Chemopreventive and immunomodulatory effects of phenolic-rich extract of Commiphora leptophloeos against inflammatory bowel disease: Preclinical evidence.

ETHNOPHARMACOLOGY RELEVANCE: Commiphora leptophloeos (Mart.) J.B. Gillet (Burseraceae) is a medicinal plant native to Brazil, popularly known as "imburana". Homemade leaf decoction and maceration were used to treat general inflammatory problems in the Brazilian Northeast population. Our previous research confirmed the anti-inflammatory activity of the C. leptophloeos hydroalcoholic leaf extract. AIM OF THE STUDY: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut with no ideal treatment to maintain the remissive status. This work aimed to characterize the phytochemical composition and physicochemical properties of the C. leptophloeos hydroalcoholic leaf extract and its efficacy in chemopreventive and immunomodulatory responses in inflammatory bowel disease in non-clinical models. MATERIALS AND METHODS: Mass spectrometry and physicochemical tests determined the phytochemical profile and physicochemical characteristics of the Commiphora leptophloeos (CL) extract. The chemopreventive and immunomodulatory effects of CL extract (50 and 125 µg/mL) were evaluated in vitro in the RAW 264.7 lipopolysaccharide (LPS) induced cell assay and in vivo in the model of intestinal inflammation induced by 2,4-Dinitrobenzenesulfonic acid (DNBS) in mice when they were treated with CL extract by intragastric gavage (i.g.) at doses of 300, 400 and 500 mg/kg. RESULTS: Phytochemical annotation of CL extract showed a complex phenolic composition, characterized as phenolic acids and flavonoids, and satisfactory physicochemical characteristics. In addition, CL extract maintained the viability of RAW macrophages, reduced ROS and NO production, and negatively regulated COX-2, iNOS, TNF-α, IL-1ß, IL-6, and IL-17 (p < 0.05). In the intestinal inflammation model, CL extract was able to downregulate NF-κB p65/COX-2, mTOR, iNOS, IL-17, decrease levels of malondialdehyde and myeloperoxidase and cytokines TNF-α, IL-1ß and IL-6 (p < 0.05). CONCLUSION: Based on these findings, CL extract reduced inflammatory responses by down-regulating pro-inflammatory markers in macrophages induced by LPS and DNBS-induced colitis in mice through NF-κB p65/COX-2 signaling. CL leaf extract requires further investigation as a candidate for treating inflammatory bowel disease.

Ultrasonic-assisted extraction to enhance the recovery of bioactive phenolic compounds from Commiphora gileadensis leaves.

The "ultrasonic-assisted extraction (UAE)" method was utilized in this work to assess how different process parameters affected the yield and recovery of phenolic compounds from the leaf of Commiphora gileadensis, which is one of the medicinal plants with a variety of biological functions. Its leaf is used for a various of therapeutic applications, such as the treatment of bacterial infections, inflammation, and wound healing. The "One-Factor-At-a-Time (OFAT)" approach was employed to examine the impacts of various UAE process parameters on the process of extraction, which include time of extraction, sample/solvent ratio, ultrasonic frequency, and solvent (ethanol) concentration. The extracts were then investigated for the presence of several phytochemicals using analytical techniques such as "Gas Chromatography-Mass Spectroscopy (GC-MS)" and "Fourier Transform Infrared Spectroscopy (FTIR)" studies. The findings showed that the maximum extraction yield, the total phenolic content (TPC), and the total flavonoids content (TFC) of the ethanolic extract of the leaves of C. gileadensis using the UAE method were at 31.80 ± 0.41 %, 96.55 ± 2.81 mg GAE/g d.w. and 31.66 ± 2.01 mg QE/g d.w. accordingly under a procedure duration of 15 min, ultrasonic frequency of 20 kHz, solvent/sample ratio of 1:20 g/mL, and solvent concentration of 40 % v/v. The leaves extract of C. gileadensis included 25 phenolic compounds that were previously unreported, and GC-MS analysis confirmed their presence. Hence, it follows that the UAE technique can successfully extract the phytochemicals from C. gileadensis for a variety of therapeutic uses.

