Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

Andrographolide, an Anti-Inflammatory Multitarget Drug: All Roads Lead to Cellular Metabolism

Andrographolide is a labdane diterpene and the main active ingredient isolated from the herb Andrographis paniculata. Andrographolide possesses diverse biological effects including anti-inflammatory, antioxidant, and antineoplastic properties. Clinical studies have demonstrated that andrographolide could be useful in therapy for a wide range of diseases such as osteoarthritis, upper respiratory diseases, and multiple sclerosis. Several targets are described for andrographolide, including the interference of transcription factors NF-κB, AP-1, and HIF-1 and signaling pathways such as PI3K/Akt, MAPK, and JAK/STAT. In addition, an increase in the Nrf2 (nuclear factor erythroid 2–related factor 2) signaling pathway also supports its antioxidant and anti-inflammatory properties. However, this scenario could be more complex since recent evidence suggests that andrographolide targets can modulate glucose metabolism. The metabolic effect of andrographolide might be the key to explaining the diverse therapeutic effects described in preclinical and clinical studies. This review discusses some of the most recent evidence about the anti-inflammatory and metabolic effects of andrographolide.

Anticancer potential of sclareol against human KB oral carcinoma cell line invitro

Sclareol, a labdane diterpene phytochemical in the various genus Salvia of the herbaceous plant has been anti-carcinogenic properties on numerous human cancer cell lines. Till known the anticancer properties of sclareol on human oral KB cancer cells are not revealed. Therefore, we scrutinized the viability, nucleate damage associated with apoptosis in KB cells treated with sclareol.The cytotoxicity of KB cells displayed to sclareol was evaluated by hexosaminidase and trypan blue exclusion assay. Apoptosis was noticed by Hoechst staining and affirmed by nucleate damage. We discovered that sclareol treatment for KB cells with expressively lessened cell proliferation or viability and evoked cell death in a dose-dependent manner compared with untreated control. Sclareol stimulated inhibition of growing of oral KB cells came along to be induction nucleate damage. Our data proved that sclareol on stimulated apoptosis in human oral KB cancer cells through nucleate damage. These observations recommend the anti-cancer properties of sclareol.

Design Based Ultrasound-Assisted Extraction of Marrubium vulgare Linn and Comparative Evaluation of Extracts for Furan Labdane Diterpene (Marrubiin) Concentration and Antihypertensive Potential

Background: Improvement in extract quality in terms of concentration of secondary metabolites and pharmacological activity has always been the need of the hour. In the present research, the target was to extract the selected medicinal herb using the ultrasound waves and to optimize the extraction conditions for the improvement in the quality of extract with respect to furan labdane diterpene (marrubiin) concentration and antihypertensive potential. Methods: The whole plant of Marrubium vulgare Linn. was collected from the fields of Pulwama district of Jammu and Kashmir state in India and extracted by cold maceration (MVM) and ultrasound assisted extraction techniques (MVU). The response surface methodology coupled with the central composite design was employed to optimize the selected extraction parameters in UAE method. The marrubiin concentration in different extracts was determined by HPTLC. The extracts were also evaluated for the antihypertensive potential by non-invasive blood pressure monitoring (NIBPM) method. Results: The extract yield (14.2 ± 0.9%) and concentration of marrubiin (0.91 ± 0.04%) were significantly improved at the optimized UAE conditions (Ultrasound power 467 W, sonication time of 47 minutes and solvent concentration of 33 mL per g of drug) as compared to the conventional method. Furthermore, the MVU extract (200 mg/kg) along with ethanol significantly (p<0.01) prevented the rise in mean systolic blood pressure (MSBP) of animals and also the GSH was significantly (p<0.05) enhanced as compared to ethanol-treated animals. Conclusion: The elevation in MSBP and decrease in reduced glutathione concentration (GSH) by the chronic ethanol consumption were significantly altered by MVU extract as compared to MVM extract. The enhanced antihypertensive effect of selected herb may be attributed to the improved concentration of secondary metabolites (marrubiin) in MVU extract obtained at optimized conditions.

Marrubium vulgare L.: A Phytochemical and Pharmacological Overview

Marrubium vulgare is a plant with high bioactive potential. It contains marrubiin, a labdane diterpene that is characteristic for this genus, as well as a complex mixture of phenolic compounds. According to numerous studies, M. vulgare acts as a good antioxidant agent, and due to this, it could potentially be useful in treatments of cancer, diabetes mellitus, and liver diseases. In addition, its anti-inflammatory, wound-healing, antihypertensive, hypolipidemic, and sedative potential are discussed. Apart from that, its antimicrobial activity, especially against Gram+ bacteria, fungi, herpes simplex virus, and parasites such as Toxoplasma gondii, Trichomonas vaginalis, and Plasmodium berghei-berghei was recorded. Additionally, it could be used as a chicken lice repellent, herbicide, and natural insecticide against mosquito larvae and natural molluscicide. In veterinary medicine, M. vulgare can be used as an anthelmintic against the eggs and larvae of bovine strongyles parasites, and as an antibiotic against bovine mastitis caused by resistant bacterial strains. Due to the mentioned benefits, there is a tendency for the cultivation of M. vulgare in order to ensure high-quality raw material, but more firm scientific evidence and well-designed clinical trials are necessary for the well-established use of M. vulgare herb and its preparations.