Guggul extract is derived from the mukul myrrh tree that grows in India. Guggulipid is an ethyl acetate extract of resin known as guggul from the tree Commiphora wightii/mukul (Arn.) Bhandari. Chemical analysis revealed that the compounds responsible for the major activities of gum guggul are the isomers E- and Z-guggulsterone. Guggul has been used for thousands of years in the treatment of arthritis, inflammation, obesity, cardiac protection, anti-ulcer, anti-epileptic, and disorders of lipid metabolism. This review is an assortment of available information reported on its chemical, pharmacological and toxicological properties in various research studies. The available therapeutic properties of guggulipid make it suitable natural product for the treatment of various disorders like inflammation, pain, wounds, liver disorder and Acne etc.³⁶

Guggul exerts effective lipid-lowering activity, lowering both cholesterol and triglyceride levels. Guggul lowers VLDL and LDL cholesterol while at the same time elevating HDL cholesterol, protection against heart disease due to atherosclerosis. Guggul contains a group of compounds known as guggulsterones that account for the lipid-lowering action of the extracts. Z-guggulsterone and E-guggulsterone are believed to be the most active guggulsterone-components in guggul responsible for lipid-lowering effects. It is believed Guggul works by two distinctive mechanisms: 1) improving the liver’s ability to process, metabolize and excrete cholesterol, in particular LDL cholesterol; 2) by improving thyroid function by increasing T-4 to T-3 conversion. Guggul is traditionally used for arthritis and its anti-inflammatory activity has been confirmed. 

It also aids in weight loss because of this effect and may also be effective in cystic acne. Guggul extract decreases LDL and triglycerides by about 12%. Guggul works much better in combination with niacin, plant sterols, red yeast, and other lipid lowering agents. Guggul has also shown to decrease platelet adhesiveness, and increase fibrinolytic activity. It has shown not only an ability to prevent atherosclerosis, but also has helped regress pre-existing atherosclerotic plague in animal studies.^1-6

Six randomized clinical trials of guggul, involving 388 patients with different diagnoses, were identified.^7-12 Five were conducted in India and one in the United States; four were placebo-controlled; and one compared guggul with two reference compounds. The results suggest reductions in total serum cholesterol from 10% to 27% compared with baseline level.

High-density lipoprotein (HDL) cholesterol levels were measured in three of the studies.^7-9 A significant increase was seen after eight weeks of treatment in one study;⁹ in the others, no significant differences were seen.^7,8 A statistically significant decrease in lipid peroxide levels was reported in one study, with no corresponding change in the placebo-treated group.⁷

In one recent study, its was found that guggul and its cholesterol-lowering component, guggulsterone, effectively inhibited LDL oxidation.¹²

Cardiovascular Benefits of Guggul Multi-Targeting

The cardiovascular benefits of the therapy are derived from the multiple pharmacological activities associated with guggul or guggulsterone, notably its hypolipidemic, antioxidant, and antiinflammatory activities. It has been established that guggulsterone is an antagonist at farnesoid x receptor (FXR), a key transcriptional regulator for the maintenance of cholesterol and bile acid homeostasis. The FXR antagonism by guggulsterone has been proposed as a mechanism for its hypolipidemic effect. A recent study demonstrates that guggulsterone upregulates the bile salt export pump (BSEP), an efflux transporter responsible for removal of cholesterol metabolites, bile acids from the liver. Such upregulation of BSEP expression by guggulsterone favors cholesterol metabolism into bile acids, and thus represents another possible mechanism for its hypolipidemic activity. Guggulsterone has been found to potently inhibit the activation of nuclear factor-kappaB (NF-kappaB), a critical regulator of inflammatory responses. Such repression of NF-kappaB activation by guggulsterone has been proposed as a mechanism of the antiinflammatory effect of guggulsterone.¹⁵