Bio-nanocomposite active packaging films based on carboxymethyl cellulose, myrrh gum, TiO2 nanoparticles and dill essential oil for preserving fresh-fish (Cyprinus carpio) meat quality.

This study developed a composite film for packaging refrigerated common carp fillets using carboxymethyl cellulose (CMC) (1.5 % w/v)/Myrrh gum (MG) (0.25 % w/v) base with the addition of titanium dioxide nanoparticles (TiO2 NPs) (0.25 %, 0.5 %, and 1 %) and Dill essential oil (DEO) (1.5 %, 2.25 %, and 3 %). The film was produced using a casting method and optimized for mechanical and barrier properties. The incorporation of DEO and TiO2 NPs into CMC/MG composite films significantly reduced moisture content (MC) and water vapor permeability (WVP), improved their tensile strength (TS), and increased their antimicrobial and antioxidant properties. Moreover, MG can improve the physicomechanical properties of the CMC/MG composite films. The film components had good compatibility without significant aggregation or cracks. In conclusion, the optimized CMC/MG (1.5 %/0.25 %) film containing TiO2 NPs (0.5 %), and DEO (2.25 %) has the best overall performance and can be a good source for making edible film. Functionally, this bioactive nanocomposite film significantly increased the shelf life of refrigerated fish fillet samples for 12 days by inhibiting microbial growth and reducing the oxidation rate compared to the control sample. The knowledge obtained from this study can guide the development of bio-nanocomposite and biodegradable food packaging films based on CMC/MG to increase the shelf life of food products and environmental protection.

Undescribed sesquiterpenoids with NO production inhibitory activity from oleo-gum resin of Commiphora myrrha.

Six undescribed cadinane sesquiterpenoids (1-6), two undescribed guaiane sesquiterpenoids (7-8), and an undescribed germacrane sesquiterpenoid (9) were isolated from the oleo-gum resin of Commiphora myrrha. Their structures were determined by the analysis of 1D/2D NMR and HRESIMS data, as well as quantum chemical ECD and NMR calculations. All the sesquiterpenoids were evaluated for their NO production inhibitory activity in LPS-stimulated RAW 264.7 mouse monocyte-macrophages. The results revealed that commiphone A (1) and commipholide D (7) exhibited significant inhibitory effect on NO generation with IC50 values of 18.6 ± 2.0 and 37.5 ± 1.5 µM, respectively. Furthermore, 1 and 7 dose-dependently inhibited the mRNA expression of inflammatory cytokines IL-1ß, IL-6 and TNF-α induced by LPS in the RAW264.7 cells, indicating that 1 and 7 possess potent anti-inflammatory activity in vitro.

Chemometrics-based Chemical Analysis of Myrrh and Its Vinegar-processed Products by UPLC-MS/MS.

Myrrh is widely used in clinical practice but accompanied by obvious toxicity. According to traditional Chinese medicines theory, processing with vinegar can effectively reduce its toxicity. However, the detoxification processing technology of Myrrh and the corresponding mechanism have been unclear. The objective of this study is to systematically analyze the variation in chemical composition of raw Myrrh and its processed products using UPLC-Q-TOF-MS/MS coupled with chemometrics. A total of 75 compounds including 56 sesquiterpenoids, 2 diterpenoids, 15 triterpenoids and 2 other types were identified. Raw Myrrh and its processed products were divided into two major groups, and 14 chemical markers were selected out by principal component analysis and partial least square discriminant analysis. Additionally, the exact content of 5 representative chemical markers was determined to be significantly reduced after vinegar-processing by UPLC-QQQ-MS/MS. Moreover, multivariate statistical analysis and the quantitative results comprehensively indicated that the optimized processing method was processing at a ratio of 200 : 5 (Myrrh:vinegar). This research provides not only a reliable foundation for the study of Myrrh, but also a scientific reference for clinical use of this herb.

