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Title: Guggulsterone Structural Type Steroids: Chemical Characterization, Biological Activities, and Therapeutic Potential

Genomic and Biotechnological Approaches to Guggulsterone Production in Commiphora Species

Genomic approaches to guggulsterone production in Commiphora species have centered on identifying key biosynthetic genes. The CSIR-National Botanical Research Institute, Lucknow, India, maintains 53 guggul germplasms (IC-471198 to IC-471282) collected from Rajasthan, India, and used young leaves from a two-month-old seedling of genotype IC471203—with the highest guggulsterone content (20.37 mg g⁻¹)—for de novo draft genome sequencing [1]. Analysis of this genome identified multiple genes and transcription factors linked to phytosterol biosynthesis, as summarized below:

Key Biosynthetic Genes and Transcription Factors Identified in Commiphora Species

Gene/Transcription Factor	Sequence ID	Homologous/Orthologous Reference	Identity/Homology	Citation
Cycloartenol synthase 1 (CAS1)	g234.t1	Arabidopsis CAS1 (sp	P38605	CAS1_ARATH)
Squalene epoxidase	g116.t1	Arabidopsis squalene epoxidase (NC_003071.7: c9726384-9723615_SQE2_ARATH_GeneID=816814)	75% identity	[1]
3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 (HMGR)	g892.t1	Solanum lycopersicum HMGR (NC_015439.3:c46508678-46505935_HMGR_SOLLC_GeneID=543702)	67.5% homology	[1]
WRKY1	—	Orthologous to phytosterol biosynthesis-associated WRKY1	—	[1]
MYC2	—	Orthologous to phytosterol biosynthesis-associated MYC2	—	[1]

Biotechnological strategies for guggulsterone production include clonal propagation, somatic embryogenesis, and cell suspension cultures [2]. Key outcomes of these strategies are detailed in the table below:

Outcomes of Biotechnological Strategies for Guggulsterone Production

Strategy	Method Details	Key Outcome	Citation
Clonal propagation	Stem explants on MS medium with benzyladenine, kinetin, glutamine, thiamine HCl, and activated charcoal	60% survival at hardening stage; vigorous, uniform growth	[2]
Somatic embryogenesis	Immature zygotic embryos on B5 medium with 2,4,5-trichlorophenoxy acetic acid and kinetin	25% conversion of cotyledonary stage embryos to plantlets; 95% survivability in garden soil	[2]
Cell suspension cultures	Leaf callus-derived cultures in MS medium with 2,4-D and kinetin (25-day-old)	0.32% guggulsterol (vs. 1.97% in stem explants and 0.22% in two-month-old callus)	[2]

Optimization of cell suspension cultures has further enhanced guggulsterone accumulation. Cultures were maintained in modified MS medium (NH₄NO₃ 825 mg l⁻¹, KNO₃ 950 mg l⁻¹, CaCl₂·6H₂O 220 mg l⁻¹) supplemented with 0.25 mg l⁻¹ 2,4,5-trichlorophenoxyacetic acid, 1 mg l⁻¹ 2iP, and 3% sucrose to test plant growth retardants, fungal elicitors, and fed-batch systems [3]. A two-stage fed-batch system—where cells were first grown in growth medium for 12 days, then transferred to production medium (PM: NH₄NO₃ 1650 mg l⁻¹, KNO₃ 475 mg l⁻¹, CaCl₂·6H₂O 220 mg l⁻¹, 1 mg l⁻¹ 2iP, and 4% sucrose:glucose (1:1))—yielded significant improvements. Adding 1 mg l⁻¹ CCC, 500 mg l⁻¹ Fusarium fungal cell wall powder, and twice-fed sugars (sucrose:glucose 1:1) on days 7 and 10 resulted in a 3.5-fold increase in total guggulsterone yield (353 μg l⁻¹) and dry cell weight (10.8 g l⁻¹) [3]. Key results from plant growth retardant testing are summarized below:

Guggulsterone Accumulation with Plant Growth Retardants in Cell Suspension Cultures