The hydroalcoholic extract of guggul significantly improved cardiac function and prevented myocardial ischemic impairment manifested in the form of increased heart rate, decreased arterial pressure, increased left ventricular end diastolic pressure, and altered myocardial contractility indices. C. mukul treatment additionally also produced a significant increase in lactate dehydrogenase levels and prevented decline of protein content in heart. C. mukul preserved the structural integrity of myocardium. Reduced leakage of myocyte enzyme lactate dehydrogenase and maintenance of structural integrity of myocardium along with favorable modulation of cardiac function and improved cardiac performance indicate the salvage of myocardium with C. mukul treatment. Guggulsterones which are considered to be responsible for most of the therapeutic properties of C. mukul may underlie the observed cardioprotective effect of C. mukul against cardiac dysfunction in isoproterenol-induced ischemic rats.¹³

Anti-Diabetic Activity

The ethyl acetate extract of the gum of the guggul tree, Commiphora mukul (guggulipid), is marketed for the treatment of dyslipidaemia and obesity. We have found that it protects Lep(ob)/Lep(ob) mice from diabetes and have investigated possible molecular mechanisms for its metabolic effects, in particular those due to a newly identified component, commipheric acid. Both guggulipid (EC(50)=0.82 mug/ml) and commipheric acid (EC(50)=0.26 mug/ml) activated human peroxisome proliferator-activated receptor alpha (PPARalpha) in COS-7 cells transiently transfected with the receptor and a reporter gene construct. Similarly, both guggulipid (EC(50)=2.3 mug/ml) and commipheric acid (EC(50)=0.3 mug/ml) activated PPARgamma and both promoted the differentiation of 3T3 L1 preadipocytes to adipocytes. Guggulipid (EC(50)=0.66 mug/ml), but not commipheric acid, activated liver X receptor alpha (LXRalpha). E- and Z-guggulsterones, which are largely responsible for guggulipid’s hypocholesterolaemic effect, had no effects in these assays. Guggulipid (20 g/kg diet) improved glucose tolerance in female Lep(ob)/Lep(ob) mice. Pure commipheric acid, given orally (960 mg/kg body weight, once daily), increased liver weight but did not affect body weight or glucose tolerance. However, the ethyl ester of commipheric acid (150 mg/kg, twice daily) lowered fasting blood glucose and plasma insulin, and plasma triglycerides without affecting food intake or body weight. These results raise the possibility that guggulipid has anti-diabetic activity due partly to commipheric acid’s PPARalpha/gamma agonism.¹⁶

Anti-Diabetic/Lipid Lowering Effects in High Fat Diet Induced Diabetic Rats

Sedentary lifestyle, consumption of energy-rich diet, obesity and longer lifespan are some of the major reasons for the rise of metabolic disorders like type II diabetes, obesity, hypertension and dyslipidemia among people of various age groups. High fat diet induced diabetic rodent models resembling type II diabetic condition in human population were used to assess the anti-diabetic and hypolipidemic activity of guggulsterone (isolated from Commiphora mukul resin). Four groups of rats were fed a high fat diet for 16 weeks. On feeding the normal rats with a fat rich diet they showed increased serum glucose, cholesterol and triglyceride levels along with an increase in insulin resistance significantly (p<0.05) in comparison to control animals. Different biochemical parameters like GTT, glycogen content, glucose homeostatic enzymes (like glucose-6-phosphatase, hexokinase), insulin release in vivo and expression profiles of various genes involved in carbohydrate and lipid metabolism clearly demonstrated the hypoglycemic effect of this extract. Guggulsterone demonstrated a differential effect with a significantly improved PPARgamma expression and activity in in vivo and in vitro conditions, respectively. However, it inhibited 3T3-L1 preadipocyte differentiation in vitro. The results presented here suggest that the guggulsterone has both hypoglycemic and hypolipidemic effect which can help to cure type II diabetes.¹⁸

Guggul and Atorvastatin Monotherapy in Comparison to Their Combination in High Cholesterol Diet-Induced Hyperlipidemia in Rabbits.

Background: Hypolipidemic activity of gugulipid has been widely described in traditional literature.

Objective: This study was done to evaluate hypolipidemic activity of guggul and atorvastatin monotherapy in comparison to their combination in rabbits.