In-vivo anti-diabetic and anti-hyperlipidemic effects of natural metabolites from resin of Commiphora mukul and their in-silico to in-vitro target fishing.

Diabetes mellitus is a rapidly spreading global metabolic disorder that has serious social, health, and economic consequences. Herein, we have evaluated in vivo antidiabetic and antihyperlipidemic effects of myrrhanone-B and myrrhanol-B (isolated from Commiphora mukul Hook). We observed that treatment with myrrhanone-B and myrrhanol-B at a dose of 5 and 10 mg/kg body weight for 21 days significantly improved body weight loss, water consumption, and the concentration of blood glucose level (BGL) in alloxan (120 mg/kg) induced diabetic mice, which indicates that the compounds possess strong anti-diabetic activities. In the biochemical analysis, these compounds improved an abnormal level of total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein cholesterol (LDL-C) to a normal level and increased the high-density lipoprotein cholesterol level (HDLC). Later, drug target of compounds was predicted through in-silico docking which shows that these compounds nicely fit in the active site of α-glucosidase enzyme and mediates excellent interactions with the catalytic residues, Asp214 and Asp349. The in-silico results were confirmed by in-vitro testing of myrrhanone-B and myrrhanol-B against α-glucosidase where both the compounds exhibited excellent inhibitory potency with IC50 values of 19.50 ± 0.71, and 16.11 ± 0.69 µM, respectively. Furthermore, mechanistic study was conducted to observe their binding mechanism, which reflect that myrrhanol-B has mixed type of inhibition (ki = 12.33 ± 0.030 µM), while myrrhanone-B demonstrates competitive type of inhibition (ki =14.53 ± 0.040 µM).

Toxicological safety, antioxidant activity and phytochemical characterization of leaf and bark aqueous extracts of Commiphora leptophloeos (Mart.) J.B. Gillett.

This study aimed to characterize the phytochemical profile of bark and leaves aqueous extract Commiphora leptophloeos, and conduct in vivo and in vitro assays to determine the presence of any toxicological consequences due to exposure. The phytochemical analysis was carried out using high-performance liquid chromatography (HPLC). The antioxidant activity was estimated utilizing DPPH free radical scavenging and phosphomolybdenum assays. Cell viability was measured by the MTT method on J774 and human adenocarcinoma cells, which were treated with concentrations of 12,5, 25, 50, 100 or 200 µg/ml of both extracts. Acute oral toxicity, genotoxicity, and mutagenicity assays were determined using a single oral dose of 2000 g/kg in male Swiss albino mice (Mus musculus). Biochemical analysis of the blood and histological analyses of the kidneys, liver, spleen, pylorus, duodenum and jejunum were undertaken. Genotoxicity and mutagenicity were determined utilizing blood samples. Gallic acid, catechin, and epicatechin were identified in the bark and chlorogenic acid in leaves. Data demonstrated a high content of phenolic compounds and flavonoids associated with significant antioxidant potential. No significant signs in damage or symptoms of toxicity were detected. No marked reduction in cell viability was found at lower concentrations tested. On histomorphometry, only the gastrointestinal organs exhibited significant difference. Renal hepatic and blood parameters were within the normal range. No apparent signs of toxicity, genotoxicity, mutagenicity or cytotoxicity were found in vivo and in vitro experiments.

Commiphora mukul (Hook. ex Stocks) Engl.: Historical records, application rules, phytochemistry, pharmacology, clinical research, and adverse reaction.