Retardant	Concentration	Addition Timing	Maximum Guggulsterone Content	Citation
CCC	1.0 mg l⁻¹	5th day post-inoculation	123 μg l⁻¹	[3]
ALAR	2.5 mg l⁻¹	10th day post-inoculation	116 μg l⁻¹	[3]

Chemical Characterization and Quantification of Guggulsterone Structural Type Steroids and Related Metabolites

Guggulsterone structural type steroids—including the Z- and E-isomers of guggulsterone—are key components of the oleogum resin from Commiphora species such as C. wightii, C. mukul, C. molmol, C. abyssinica, and C. Burseraceae [4][5]. The volatile constituents of guggul resin include these ketone steroids alongside guggulsterols I, II, and III [4], while additional related metabolites identified in C. wightii bark include guggulsterone-M (GS-M), 4-pregnene-3,16-dione, myrrhanol-C, campesterol, guggulsterol-II, β-sitosterol, dehydroguggulsterone-M, guggulsterol-I, guggulsterol-VI, myrrhanolide-A, guggulsterol-III, and guggulsterol-IV [6].

Chemical characterization and quantification of these steroids have been performed using various analytical methods, with key parameters for guggulsterone isomers summarized below:

Key Analytical Parameters for E- and Z-Guggulsterone Quantification

Method	Parameters Measured	E-Guggulsterone (E-GS) Values	Z-Guggulsterone (Z-GS) Values	Citations
HPTLC	Rf, λmax (standards/samples), r²	Rf=0.43; λmax=250 nm (standard), 249–250 nm (sample); r²=0.9979	Rf=0.48; λmax=250 nm (standard), 251–257 nm (sample); r²=0.9991	[7]
HPLC (Agilent Zorbax XDB-C18 column)	Retention time (Rt), linear range, r²	Rt=6.534 min; linear range=2–65 mg/mL; r²=0.99988	Rt=8.528 min; linear range=2–65 mg/mL; r²=0.99985	[8]
HPLC (ICH-validated)	LOD, LOQ, r², intraday precision RSD (detection at 242 nm)	LOD=0.50 mg/mL; LOQ=1.0 mg/mL; r²>0.999; RSD=2.86%	LOD=0.50 mg/mL; LOQ=1.0 mg/mL; r²>0.999; RSD=2.31%	[6]

Geographical and tissue-specific variations in guggulsterone content have been observed: C. wightii bark contains higher total E- and Z-guggulsterone concentrations (0.55–1.74 mg/g) than stems (0.09–0.39 mg/g) across regions, with hydro-alcoholic bark extracts showing concentrations of 1.66–3.93 mg/g [6]. Resin samples from Sindh, Pakistan, have higher total guggulsterone content (0.9–3.0% w/w) than those from Baluchistan (0.12–0.54% w/w) [8]. In herbal formulations, E-GS is present in most samples (except one), Z-GS is ubiquitous, and total content ranges from 0.362% w/w (Indian tablets) to 2.944% w/w (USA tablets) [7][8].

Extraction and purification methods for related metabolites include reflux extraction of C. mukul resin with 50% aqueous methanol, followed by partitioning into ethyl acetate (EtOAc) and water fractions; the EtOAc fraction is further purified via silica gel column chromatography and HPLC to isolate polypodane-type triterpenes (e.g., myrrhanol A, myrrhanone A) and a lignan [(±)-diayangambin] [9]. Synthetic routes for guggulsterone have also been developed using various steroid precursors, with structural modifications aimed at improving biological properties [5].

Anti-Inflammatory and Metabolic Regulatory Activities of Guggulsterone Structural Type Steroids

Guggulsterone, a phytosterol derived from the gum resin of guggul plants (e.g., Commiphora mukul), has traditional uses in treating burns, wounds, gastric ulcers, and intestinal worms, and exhibits anti-inflammatory and antioxidative properties[10]. Its bioactive E and Z isomers primarily contribute to effects on lipid and cholesterol levels[11], with recent research also highlighting anticancer properties[11]. Guggul gum, which contains guggulsterone, has been used in traditional Persian medicine to alleviate stomach distention, swelling, belching, intestinal ulcers, inflammatory bowel disease (IBD), and hemorrhoids[12]. Guggulsterone is also recognized as a potential hypolipidemic agent[13].