Materials and Methods: Male New Zealand White rabbits (body weight 1.3-1.8 kg and age 8-10 weeks) were made hyperlipidemic by feeding cholesterol (0.5 g/kg) for three weeks and randomly divided into a control and three treatment groups receiving: atorvastatin (3.7 mg/kg), guggul(3.5 mg/kg) and their combination (same dose) for the next three weeks. Body weight measurements, estimation of serum lipid profile were done at the beginning, after three and six weeks, respectively. Histopathological examination of liver, heart, and aorta was done after six weeks. Statistical analysis was done with SPSS version 16.0 using one-way and repeated measures analysis of variance (ANOVA) followed by a post-hoc multiple comparison test with two tailed P value < 0.05 as significant.

Results: All treated groups had significant reduction in cholesterol, triglyceride, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) in comparison to pre-treatment values and control group, and had significant increase in high-density lipoprotein (HDL) in comparison to pre-treatment values.

Conclusion: Combination of atorvastatin and guggul was comparable to their monotherapies in improving lipid profile.³¹

Protective Effect of Guggulipid in High Fat Diet and Middle Cerebral Artery Occlusion (MCAO) Induced Ischemic Cerebral Injury in Rats

Aim: The role of guggulipid was evaluated in high fat diet and middle cerebral artery occlusion (MCAO) induced ischemic cerebral dysfunctions in rats of either sex. Materials and Methods: Ethyl acetate extract of guggul known as guggulipid was prepared and administered to rats. Animals were divided into nine groups, consisting six rats, each receiving different treatments per orally for eight weeks. Control group rats received a normal control diet while the rest of the other groups’ animals were fed a high fat diet (HFD) for eight weeks. Cerebral ischemia was induced for 2 h followed by reperfusion for 22 h. Locomotor activity and grip strength tests were performed immediately after 24 h of reperfusion followed by biochemical estimations and histopathology. Results: Locomotor activity and grip strength were significantly decreased in HFD and HFD fed MCAO groups and improved significantly in pretreatment groups. Cerebral infarction, thiobarbituric acid reactive substances (TBARs), nitric oxide and tumor necrosis factor alfa (TNFα) levels were increased, pretreatment of guggulipid alone and with aspirin significantly reduced these markers. Reduced glutathione (GSH), superoxide dismutase (SOD) and catalase levels were decreased but all drug pretreated groups showed significant improvement in those markers. Conclusion: Guggulipid demonstrated neuroprotection owing to its hypolipidemic, antioxidant, anti-inflammatory and anti-thrombotic activities but further research is warranted to confirm its role in cerebral ischemia.³²

Guggulsterone Modulates MAPK & NF-kB and Inhibits Skin Cancer

Guggulsterone (GUG), a resin of the Commiphora mukul tree, has been used in ayurvedic medicine for centuries to treat a variety of ailments. Recent studies have suggested that GUG may also possess anticancer effects. In the present study, we show that GUG possesses antitumor-promoting effects in the SENCAR mouse skin tumorigenesis model. We first determined the effect of topical application of GUG to mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of GUG (1.6 micromol per mouse) 30 min prior to TPA (3.2 nmol per mouse) application onto the skin of mice afforded significant inhibition against TPA-mediated increase in skin edema and hyperplasia. Topical application of GUG was also found to result in substantial inhibition against TPA-induced epidermal (i) ornithine decarboxylase (ODC) activity; (ii) ODC, cyclooxygenase-2 and inducible nitric oxide synthase protein expressions; (iii) phosphorylation of extracellular signal-regulated kinase 1/2, c-jun N-terminal kinases and p38; (iv) activation of NF-kappaB/p65 and IKK alpha/beta and (v) phosphorylation and degradation of I kappaB alpha. We next assessed the effect of topically applied GUG on TPA-induced skin tumor promotion in 7,12-dimethyl benz[a]anthracene-initiated mice. Compared with non-GUG-pretreated mice, animals pretreated with GUG showed significantly reduced tumor incidence, lower tumor body burden and a significant delay in the latency period for tumor appearance from 5 to 11 weeks. These results provide the first evidence that GUG possesses anti-skin tumor-promoting effects in SENCAR mice and inhibits conventional as well as novel biomarkers of tumor promotion. In summary, GUG could be useful for delaying tumor growth in humans.¹⁴