ETHNOPHARMACOLOGICAL RELEVANCE: Commiphora mukul (Hook. ex Stocks) Engl. (also known as Guggulu) is one of the oldest and most prominent herb used in Ayurvedic medicine. Commiphora mukul plants have traditionally been used to treat inflammation, diabetes, rheumatism, arthritis, obesity, and hyperlipidemia. It has long been used in China, India, Greece, and other countries. Commiphora mukul is an over-the-counter dietary supplement in the United States and Western countries. Commiphora mukul has excellent medicinal and commercial value and deserves further investigation. AIM OF THE STUDY: This paper systematically reviews the historical records, application rules, phytochemistry, pharmacokinetics, pharmacology, clinical research, and adverse reactions of C. mukul and provides a reference for its comprehensive application in basic research, new drug development, and clinical treatment. MATERIALS AND METHODS: Literature were collected from databases such as PubMed, CNKI, Web of Science, TBRC, and other sources such as ancient books on traditional medicine, classic books on herbal medicine, and modern monographs. In this study, the application history and modern pharmacological research on C. mukul in the medicine of all ethnic groups were comprehensively and systematically reviewed. RESULTS: According to the vast literature, the varieties, morphological characteristics, distribution, and description of C. mukul used in Unani medicine, Ayurveda, traditional Chinese medicine, Tibetan medicine, Mongolian medicine, and Uygur medicine are highly consistent. Commiphora mukul is mainly used to treat rheumatoid arthritis, heart disease, obesity, hemorrhoids, urinary system diseases, skin diseases, inflammation, diabetes, hyperlipidemia, tumors, and other diseases. The core medicinal material combination in different ethnic medical preparations was C. mukul-Terminalia chebula Retz. (101 times), C. mukul-Moschus (55 times), C. mukul-Aucklandia lappa (Decne.) Decne. (52 times), and C. mukul-Acorus calamus L (27 times). Phytochemical studies confirmed that 150 components with different structures had been isolated and identified. Z-and E-guggulsterone are the main isomers in C. mukul. C. mukul has anti-cancer, anti-inflammatory, antioxidant, hypolipidemic, bone resorption, nervous system protection, myocardial protection, antibacterial, and other pharmacological properties. Clinical studies have only identified the role of C. mukul in treating hemorrhoids and lowering blood lipids. CONCLUSIONS: As an essential traditional medicine, C. mukul is widely used in the national traditional medicine system, and rich in chemical constituents and exhibit pharmacological activities. This study found that current research on C. mukul mainly focuses on its chemical composition and pharmacological properties. However, scientific research on the quality control of medicinal materials, identification of original plants, pharmacokinetics, and toxicology are relatively weak, and research in this area needs to be strengthened.

Protective effect of oleo-gum resin of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease-linked lung inflammation and emphysema: Isolation and identification of key bioactive phytoconstituent.

ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.

Sesquiterpenoids from the Resina Commiphora Promoting the Apoptotic Activity of PC-3 Prostate Cancer Cells.

Four new germacrane-type sesquiterpenes commiphoranes M1-M4 (1-4) together with eighteen sesquiterpenes were isolated from the Resina Commiphora. The structures and relative configurations of new substances were determined by using spectroscopic methods. Biological activity investigation revealed that nine compounds including 7, 9, 14, 16, (+)-17, (-)-17, 18, 19, and 20 could induce the apoptosis of prostate cancer originated PC-3 cells, through classic apoptosis signaling pathway, even using flow cytometry showed that the compound (+)-17 caused apoptosis of PC-3 cells more than 40 %, suggesting their potential therapeutic application in the development of novel drugs against prostate cancer.

Exploratory quasi-experimental study of anti-arthritic activity of Ayurvedic polyherbal formulation, Abha Guggulu in osteoarthritis patients.

OBJECTIVES: Abha Guggulu (AG) is a traditional Ayurvedic herbal formulation used for treating joint disorders and bone fractures. Individually, the ingredients are known for their promising anti-inflammatory and rejuvenating actions. The present study attempts to explore the anti-arthritic potential of AG through an exploratory clinical trial. METHODS: The study was conducted using a quasi-experimental model. The clinical trial has been registered in Clinical Trials Registry of India (registration number: CTRI/2019/09/021354). Osteoarthritis patients of both genders (n=12, 40-70 years age group), meeting the inclusion/exclusion criteria, were recruited in the single arm study. AG was administered in tablet form in a dose of 1.5 g, twice daily. The WOMAC score was used as a primary outcome measure. The WOMAC scale of patients was recorded on 0th, 15th and 30th days of treatment. RESULTS: At the end of treatment, there was a significant difference in the scores of the outcome measure. As per WOMAC total score, participants were significantly improved (p=0.002) after consuming the drug for 1 month. CONCLUSIONS: Overall, the data indicates significant improvement of subjects in both scales and objective measures used for assessment purposes. There were no adverse drug reactions reported during the trial. AG may be used as a safe and effective supplement to reduce symptoms of osteoarthritis. The clinical efficacy of the formulation might be mediated through the synergistic blend of herbal bioactive compounds from AG.