Anti-Inflammatory and Formulation Efficacy of Guggulsterone and Related Compounds

Agent/Formulation	Model/Assay	Key Findings	Citation
Guggulsterone	GR protein docking (PDB ID 2V95)	Bound to GR, good GOLD score, interacted with active site amino acid ASP 256	[14]
Guggulsterone	Croton oil-induced ear edema (acute)	Significantly inhibited edema	[14]
Guggulsterone	Cotton pellet-induced granuloma (chronic)	Inhibited granuloma; order: boswellic acid > withaferin A > guggulsterone	[14]
Guggulsterone	Cotton pellet-induced granuloma rats	Reduced serum IL-6; no significant effect on TNF-α	[14]
Guggulsterone	Mouse colitis models	Exhibited anti-inflammatory activity by targeting lamina propria T cells	[12]
Guggul lipid nanoparticle (GLN-3)	Edema inhibition assay	Maximum edema inhibition (99.83%) vs. conventional extract (50.54%) and indomethacin (79.25%)	[15]

A randomized controlled trial in 99 patients with hemorrhoids found that 3 g/day guggul gum for 4 weeks significantly reduced flatulence, dyspepsia, gastro-esophageal reflux, colonoscopic grading scores, constipation, and proctorrhagia compared to control[12]. Guggul lipid, which contains guggulsterone, has been formulated into nanoparticles (e.g., GLN-3) that showed high stability and enhanced flux[15].

Molecular Targets and Mechanisms of Action of Guggulsterone Structural Type Steroids

Guggulsterone is a steroidal molecule with two α,β-unsaturated carbonyls (enones) that exhibits diverse molecular targets and mechanisms of action across therapeutic contexts. Its activities span anti-inflammatory, antiviral, cancer, and cardioprotective pathways, with key interactions and effects documented in various studies. Below is a consolidated summary of its mechanisms, targets, and associated outcomes:

Guggulsterone Mechanisms, Targets, and Outcomes Across Therapeutic Contexts

Therapeutic Context	Target/Pathway	Key Observations & Outcomes	Citations
General molecular action	IκBα kinase	Inhibits activation	[16]
SARS-CoV-2	Viral ADP-ribose phosphatase (ARP)	Proposed antagonist via 100 ns Desmond/Schrodinger simulations; stable macromolecular RMSD (1–1.6), ligand RMSD < 0.15–0.45; interactions with Ala38, Phe132, Leu160, Gly46, Gly47, Phe156, Asp157, Ile131 (H-bonds, hydrophobic, water-bridges)	[17]
Anti-inflammatory	Glucocorticoid receptor (GR; PDB ID 2V95)	Good GOLD docking score; interacts with Asp256	[14]
Anti-inflammatory	Inflammation models	Inhibits croton oil-induced ear edema and cotton pellet-induced granuloma (order: boswellic acid > withaferin A > guggulsterone); reduces IL-6 levels but not TNF-α in granuloma models	[14]
PXR modulation	Pregnane X receptor (PXR)	Acts as human PXR agonist; inhibits rifampicin-induced PXR activation	[18]
Cancer	P-glycoprotein (P-gp)	Inhibits P-gp in KB-C2 cells (increases rhodamine-123/daunorubicin concentrations); stimulates P-gp ATPase activity (substrate/competitive inhibitor)	[19]
Cancer	PI3K-α	High binding affinity (−10.0)	[20]
Cardioprotection	H9C2 myocardial cells	10–30 μM protects from doxorubicin (DOX)-induced cytotoxicity (MTT/LDH assays); reduces ROS, lipid peroxidation, apoptosis (reverses PARP/caspase-3/bcl-2/bax/cytochrome C expression; lowers caspase-3 activity)	[21]
Cardioprotection	DLD-1 colon adenocarcinoma cells	Does not interfere with DOX-induced cell death	[21]

Notably, guggulsterone’s dual roles—such as acting as both an agonist and antagonist for PXR—highlight its context-dependent activity. Its ability to selectively protect myocardial cells from DOX toxicity without compromising DOX’s anticancer effects on colon adenocarcinoma cells further underscores its potential as a targeted therapeutic agent. These diverse mechanisms, supported by computational simulations, in vitro assays, and in vivo models, collectively demonstrate guggulsterone’s broad therapeutic potential across multiple disease contexts.

