The Clinical Translation of α-humulene - A Scoping Review.

α-humulene, a sesquiterpene found in essential oils of various plant species, has garnered interest due to its potential therapeutic applications. This scoping review aims to consolidate α-humulene's evidence base, informing clinical translation, and guiding future research directions. A scoping review was conducted of EMBASE, MEDLINE, and PubMed databases up to 14th July 2023. All studies describing original research on α-humulene extraction, as well as pre-clinical and clinical research, were included for review. Three hundred and forty articles were analysed. α-humulene yields ranged from negligible to 60.90% across plant species. In vitro experiments demonstrated cytotoxicity against adenocarcinomas (such as colorectal, pulmonary, breast, prostatic, lung, and ovarian), with varying responses in other cell models. Mechanistic insights revealed its involvement in mitochondrial dysfunction, diminished intracellular glutathione levels, and the induction of oxidative stress. In rodent studies, oral administration of α-humulene at 50 mg/kg reduced inflammation markers in paw oedema and ovalbumin-induced airway inflammation. Intraperitoneal administration of α-humulene (50 - 200 mg/kg) exhibited cannabimimetic properties through cannabinoid 1 and adenosine A2a receptors. α-humulene also exhibited a multitude of properties with potential scope for therapeutic utilisation. However, there is a paucity of studies that have successfully translated this research into clinical populations with the associated disease. Potential barriers to clinical translation were identified, including yield variability, limited isolation studies, and challenges associated with terpene bioavailability. Consequently, rigorous pharmacokinetic studies and further mechanistic investigations are warranted to effectively uncover the potential of α-humulene.

In Vitro Anti-Inflammatory Activity of Essential Oil and ß-Bisabolol Derived from Cotton Gin Trash.

Natural α-bisabolol has been widely used in cosmetics and is sourced mainly from the stems of Candeia trees that have become endangered due to over exploitation. The in vitro anti-inflammatory activity of cotton gin trash (CGT) essential oil and the major terpenoid (ß-bisabolol) purified from the oil were investigated against lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages as well as the 3t3 and HS27 fibroblast cell lines. Nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8) were measured using Greiss reagent, enzyme-linked immunosorbent assay (ELISA), and cytokine bead array (CBA)-flow cytometry. Non-toxic concentrations of CGT oil and ß-bisabolol (1.6-50.0 µg/mL) significantly inhibited the production of the inflammatory mediators in a dose-dependent manner. Maximal inhibition by ß-bisabolol was 55.5% for NO, 62.3% for PGE2, and 45.3% for TNF-α production in RAW cells. ß-Bisabolol induced a level of inhibition similar to an equal concentration of α-bisabolol (50.0 µg/mL), a known anti-inflammatory agent. These results suggest ß-bisabolol exerts similar in vitro effects to known topical anti-inflammatory agents and could therefore be exploited for cosmetic and therapeutic uses. This is the first study to report the in vitro anti-inflammatory activity of ß-bisabolol in CGT essential oil.

Role of Caryophyllane Sesquiterpenes in the Entourage Effect of Felina 32 Hemp Inflorescence Phytocomplex in Triple Negative MDA-MB-468 Breast Cancer Cells.

Cannabis sativa L. crops have been traditionally exploited as sources of fibers, nutrients, and bioactive phytochemicals of medical interest. In the present study, two terpene-rich organic extracts, namely FOJ and FOS, obtained from Felina 32 hemp inflorescences collected in June and September, respectively, have been studied for their in vitro anticancer properties. Particularly, their cytotoxicity was evaluated in different cancer cell lines, and the possible entourage effect between nonintoxicating phytocannabinoids (cannabidiol and cannabichromene) and caryophyllane sesquiterpenes (ß-caryophyllene, ß-caryophyllene oxide and α-humulene), as identified at GC/MS analysis, was characterized. Modulation of cannabinoid CB1 and CB2 receptors was studied as a mechanistic hypothesis. Results highlighted marked cytotoxic effects of FOJ, FOS, and pure compounds in triple negative breast cancer MDA-MB-468 cells, likely mediated by a CB2 receptor activation. Cannabidiol was the main cytotoxic constituent, although low levels of caryophyllane sesquiterpenes and cannabichromene induced potentiating effects; the presence in the extracts of unknown antagonistic compounds has been highlighted too. These results suggest an interest in Felina 32 hemp inflorescences as a source of bioactive phytocomplexes with anticancer properties and strengthen the importance of considering the possible involvement of minor terpenes, such as caryophyllane sesquiterpenes, in the entourage effect of hemp-based extracts.