Exploring the Chemical Constituents, Antioxidant, Xanthine Oxidase and COX Inhibitory Activity of Commiphora gileadensis Commonly Grown Wild in Saudi Arabia.

The use of the synthetic drugs has increased in the last few decades; however, these drugs exhibit various side effects. Scientists are therefore seeking alternatives from natural sources. Commiphora gileadensis has long been used to treat various disorders. It is commonly known as bisham or balm of Makkah. This plant contains various phytochemicals, including polyphenols and flavonoids, with biological potential. We found that steam-distilled essential oil of C. gileadensis exhibited higher antioxidant activity (IC50, 22.2 µg/mL) than ascorbic acid (IC50, 1.25 µg/mL). The major constituents (>2%) in the essential oil were ß-myrcene, nonane, verticiol, ß-phellandrene, ß-cadinene, terpinen-4-ol, ß-eudesmol, α-pinene, cis-ß-copaene and verticillol, which might be responsible for the antioxidant and antimicrobial activity against Gram-positive bacteria. The extract of C. gileadensis exhibited inhibitory activity against cyclooxygenase (IC50, 450.1 µg/mL), xanthine oxidase (251.2 µg/mL) and protein denaturation (110.5 µg/mL) compared to standard treatments, making it a viable treatment from a natural plant source. LC-MS analysis revealed the presence of phenolic compounds such as caffeic acid phenyl ester, hesperetin, hesperidin, chrysin and transient amounts of catechin, gallic acid, rutin and caffeic acid. The chemical constituents of this plant can be explored further to investigate its wide variety of therapeutic potential.

Terpenoids from Myrrh and Their Cytotoxic Activity against HeLa Cells.

The oleo-gum resin of Commiphora myrrha (Nees) Engl. has a long history of medicinal use, although many of its constituents are still unknown. In the present investigation, 34 secondary metabolites were isolated from myrrh resin using different chromatographic techniques (silica flash chromatography, CPC, and preparative HPLC) and their structures were elucidated with NMR spectroscopy, HRESIMS, CD spectroscopy, and ECD calculations. Among the isolated substances are seven sesquiterpenes (1-7), one disesquiterpene (8), and two triterpenes (23, 24), which were hitherto unknown, and numerous substances are described here for the first time for C. myrrha or the genus Commiphora. Furthermore, the effects of selected terpenes on cervix cancer cells (HeLa) were studied in an MTT-based in vitro assay. Three triterpenes were observed to be the most toxic with moderate IC50 values of 60.3 (29), 74.5 (33), and 78.9 µM (26). Due to the different activity of the structurally similar triterpenoids, the impact of different structural elements on the cytotoxic effect could be discussed and linked to the presence of a 1,2,3-trihydroxy substructure in the A ring. The influence on TNF-α dependent expression of the intercellular adhesion molecule 1 (ICAM-1) in human microvascular endothelial cells (HMEC-1) was also tested for 4-6, 9-11, 17, 18, 20, and 27 in vitro, but revealed less than 20% ICAM-1 reduction and, therefore, no significant anti-inflammatory activity.

Pharmacological Studies on the Antidiabetic, Antioxidant, and Antimicrobial Efficacies of Commiphora myrrha Resin in Streptozotocin-Induced Diabetes in Rats: A Preclinical Study.