Cancer Chemopreventive and Therapeutic Potential of Guggulsterone

Guggulsterone (GS) is a phytosterol derived from the gum resin of guggul plants that have been used traditionally to treat various disorders such as burns, wounds, gastric ulcer, cough, gum diseases, urinary complaints, diarrhea, stomach cramps, fascioliasis, and intestinal worms. It has anti-inflammatory and antioxidative properties and has recently attracted substantial attention due to its cancer chemopreventive and therapeutic potential exemplified by its antiproliferative, antimetastatic, and proapoptotic properties in many cancer cell lines and animal models. This review highlights some of the cancer chemopreventive/therapeutic targets of GS and the underlying molecular mechanisms.¹⁹

One common mechanism of the anticarcinogenic activity of Guggulterone is its proapoptotic effect. Thus Guggulterone significantly induces apoptosis in several different types of cancer cells while it has a minimal effect on normal cell viability.^20-23 

Guggul: Anti-Angiogenic – Down-Regulates VEGF

Our previous studies have shown that z-guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, inhibits the growth of human prostate cancer cells by causing apoptosis. We now report a novel response to z-guggulsterone involving the inhibition of angiogenesis in vitro and in vivo. The z-guggulsterone treatment inhibited capillary-like tube formation (in vitro neovascularization) by human umbilical vein endothelial cells (HUVEC) and migration by HUVEC and DU145 human prostate cancer cells in a concentration- and time-dependent manner. The z- and E-isomers of guggulsterone seemed equipotent as inhibitors of HUVEC tube formation. The z-guggulsterone-mediated inhibition of angiogenesis in vitro correlated with the suppression of secretion of proangiogenic growth factors [e.g., vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor], down-regulation of VEGF receptor 2 (VEGF-R2) protein level, and inactivation of Akt. The z-guggulsterone-mediated suppression of DU145 cell migration was increased by knockdown of VEGF-R2 protein level. Ectopic expression of constitutively active Akt in DU145 cells conferred protection against z-guggulsterone-mediated inhibition of cell migration. Oral gavage of 1 mg z-guggulsterone/d (five times/wk) to male nude mice inhibited in vivo angiogenesis in DU145-Matrigel plug assay as evidenced by a statistically significant decrease in tumor burden, microvessel area (staining for angiogenic markers factor VIII and CD31), and VEGF-R2 protein expression. In conclusion, the present study reveals that z-guggulsterone inhibits angiogenesis by suppressing the VEGF-VEGF-R2-Akt signaling axis. Together, our results provide compelling rationale for further preclinical and clinical investigation of z-guggulsterone for its efficacy against prostate cancer.¹⁷

Reversion of P-Glycoprotein-Mediated Multidrug Resistance by Guggulsterone in Multidrug-Resistant Human Cancer Cell Lines

Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that guggulsterone could reverse MDR through inhibiting the function and expression of P-glycoprotein (P-gp). The present study is to further investigate the reversal effects of guggulsterone on MDR in drug-resistant cancer cell lines. The effects of guggulsterone on MDR1mRNA gene expression, intracellular pH, P-gp ATPase activity and glucosylceramide synthase (GCS) expression were assessed by RT-PCR, Laser Scanning Confocal Microscope using the pH-sensitive fluorescent probe BCECF-AM, Pgp-Glo assay system, and flow cytometric technology, respectively. The results showed that guggulsterone ranging from 2.5 to 80μM significantly promoted the activity of P-gp ATPase in a dose-dependent manner. The intracellular pH of K562/DOX cells was found to be higher than K562 cells. After treatment with guggulsterone (1, 3, 10, 30, 100μM), intracellular pH of K562/DOX cells decreased in a dose- and time-dependent manner. However, the present study revealed that guggulsterone ranging from 3 to 100μM had little influence on MDR1 gene expression in K562/DOX cells. Further, the isogenic doxorubicin-resistant MCF-7/DOX cells exhibited a 4.9-fold increase in GCS level as compared with parental MCF-7 human breast cancer cells. After treatment with guggulsterone (0.1, 1, 10μM) for 48h, MCF-7/DOX cells were found to have no change of GCS protein expression amount. Guggulsterone might be a potent MDR reversal agent, and its mechanism on MDR needs more research.²⁴