Antimicrobial and cytotoxic phenolic bisabolane sesquiterpenoids from the fungus Aspergillus flavipes 297.

Phenolic bisabolane-type sesquiterpenoids (PBS) represent a rare class of natural products with diverse biological activities. In this study, chemical investigations of the fungus Aspergillus flavipes 297 resulted in the isolation and identification of seven PBS, including a pair of new enantiomers (+)-1a and (-)-1b, a new derivative 2, and five previously reported ones 3-7. The chemical structures of the isolated PBS were determined by extensive NMR and HRESIMS spectroscopic analysis. The absolute configurations of the separated enantiomers (+)-1a and (-)-1b were solved by comparison of the experimental ECD spectra with those of the TDDFT-ECD calculated spectra. The new compounds 1 and 2 represent rare cases of PBS bearing a methylsulfinyl group, which was distinct from the commonly-observed PBS structurally. All the isolated compounds 1-7 were evaluated their antimicrobial and cytotoxic activities. As a result, the tested compounds showed selective antimicrobial activity against several pathogenic bacteria and fungi with the MIC (minimum inhibiting concentrations) values ranging from 2 to 64 µg/mL. Moreover, enantiomers (+)-1a and (-)-1b, together with compound 2, exhibited promising cytotoxicity against MKN-45 and HepG2 cell lines, respectively, indicating that the methylsulfinyl substituent enhanced cytotoxicity to a certain degree.

New bisabolane-type phenolic sesquiterpenoids from the marine sponge Plakortis simplex.

Six new bisabolane-type phenolic sesquiterpenoids, including plakordiols A-D (1-4), (7R, 10R)-hydroxycurcudiol (5) and (7R, 10S)-hydroxycurcudiol (6) were isolated from the marine sponge Plakortis simplex collected from the South China Sea. Their structures were determined based on extensive analysis of spectroscopic data. Their configurations were assigned by coupling constant analysis, NOESY correlations, and the modified Mosher's method. Furthermore, their cytotoxic and antibacterial activities were evaluated.

Anti-inflammatory and anti-apoptotic effect of zingiberene on isoproterenol-induced myocardial infarction in experimental animals.

This study aimed to investigate the antihyperlipidemic and anti-inflammatory effect of zingiberene (ZBN) on isoproterenol-(ISO) induced myocardial infarction in rats. ZBN (10 mg/kg b.wt.) was orally administered to rats for 21 days and ISO (85 mg/kg b.wt.) was subcutaneously injected into the rats at 24 h intervals for the last 2 consecutive days. We observed increased serum creatine kinase, creatine kinase-MB, cardiac troponin T, and I levels in ISO-treated MI rats. Conversely, ZBN oral administration significantly prevented in cardiac marker enzyme activities in ISO-mediated rats. We also noticed that ZBN oral administration prevented ISO-induced expression of lipid peroxidative markers, total cholesterol, triglycerides, phospholipids, free fatty acids, very-low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C) to the normal basal level. Furthermore, ZBN restored ISO-mediated antioxidant status, increased level of high-density lipoprotein cholesterol (HDL-C), and tissue phospholipids to the near-normal levels. Besides, ZBN pre-treatment significantly reduced the level of inflammatory markers (TNF-α, IL-6, NF-κB, and IL-1ß) in ISO-induced MI in rats. We noticed that ZBN pretreatment inhibited the pro-apoptotic proteins Bax and cytochrome c and increased the Bcl-2 expression in ISO induced rats. The gene expression profiling by qRT-PCR array illustrates that ZBN treatment prevents the ISO mediated activation of cardiac markers, inflammatory, and fibrosis-related genes in the heart tissue. Taken together, pre-treatment with ZBN attenuated ISO-induced MI resolved exhibits the anti-inflammatory and antiapoptotic effect.

Zingiberene targets the miR-16/cyclin-B1 axis to regulate the growth, migration and invasion of human liver cancer cells.