Results: The aqueous extracts of MAE were phytochemically analyzed, and the results revealed the presence of high concentrations of tannins, sterols, and isoprenoids (terpenoids), while steroids and flavonoids were found in moderate concentrations. The plant extract showed promising inhibition of the growth of gram-positive and gram-negative pathogens. It also showed that MAE has potential antihyperglycemic and antioxidant activities. Microscopic examination of the pancreas showed degenerative changes and atrophy associated with dilatation of the exocrine ducts in the STZ-induced diabetic rats, while the treatment revealed that the Langerhans islets were close to normal without any histopathological alteration. Conclusion: The present results suggested that an aqueous extract of MAE could be considered an efficient antidiabetic, antioxidant, and antimicrobial treatment in the future.

Commiphora wildii Merxm. Essential Oil: Natural Heptane Source and Co-Product Valorization.

As an alternative to fossil volatile hydrocarbon solvents used nowadays in perfumery, investigation on essential oil of Commiphora wildii Merxm. oleo gum resin as a source of heptane is reported here. Heptane, representing up to 30 wt-% of this oleo gum resin, was successfully isolated from the C. wildii essential oil, using an innovative double distillation process. Isolated heptane was then used as a solvent in order to extract some noble plants of perfumery. It was found that extracts obtained with this solvent were more promising in terms of sensory analysis than those obtained from fossil-based heptane. In addition, in order to valorize the essential oil depleted from heptane, chemical composition of this oil was found to obtain, and potential biological activity properties were studied. A total of 172 different compounds were identified by GC-MS in the remaining oil. In vitro tests-including hyaluronidase, tyrosinase, antioxidant, elastase and lipoxygenase, as well as inhibitory tests against two yeasts and 21 bacterial strains commonly found on the skin-were carried out. Overall, bioassays results suggest this heptane-depleted essential oil is a promising active ingredient for cosmetic applications.

A new benzofuran compound from the resinous exudates of Commiphora myrrha.

A new benzofuran derivative, identified as myrrhain A (1), was isolated from the resinous exudates of Commiphora myrrha, together with the four known compounds: commipharane (2), myrrhterpeniod (3), myrrhone (4), and 9-methoxymyrrhone (5). All structures were elucidated by NMR and MS analyses. DPPH assay of compounds 1-5 revealed for the first time that all of them possess moderate antioxidative activity.

Guggulsterone from Commiphora mukul potentiates anti-glioblastoma efficacy of temozolomide in vitro and in vivo via down-regulating EGFR/PI3K/Akt signaling and NF-κB activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. AIM OF THE STUDY: The present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. MATERIALS AND METHODS: Cell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. RESULTS: The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. CONCLUSIONS: The present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.

