
Figure 3. Extraction methods of friedelin from different plant materials.Figure 3. Extraction methods of friedelin from different plant materials.

Figure 3 .
Figure 3. Extraction methods of friedelin from different plant materials.Figure 3. Extraction methods of friedelin from different plant materials.

Figure 6 .
Figure 6.Schematic diagram of antidiabetic activity of friedelin.Sunil et al. [21] used STZ-induced diabetic Wistar rats to show the antidiabetic mechanism of isolated friedelin from A. tetracantha.Diabetic rats had decreased protein expres-

Table 1 .
Plant materials containing friedelin and solvent used for their extraction.

Table 2 .
Extraction of friedelin using Soxhlet methods from different plant sources.
NA-Not available.

Table 3 .
IC50 values toward different cell lines treated with friedelin.

Table 3 .
IC 50 values toward different cell lines treated with friedelin.

Table 4 .
Antimicrobial activity of friedelin extracted from different plant sources.

Table 4 .
Antimicrobial activity of friedelin extracted from different plant sources.