PURPOSE: Liver cancer or hepatocellular carcinoma (HCC) is considered as one of the most frequent malignancies with significantly high morbidity and mortality across the globe. MicroRNAs (miRs) are regarded as important regulators of liver cancer formation and its development. However, the full biochemical mechanism of their role is still very less understood. The main objective of the current research work was to examine the role of miR-16/cyclin-B1 axis in liver cancer regulation and how this pathway along with liver cancer migration and invasion are targeted by zingiberene molecule. METHODS: Quantitative reverse transcriptase polymerase chain reaction was used to evaluate miR-16 expression in HCC cell lines. Western blotting was performed to evaluate the expression of the miR-16 target genes. Effects on cell migration and invasion were evaluated by in vitro wound healing assay and transwell Matrigel assay, respectively. Effects of zingiberene on HCC cell viability were evaluated by MTT assay. RESULTS: Zingiberene treatment led to downregulation of miR-16 in HepG2 human hepatocellular carcinoma cells, accompanied by induction of G0/G1 cell cycle arrest targeting cyclin B1 as direct target. These effects were also accompanied by inhibition of cell migration and invasion, indicating that miR-16 can have a significant role as liver cancer suppressor after zingiberene treatment. Luciferase reporter assay confirmed that miR-16, which was one of HCC downregulated miRs, directly targeted Cyclin B1 in HCC cells. CONCLUSION: The current study indicates miR-16/cyclin B1 axis might have significant applications as a therapeutic target for patients with liver cancer.

α-Bisabolol, a Dietary Bioactive Phytochemical Attenuates Dopaminergic Neurodegeneration through Modulation of Oxidative Stress, Neuroinflammation and Apoptosis in Rotenone-Induced Rat Model of Parkinson's disease.

Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson's disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.

Antibacterial Activity and Mechanism of Ginger Essential Oil against Escherichia coli and Staphylococcus aureus.

Though essential oils exhibit antibacterial activity against food pathogens, their underlying mechanism is understudied. We extracted ginger essential oil (GEO) using supercritical CO2 and steam distillation. A chemical composition comparison by GC-MS showed that the main components of the extracted GEOs were zingiberene and α-curcumene. Their antibacterial activity and associated mechanism against Staphylococcus aureus and Escherichia coli were investigated. The diameter of inhibition zone (DIZ) of GEO against S. aureus was 17.1 mm, with a minimum inhibition concentration (MIC) of 1.0 mg/mL, and minimum bactericide concentration (MBC) of 2.0 mg/mL. For E. coli, the DIZ was 12.3 mm with MIC and MBC values of 2.0 mg/mL and 4.0 mg/mL, respectively. The SDS-PAGE analysis revealed that some of the electrophoretic bacterial cell proteins bands disappeared with the increase in GEO concentration. Consequently, the nucleic acids content of bacterial suspension was raised significantly and the metabolic activity of bacteria was markedly decreased. GEO could thus inhibit the expression of some genes linked to bacterial energy metabolism, tricarboxylic acid cycle, cell membrane-related proteins, and DNA metabolism. Our findings speculate the bactericidal effects of GEO primarily through disruption of the bacterial cell membrane indicating its suitability in food perseveration.

Two pairs of bisabolane sesquiterpenoid stereoisomers, bisacurone D-G, from the rhizome of Curcuma longa L.

Phytochemical investigation of an extract of the rhizome of Curcuma longa L., resulted in the identification of four undescribed bisabolane sesquiterpenoids, namely as bisacurone D-G (1-4). With the aid of comprehensive spectroscopic techniques (NMR, IR, UV, MS), the structures of all isolated compounds were elucidated and subsequently screened for both anti-inflammatory and cytotoxic biological activities, Compounds 1 and 2 showed moderate inhibitory activity toward LPS-induced NO production on RAW 264.7 macrophages.

α-Bisabolol suppresses the inflammatory response and ECM catabolism in advanced glycation end products-treated chondrocytes and attenuates murine osteoarthritis.