Commiphora myrrha stimulates insulin secretion from ß-cells through activation of atypical protein kinase C and mitogen-activated protein kinase.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayurvedic medicine has been used in the treatment of diabetes mellitus for centuries. In Arabia and some areas of Africa, Commiphora myrrha (CM) has been extensively used as a plant-based remedy. We have previously shown that an aqueous CM resin solution directly stimulates insulin secretion from MIN6 cells, a mouse ß-cell line, and isolated mouse and human islets. However, the signaling pathways involved in CM-induced insulin secretion are completely unknown. Insulin secretion is normally triggered by elevations in intracellular Ca2+ ([Ca2+]i) through voltage gated Ca2+ channels (VGCC) and activation of protein kinases. Protein and lipid kinases such as protein kinase A (PKA), Ca2+-calmodulin dependent protein kinase II (CaMKII), phosphoinositide 3-kinases (PI3Ks), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK), specifically extracellular signal-regulated kinases (ERK1/2), may be involved in receptor-operated insulin secretion. Therefore, we hypothesized that CM may induce insulin secretion by modulating the activity of VGCC and/or one or more of the above kinases. AIM OF THE STUDY: To investigate the possible molecular mechanism of action of CM-induced insulin secretion. The effects of aqueous CM resin extract on [Ca2+]i and protein kinase activation from ß-cells were examined. METHODS: The effect of aqueous CM resin solution on [Ca2+]i was assessed using Ca2+ microfluorimetry. The involvement of VGCC in CM-induced insulin secretion was investigated using static and perifusion insulin secretion experiments in the presence of either EGTA, a Ca2+ chelator, or nifedipine, a blocker of VGCC. The involvement of kinase activation in the stimulatory effect of CM on insulin secretion was examined by using static and perifusion insulin secretion experiments in the presence of known pharmacological inhibitors and/or downregulation of specific kinases. The effects of CM on phosphorylation of PKCζ and ERK1/2 were also assessed using the Wes™ capillary-based protein electrophoresis. RESULTS: Ca2+ microfluorimetry measurements showed that exposing MIN6 cells to CM (0.5-2 mg/mL) was not associated with changes in [Ca2+]i. Similarly, incubating MIN6 cells and mouse islets with EGTA and nifedipine, respectively, did not attenuate the insulin secretion induced by CM. However, incubating mouse and human islets with CM in the presence of staurosporine, a non-selective protein kinase inhibitor, completely blocked the effect of CM on insulin secretion. Exposing mouse islets to CM in the presence of H89, KN62 and LY294002, inhibitors of PKA, CaMKII and PI3K, respectively, did not reduce CM-induced insulin secretion. However, incubating mouse and human islets with CM in the presence of Ro 31-8220, a pan-PKC inhibitor, diminished insulin secretion stimulated by CM, whereas inhibiting the action of typical PKC (with Go6976) and PLCß (with U73122) did not affect CM-stimulated insulin secretion. Similarly, downregulating typical and novel PKC by chronic exposure of mouse islets to phorbol 12-myristate 13-acetate (PMA) was also not associated with a decrease in the stimulatory effect of CM on insulin secretion. Interestingly, CM-induced insulin secretion from mouse islets was inhibited in the presence of the PKCζ inhibitor ZIP and a MAPK inhibitor PD 98059. In addition, Wes™ capillary-based protein electrophoresis indicated that expression of the phosphorylated forms of PKCζ and ERK1/2, a MAPK, was significantly increased following exposure of INS-1832/13 cells, a rat insulinoma cell line, to CM. CONCLUSIONS: Our data indicate that CM directly stimulates insulin secretion through activating known downstream effectors of insulin-stimulus secretion coupling. Indeed, the increase in insulin secretion seen with CM is independent of changes in [Ca2+]i and does not involve activation of VGCC. Instead, the CM stimulatory effect on insulin secretion is completely dependent on protein kinase activation. Our findings indicate that CM could induce insulin exocytosis by stimulating the phosphorylation and activation of PKCζ, which in turn phosphorylates and activates ERK1/2.

Commiphora myrrh: a phytochemical and pharmacological update.

Medicinal plants have a long track record of use in history, and one of them is Commiphora myrrh which is commonly found in the southern part of Arabia, the northeastern part of Africa, in Somalia, and Kenya. Relevant literatures were accessed via Google Scholar, PubMed, Scopus, and Web of Science to give updated information on the phytochemical constituents and pharmacological action of Commiphora myrrh. It has been used traditionally for treating wounds, mouth ulcers, aches, fractures, stomach disorders, microbial infections, and inflammatory diseases. It is used as an antiseptic, astringent, anthelmintic, carminative, emmenagogue, and as an expectorant. Phytochemical studies have shown that it contains terpenoids (monoterpenoids, sesquiterpenoids, and volatile/essential oil), diterpenoids, triterpenoids, and steroids. Its essential oil has applications in cosmetics, aromatherapy, and perfumery. Research has shown that it exerts various biological activities such as anti-inflammatory, antioxidant, anti-microbial, neuroprotective, anti-diabetic, anti-cancer, analgesic, anti-parasitic, and recently, it was found to work against respiratory infections like COVID-19. With the advancement in drug development, hopefully, its rich phytochemical components can be explored for drug development as an insecticide due to its great anti-parasitic activity. Also, its interactions with drugs can be fully elucidated.This review highlights an updated information on the history, distribution, traditional uses, phytochemical components, pharmacology, and various biological activities of Commiphora myrrh. Graphical summary of the phytochemical and pharmacological update of Commiphora myrrh.