Protective Effect of Guggulsterone Against Cardiomyocyte Injury Induced by DOX

Background: Doxorubicin (DOX) is an effective antineoplastic drug; however, clinical use of DOX is limited by its dose-dependent cardiotoxicity. It is well known that reactive oxygen species (ROS) play a vital role in the pathological process of DOX-induced cardiotoxicity. For this study, we evaluated the protective effects of guggulsterone (GS), a steroid obtained from myrrh, to determine its preliminary mechanisms in defending against DOX-induced cytotoxicity in H9C2 cells.

In this study, we used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H- tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release measurements, and Hoechst 33258 staining to evaluate the protective effect of GS against DOX-induced cytotoxicity in H9C2 cells. In addition, we observed the immunofluorescence of intracellular ROS and measured lipid peroxidation, caspase-3 activity, and apoptosis-related proteins by using Western blotting.

The MTT assay and LDH release showed that treatment using GS (1–30 muM) did not cause cytotoxicity. Furthermore, GS inhibited DOX (1 muM)-induced cytotoxicity in a concentration-dependent manner. Hoechst 33258 staining showed that GS significantly reduced DOX-induced apoptosis and cell death. Using GS at a dose of 10–30 muM significantly reduced intracellular ROS and the formation of MDA in the supernatant of DOX-treated H9C2 cells and suppressed caspase-3 activity to reference levels. In immunoblot analysis, pretreatment using GS significantly reversed DOX-induced decrease of PARP, caspase-3 and bcl-2, and increase of bax, cytochrome C release, cleaved-PARP and cleaved-caspase-3. In addition, the properties of DOX-induced cancer cell (DLD-1 cells) death did not interfere when combined GS and DOX.

These data provide considerable evidence that GS could serve as a novel cardioprotective agent against DOX-induced cardiotoxicity.²⁵

Cis-Guggulsterone Inhibits the IKK/NF-κB Pathway, Whereas Trans-Guggulsterone Inhibits MAPK/AP-1 in MCF‑7 Breast Cancer Cells: Guggulsterone Regulates MMP‑9 Expression in an Isomer-Specific Manne

Νuclear factor-κB (NF-κB) and activator protein-1 (AP-1) are major transcription factors that have been associated with breast cancer metastasis by inducing matrix metalloproteinase-9 (MMP-9) expression. In this study, we investigated the inhibitory effects of guggulsterone isomers (cis or trans) on 12-O-tetradecanoylpho-bol-13-acetate (TPA)-induced MMP-9 expression. Cis-guggulsterone inhibited TPA-induced MMP expression by blocking IκB kinase (IKK)/NF-κB signaling, whereas trans-guggulsterone blocked mitogen-activated protein kinase (MAPK)/AP-1 signaling. Cis-guggulsterone was more potent than trans-guggulsterone in the inhibition of TPA-induced MMP-9 expression and invasion of MCF-7 cells. Furthermore, we found that the combination of these isomers exerted an additive effect on the inhibition of MCF-7 cell invasion. These results suggest that guggulsterone isomers downregulate MMP-9 expression and tumor cell invasion through the isomer-specific suppression of IKK/NF-κB and MAPK/AP-1 activation. In addition, the suppression of MMP-9 expression correlated well with the inhibition of cell invasion.²⁷

Reversal of Multidrug Resistance by Guggulsterone in Drug-Resistant MCF-7 Cell Lines

Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that the MDR of K562/DOX cells could be reversed by guggulsterone through inhibiting the function and expression of P-glycoprotein. The purpose of this study was to investigate the reversal effect of guggulsterone on MDR in drug-resistant MCF-7 cells and the parental MCF-7 cells.

Methods: MTT cytotoxicity assays, flow cytometry, and Western blot analysis were performed to investigate the antiproliferative effects of the combination of anticancer drugs with guggulsterone, to study the reversal of drug resistance and to examine the inhibitory effects on MRP1 expression.