As a chronic musculoskeletal degeneration disease, osteoarthritis (OA) clinically manifests as joint pain, stiffness and a limited range of movement. OA has affected the life quality of at least one-tenth of the population but lacks satisfactory treatments. α-Bisabolol (BISA) is a small oily sesquiterpene alcohol widely found in essential oils of chamomile (Matricaria recutita), salvia and wood of Candeia and has multiple biological properties, particularly an anti-inflammatory effect. The purpose of this study is to assess the anti-inflammatory and chondroprotective effect of BISA in OA progression and explore its underlying mechanism. We isolated human chondrocytes and treated them with advanced glycation end products (AGEs) to imitate OA progression in vitro. BISA pretreatment suppressed the AGE-induced inflammatory reaction and extracellular matrix (ECM) degeneration by blocking nuclear factor kappa B (NF-κB), p38 and c-Jun N-terminal kinase (JNK) signaling. Moreover, a mouse destabilization of the medial meniscus (DMM) model was established by surgery to investigate BISA protection in vivo. BISA administration attenuated DMM-induced radiological and histopathological changes relative to the DMM group and resulted in lower OARSI scores. Taken together, the results of our study indicate the potential of BISA in OA therapy.

Antibacterial and antibiofilm effects of α-humulene against Bacteroides fragilis.

The rapid increase in antibiotic resistance has prompted the discovery of drugs that reduce antibiotic resistance or new drugs that are an alternative to antibiotics. Plant extracts have health benefits and may also exhibit antibacterial and antibiofilm activities against pathogens. This study determined the antibacterial and antibiofilm effects of α-humulene extracted from plants against enterotoxigenic Bacteroides fragilis, which causes inflammatory bowel disease. The minimum inhibitory concentration and biofilm inhibitory concentration of α-humulene for B. fragilis were 2 µg/mL, and the biofilm eradication concentration was in the range of 8-32 µg/mL. The XTT reduction assay confirmed that the cellular metabolic activity in biofilm rarely occurred at the concentration of 8-16 µg/mL. In addition, biofilm inhibition by α-humulene was also detected via confocal laser scanning microcopy. Quantitative real-time polymerase chain reaction (qPCR) was also used to investigate the effect of α-humulene on the expression of resistance-nodulation-cell division type multidrug efflux pump genes (bmeB1 and bmeB3). According to the results of qPCR, α-humulene significantly reduced the expression of bmeB1 and bmeB3 genes. This study demonstrates the potential therapeutic application of α-humulene for inhibiting the growth of B. fragilis cells and biofilms, and it expands the knowledge about biofilm medicine.

Insecticidal activity and biochemical composition of Citrullus colocynthis, Cannabis indica and Artemisia argyi extracts against cabbage aphid (Brevicoryne brassicae L.).

Plant extracts contain many active compounds, which are tremendously fruitful for plant defence against several insect pests. The prime objectives of the present study were to calculate the extraction yield and to evaluate the leaf extracts of Citrullus colocynthis (L.), Cannabis indica (L.) and Artemisia argyi (L.) against Brevicoryne brassicae and to conduct biochemical analysis by gas chromatography-mass spectrometry (GC-MS). The results suggested that when using ethanol, C. colocynthis produced a high dry yield (12.45%), followed by that of C. indica and A. argyi, which were 12.37% and 10.95%, respectively. The toxicity results showed that A. argyi was toxic to B. brassicae with an LC50 of 3.91 mg mL-1, followed by the toxicity of C. colocynthis and C. indica, exhibiting LC50 values of 6.26 and 10.04 mg mL-1, respectively, which were obtained via a residual assay; with a contact assay, the LC50 values of C. colocynthis, C. indica and A. argyi were 0.22 mg mL-1, 1.96 and 2.87 mg mL-1, respectively. The interaction of plant extracts, concentration and time revealed that the maximum mortality based on a concentration of 20 mg L-1 was 55.50%, the time-based mortality was 55% at 72 h of exposure, and the treatment-based mortality was 44.13% for A. argyi via the residual assay. On the other hand, the maximum concentration-based mortality was 74.44% at 20 mg mL-1, the time-based mortality was 66.38% after 72 h of exposure, and 57.30% treatment-based mortality was afforded by A. argyi via the contact assay. The biochemical analysis presented ten constituents in both the A. argyi and C. colocynthis extracts and twenty in that of C. indica, corresponding to 99.80%, 99.99% and 97% of the total extracts, respectively. Moreover, the detected caryophylleneonides (sesquiterpenes), α-bisabolol and dronabinol (Δ9-THC) from C. indica and erucylamide and octasiloxane hexamethyl from C. colocynthis exhibited insecticidal properties, which might be responsible for aphid mortality. However, A. argyi was evaluated for the first time against B. brassicae. It was concluded that all the plant extracts possessed significant insecticidal properties and could be introduced as botanical insecticides after field evaluations.