Therapeutic Potential of Guggulsterone Structural Type Steroids in Chronic Diseases

Guggulsterone is a plant steroid derived from the resin of guggul plants (e.g., Commiphora mukul, Commiphora wightii) [22][4][11], with its bioactive E and Z isomers primarily mediating effects on lipid and cholesterol levels [11]. Traditionally used to treat conditions ranging from burns and wounds to intestinal worms and fascioliasis [10], preclinical and clinical studies support its therapeutic potential across multiple chronic diseases.

Summary of Guggulsterone/Guggul Preparation Efficacy Across Disease Areas

Disease Area	Intervention	Key Findings	Citations
Cardiovascular Health	Guggulipid (Z-guggulsterone)	Significantly lowers serum LDL cholesterol and triglyceride levels; clinical trials show reduced LDL-C (8 weeks, p=0.01/0.006) and total cholesterol (12 weeks, p=0.047)	[4][23]
Neurodegenerative Diseases	Guggul preparations	Contain ferulic acids/phenols that scavenge superoxide radicals; Z-guggulsterone attenuates neuroinflammation-induced behavioral abnormalities and prevents scopolamine-induced memory impairment via CREB-BDNF signaling	[4]
Neurodegenerative Diseases	Guggulipids	Improve memory deficits in streptozotocin-induced dementia via cholesterol-lowering, antioxidant, and antiacetylcholine esterase activities	[4]
Neurodegenerative Diseases	Guggulsterone	May benefit Alzheimer’s disease by reducing neuronal cholesterol and inhibiting the Aβ-forming amyloidogenic pathway	[4]
Gastrointestinal Disorders	Guggul gum (oleo-gum-resin)	Traditional use for stomach distention, IBD, hemorrhoids; 3 g/day for 4 weeks reduces flatulence, dyspepsia, reflux, colonoscopic scores, constipation, and proctorrhagia in 99 hemorrhoid patients	[12]
Gastrointestinal Disorders	Guggulsterone	Exhibits anti-inflammatory activity in mouse colitis models by targeting lamina propria T cells	[12]
Oncology	Guggulsterone	Induces apoptosis in HT-29 colon cancer cells (activates caspases-3/-8; modulates cIAP-1/-2, Bcl-2, truncated Bid, Fas, p-c-Jun, p-JNK); reduces HT-29 xenograft tumor size in mice	[12]
Oncology	Guggulsterone (10–30 μM)	Protects H9C2 cardiac cells from doxorubicin-induced cytotoxicity/oxidative stress/apoptosis (reverses PARP, caspase-3, bcl-2, bax, cytochrome C changes) without interfering with doxorubicin-induced DLD-1 colon adenocarcinoma cell death	[21]
Viral Infections	Guggulsterone	Proposed as a potential SARS-CoV-2 ADP-ribose phosphatase (ARP) antagonist via 100 ns molecular dynamic simulations; stable macromolecular complex (RMSD 1–1.6 Å) with interactions via hydrogen bonds/hydrophobic/water-bridge forces	[17]
Viral Infections	Guggulsterone	Stable within SARS-CoV-2 ARP enzyme cavity (RMSD <0.15–0.45 Å; radius of gyration 3.65–3.80; molecular surface area 292–300 Ų; solvent-accessible surface area 40–120 Ų; polar surface area 86–90 Ų)	[17]

Guggulsterone also demonstrates potential against viral infections, with molecular dynamic simulations identifying it as a candidate antagonist for the SARS-CoV-2 ADP-ribose phosphatase (ARP) enzyme [17]. The compound maintains stability within the enzyme cavity, as confirmed by structural metrics including RMSD, radius of gyration, and surface area values [17]. While generally well-tolerated, adverse effects may include mild gastrointestinal discomfort, thyroid symptoms, and topical dermatitis [23].

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