Results: The results showed that co-administration of guggulsterone (10 μM) resulted in a significant increase in chemosensitivity of MCF-7/DOX cells to doxorubicin, compared with doxorubicin treatment alone (p < 0.01). The fold reversal of 10 μM guggulsterone (11.48) was comparable to that of 10 μM verapamil (13.23). Rhodamine123 and doxorubicin accumulation in MCF-7/DOX cells was significantly enhanced after the incubation with guggulsterone (10 μM), compared with untreated MCF-7/DOX cells (p < 0.01). When doxorubicin (10 μM) was combined with guggulsterone (10 μM), the mean apoptotic population of MCF-7/DOX cells was 24.91%. It was increased by 6.15 times, compared with doxorubicin (10 μM) treatment alone. However, guggulsterone had little inhibitory effect on the expression of MRP1 proteins.

Conclusion: Guggulsterone is a novel and potent MDR reversal agent with the potential to be an adjunctive agent for tumor chemotherapy.²⁸

Guggulsterone for Chemoprevention of Cancer

Guggulsterone [4, 17(20)-pregnadiene-3, 16-dione] is a plant sterol derived from the gum resin of the tree Commiphora wightii. The gum resin of the guggul tree has been used in traditional medicine for centuries to treat obesity, liver disorders, internal tumors, malignant sores, ulcers, urinary complaints, intestinal worms, leucoderma, sinus, edema and sudden paralytic seizures. Guggulsterone has been shown to modulate the nuclear receptors, farnesoid X receptor, pregnane X receptor, CYP 2b10 gene expression, and the bile salt export pump for cholesterol elimination. Recent research indicates that the active components of gum guggul, E- and Z-guggulsterone have the potential to both prevent and treat cancers. Guggulsterone inhibits the growth of a wide variety of tumor cells and induces apoptosis through down regulation of antiapoptotic gene products (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), modulation of cell cycle proteins (cyclin D1 and c-Myc), activation of caspases, inhibition of Akt, and activation of JNK. Guggulsterone modulates the expression of gene products involved in metastasis (MMP-9, COX-2, and VEGF) of tumor cells. Guggulsterone mediates gene expression through the modulation of several transcription factors, including NF-κB, STAT3, C/EBPα, androgen receptor, and glucocorticoid receptors. This review describes the anti-cancer properties, molecular targets, and the apoptotic effects of guggulsterone.³⁰

Guggulsterone-Induced Apoptosis in Cholangiocarcinoma Cells Through ROS/JNK Signaling Pathway

Cholangiocarcinoma (CCA), the most common biliary tract malignancy, is arising from the bile duct epithelium with the global significantly increased morbidity and mortality. Here, we showed the effect of guggulsterone, a steroid found in the resin of the guggul plant, on human HuCC-T1 and RBE CCA cells. Exposure to various concentrations of guggulsterone for multiple action time resulted in significant apoptosis in the CCA cells via activating both extrinsic and intrinsic pathways. Furthermore, we demonstrated that the apoptosis of CCA cells was induced by Reactive oxygen species (ROS) mediated JNK signaling pathway. Consistently, inhibition of JNK activity, overexpression of JBD, its binding protein or reduction of ROS by overexpression of catalase, all decreased apoptotic cells. Our results also revealed that guggulsterone-induced apoptosis was coupled with endoplasmic reticulum stress (ERS) in a CHOP-dependent pathway. Downregulation of CHOP instead of other ERS markers could inhibit CCA cell apoptosis. Taken together, our results showed that guggulsterone could induce apoptosis of human CCA cells through ROS/JNK signaling pathway, indicating that guggulsterone could be important for the clinical therapy of CCA.³³