New quinoline alkaloid and bisabolane-type sesquiterpenoid derivatives from the deep-sea-derived fungus Aspergillus sp. SCSIO06786.

One new quinoline alkaloid (1), two new bisabolane-type sesquiterpene derivatives (2 and 3), and a new natural product (4) along with ten known compounds (514) were isolated from the deep sea-derived fungus Aspergillus sp. SCSIO06786 which cultured on solid rice medium. Three new structures were elucidated by analysis of 1D/2D NMR data and HR-ESI-MS. The absolute configurations of 2 and 3 were established by comparison of the experimental and reported ECD values. Compounds 11-13 exhibited moderate selective inhibitory activities against the tested pathogenic bacteria with MIC values among 3.13-12.5 µg/mL.

Bisabolane sesquiterpenes from Clausena sanki with their potential anti-inflammatory activities.

The investigation on the stems and leaves of Clausena sanki led to the isolation of a previously undescribed bisabolane sesquiterpene, clausemargic A (1), together with six known analogues (2-7). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-7) were isolated from C. sanki for the first time. All isolated compounds were evaluated for their anti-inflammatory activities via examining the inhibitory activity on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro. Compounds 1-7 showed significant inhibitory activities with IC50 values comparable to that of hydrocortisone.

In vitro anthelmintic activity of Siparuna guianensis extract and essential oil against Strongyloides venezuelensis.

New therapeutic approaches are necessary to control strongyloidiasis due to the side effects of, and resistance to, currently available drugs thiabendazole, albendazole, and ivermectin. This study examined the anthelmintic properties of extracts and isolated compounds from Siparuna guianensis against Strongyloides venezuelensis eggs and larvae, using the egg hatching test (EHT) and larval motility test (LMT). Albendazole (0.025 mg/ml) and ivermectin (0.316 mg/ml) were used as the positive controls for the EHT and LMT assays, respectively. Strongyloides venezuelensis eggs or larvae (±50 specimens) were treated with ethanol extract (0.05-1.0 mg/ml), ethyl acetate and aqueous fractions (0.05-0.8 mg/ml), essential oil (0.2-1.0 mg/ml) and α-bisabolol (0.2-1.0 mg/ml) from S. guianensis, and analysed by optical microscopy after 48 h (EHT), or after 24, 48 and 72 h (LMT). All the tested compounds exhibited ovicidal activity equivalent to the positive control and changed the morphology of the eggs. The S. guianensis ethanol extract and aqueous fraction were as effective as the positive control. Phytochemical analysis of the ethanol extract and fractions revealed the presence of phenolic compounds, tannins and flavonoids. Therefore, S. guianensis is effective against S. venezuelensis eggs and larvae in vitro, and can be considered as a potential alternative treatment for strongyloidiasis.

Insecticidal activity of Vanillosmopsis arborea essential oil and of its major constituent α-bisabolol against Callosobruchus maculatus (Coleoptera: Chrysomelidae).

Vigna unguiculata, one of the most important legumes, mainly in underdeveloped countries, is susceptible to post-harvest losses in storage by Callosobruchus maculatus (Fabricius, 1775) (Coleoptera: Chrysomelidae). The work evaluated the toxicity, inhibition of oviposition, instantaneous rate of population growth (ri) and the development of fumigated C. maculatus with the essential oil of Vanillosmopsis arborea and its major constituent, α-bisabolol. The experimental units consisted of 0.8 L flasks treated with concentrations of 1.2-11.2 µL L-1of air of the essential oil of V. arborea or its major constituent applied to disks of filter paper. α-Bisabolol was quantified as 409.33 mL L-1 of the essential oil. The development rate of C. maculatus was evaluated by daily adult counts. Oviposition was evaluated at lethal concentrations (LC50, LC25, LC10 and LC1). The LC50 and LC95 of the essential oil of V. arborea and α-bisabolol were 5.23 and 12.97 µL L-1 of air and 2.47 and 8.82 µL L-1 of air, respectively. At some concentrations, the α-bisabolol was more toxic to males than to females of the insect. Increased concentrations of the essential oil reduced the ri, rate of development, oviposition, and number of eggs of C. maculatus and therefore have potential for pest control.