Prevents Bone Resorption, Improves Bone Density and Strength 

Gum guggul, a resinous exudate of the plant Commiphora mukul Engl. (Burseraceae), has been found efficacious in the treatment of bone fractures, arthritis, and hyperlipidemic disorders. The present study is an effort to explore the anti-bone-resorptive potential of the dried methanol extract of the gummy exudate of C. mukul (MECM) in ovariectomized rat model. The animals were randomly divided into five groups of equal size (n =6). Animals in all the groups were ovariectomized except group 1, which was sham operated. Groups 3, 4 and 5 were treated with Raloxifene, MECM 250 mg/kg and MECM 500 mg/kg, respectively. The 2nd group was fed with vehicles. Assessment: biochemical estimations, viz., alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), serum calcium (Ca); biomechanical evaluations, and histopathological examinations. The LD(50) of MECM was found to be > 2500 mg/kg orally. A significant elevation was observed in the ALP, TRAP, Ca and cholesterol levels in the 2nd group with a significant reduction in biomechanical strength. Groups 3, 4 and 5, showed a significant reduction in TRAP and ALP levels (p < 0.001). The Ca levels were normalized in the groups 4 and 5, while cholesterol levels dropped in group 5. The bone strength, however, was normalized in all the groups (p < 0.001) along with the histopathology. Findings suggested a significant gain in bone strength and nearly complete restoration of bone microarchitecture along with lowered levels of TRAP indicating the anti-bone resorptive potential of the extract.²⁶

The appetite regulatory effect of guggulsterones in rats: a repertoire of plasma hormones and neurotransmitters.

Guggulsterone or guggulipid is a steroidal constituent present in the neutral fraction of gum resin of Commiphora mukul, commonly known as guggul. The traditional uses of guggul-resin extract are well documented in the Ayurveda-where it is prescribed to treat a variety of ailments including lipid-related disorders such as obesity and arteriosclerosis. The hypolipidemic activity of the extracts known since ancient times can be traced to the two closely related steroidal ketones, E-guggulsterone and Z-guggulsterone. In this study, we have investigated the dose dependent (100, 200, 400 mg/kg body weight) effect of guggulsterones on appetite regulating hormones [ghrelin, leptin, cholecystokinin (CCK)] and neurotransmitters (serotonin and dopamine), which play a major role in the energy homeostasis and thus influence obesity related factors. We have also studied its effect on food intake, body weight and plasma triglycerides and glucose in rats. Guggulsterones at the dose of 400 mg/kg body weight was able to significantly reduce food intake and limit body weight gain over a period of 15 days. It also significantly decreased the plasma ghrelin, glucose, triglyceride levels and increased plasma leptin, serotonin, dopamine levels, but did not show much effect on CCK levels.²⁹

Guggul (Commiphora and Boswellia) for Prevention of Chronic Diseases

Extensive research during the last two decades has revealed that most drugs discovered today cost billions of dollars for discovery, and yet they are highly ineffective in their clinical response. For instance, the European Medicines Agency has approved 68 anti-cancer drugs, and out of which 39 has reached the market level with no indication of increased survival nor betterment of quality of life. Even when drugs did improve survival rate compared to available treatment strategies, most of these were found to be clinically insignificant. This is a fundamental problem with modern drug discovery which is based on thinking that most chronic diseases are caused by alteration of a single gene and thus most therapies are single gene-targeted therapies. However, extensive research has revealed that most chronic diseases are caused by multiple gene products. Although most drugs designed by man are mono-targeted therapies, those designed by “mother nature” and have been used for thousands of years, are “multi-targeted” therapies. In this review, we examine two agents that have been around for thousands of years, namely “guggul” from Commiphora and Boswellia. Although we are all familiar with the search engine “google,” this is another type of “guggul” that has been used for centuries and being explored for its various biological activities. The current review summarizes the traditional uses, chemistry, in vitro and in vivo biological activities, molecular targets, and clinical trials performed with these agents.

Pharmacological Properties of Guggulsterones, the Major Active Components of Guggul

Commiphora mukul is a short thorny shrub that is native to the Indian subcontinent. 

• Oleo gum resin extracted by incision of the bark is a very complex mixture of gum, minerals, essential oils, terpenes, sterols, ferrulates, flavanones and sterones. 
• Its active constituents, the Z- and E-guggulsterones, have been demonstrated to exhibit their biological activities by binding to nuclear receptors and modulating the expression of proteins involved in carcinogenic activities. 
• Guggulsterones regulate gene expression by exhibiting control over other molecular targets including transcription factors such as nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT) and steroid receptors. 
• Considerable scientific evidence indicates the use of gum guggul as a therapeutic agent in the treatment of inflammation, nervous disorders, hyperlipidaemia and associated cardiac disorders such as hypertension and ischemia, skin disorders, cancer and urinary disorders. 

This review highlights the taxonomic details, phytochemical properties and pharmacological profile of gum guggul.³⁵

Various molecular targets of guggul from Commiphora and Boswellia (A) Molecular targets of guggul from Commiphora includes Bcl2, B-cell lymphoma 2; CDC 2, cell division cycle kinase 2; c-FLIP, cellular caspase-8 (FLICE)-like inhibitory protein; COX, cyclooxygenase; FXR, farnesoid X receptor; IKK, IκB kinase; IAP, Inhibitors of apoptosis proteins; JNK, c-Jun N-terminal kinase; MKK4, mitogen-activated protein kinase kinase 4; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; RANKL, Receptor activator of nuclear factor kappa-B ligand; VEGF, vascular endothelial growth factor; XIAP, x-linked inhibitor of apoptosis protein. (B) Molecular targets of guggul from Boswellia includes Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra-large; CXCR-4, C-X-C chemokine receptor type 4; DR, Death receptor; 5-LOX, 5-Lipoxygenase; MMP, Matrix metalloproteinase; NF-κB, nuclear factor-κB; Topo, Topoisomerase; ICAM-1, Intercellular adhesion molecule 1; STAT-3, Signal transducer and activator of transcription 3; IL-6, Interleukin 6; PARP, Poly ADP ribose polymerase; Mcl-1, Myeloid leukemia cell differentiation protein; bFGF, Basic fibroblast growth factor; ERK-1,-2, Extracellular signal-regulated kinases.

³⁴

Guggulsterone Induces Apoptosis in Multiple Myeloma Cells

Multiple myeloma (MM) is a hematological disorder characterized by the abnormal expansion of plasma cells in the bone marrow. Despite great advances over the past three decades in discovering the efficacious therapies for MM, the disease remains incurable for most patients owing to emergence of drug-resistant cancerous cells. Guggulsterone (GS), a phytosteroid, extracted from the gum resin of guggul plant, has displayed various anticancer activities in vitro and in vivo; however, the molecular mechanisms of its anticancer activity have not been evaluated in MM cells. Therefore, in this study, we investigated the anticancer activity of GS in various MM cell lines (U266, MM.1S, and RPMI 8226) and the mechanisms involved. GS treatment of MM cells caused inhibition of cell proliferation and induction of apoptotic cell death as indicated by increased Bax protein expression, activation of caspases, and cleavage of poly (ADP-ribose) polymerase. This was associated with the downregulation of various proliferative and antiapoptotic gene products, including cyclin D, Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. GS also suppressed the constitutive and interleukin 6-induced activation of STAT3. Interestingly, the inhibition of Janus activated kinase or STAT3 activity by the specific inhibitors or by siRNA knockdown of STAT3 resulted in the downregulation of HMGB1, suggesting an association between GS, STAT3, and HMGB1. Finally, GS potentiated the anticancer effects of bortezomib (BTZ) in MM cells. Herein, we demonstrated that GS could be a potential therapeutic agent for the treatment of MM, possibly alone or in combination with BTZ.³⁷

Guggulsterone Anti-Cancer Activity by Modulating Apoptotic Markers: A Systematic Review and Meta-Analysis

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C₂₁H₂₈O₂) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani systems of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized. 

Pleotrophic effects of guggulsterone

Modulation of various signalling pathways involved in cancer by Guggulsterone (GS). Guggulsterone modulates the expression of numerous proteins involved in cell survival, cell proliferation, migration, invasion, angiogenesis and inflammation.

Methods: Using seven databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta-analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool. Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/β-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty-three studies were selected for meta-analysis following the PRISMA statements. A fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment. Conclusion: This study suggested that Guggulsterones have apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.³⁸

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