Natural Products Journal, The - Volume 12, Issue 4, 2022

Type 2 diabetes is strongly associated with the development of insulin resistance in metabolically active tissues. Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of hepatic insulin resistance. Saturated fatty acids such as palmitic acid (PA) induce insulin resistance, which may be studied for therapeutic prevention by herbal agents. In the present study, the role of naringenin, a bioflavonoid, is examined in PA-induced cytotoxicity in human hepatocellular carcinoma (HepG2) cells. PA causes significant inflammation and apoptosis in these cells primarily by inhibiting phosphorylation of Akt at serine 473 residue. Apoptosis assay, mitochondrial transmembrane potential measurement and immunoblotting for protein expressions have been used for demonstrating PA-induced abnormalities. Naringenin treatment effectively inhibits the fatty acid-induced inflammation and cytotoxicity, along with improvement of insulin signalling. Naringenin has a potential to prevent the fatty acid-induced stresses in hepatocytes, and may be beneficial for improving hepatic insulin sensitivity and mitigating lipotoxicity.

Background: Quercetin, one of the most beneficial flavonoids, has been included in the human diet due to its therapeutic effect on health. Recently, quercetin has been gaining scientific attraction for its multifarious activities, including anti-oxidant, anti-inflammatory, antiviral, anti-diabetic, anti-cancer, and anti-arthritic activities and its function in easing some cardiovascular diseases. However, these applications of quercetin in the pharmaceutical field are limited due to its poor aqueous solubility and poor permeability. Objective: The present review summarizes various pharmacological activities of quercetin, analyzes the barriers like solubility and permeability, which restrict the therapeutic efficiency of quercetin, and also discusses novel approaches to enhance aqueous solubility and permeability of quercetin for its effective clinical use. Methods: The current review information sources were peer-reviewed relevant scientific articles of recognized journals from scientific engines and databases (Scopus, Web of Science, PubMed, Science Direct, Google Scholar) using different keywords related to quercetin pharmacological effects, mechanism, solubility, permeability, absorption barriers, and formulation approaches. Results: Various novel approaches, including solid dispersions, inclusion complex, pro-drugs, nanoemulsion, micelles, liposomes, SNEEDS, and microspheres, have been developed to overcome the solubility and permeability barriers for efficient quercetin delivery. Conclusion: This review revealed that the multifaceted pharmacological activities of quercetin for the management of various diseases are enormously dependent on the development of novel and safe drug delivery systems of quercetin.

Background: Herbs have long been used as natural therapeutics, and recent controlled clinical studies have confirmed some of the presumed benefits. Hedera helix(ivy leaves) is a valuable common form related to the family Araliaceae. Many herbal preparations include extracts from their leaves as the principle active ingredient. Objective: The objective of this article is to summarize the pharmacological activities and phytochemical screening of H. helix. Methods: To prepare this article, the data was collected from different sources, including books, thesis, research and etc. Results: The all-published studies depend on isolation, identification, and characterization of different active constituents of H. helix leaves, followed by the determination of biological activities in vivo and in vivo. Chemical screening has shown that H. helix leaves are a rich source of phytochemicals demonstrating therapeutic activities, such as sterols, tannins, terpenoids, glycosides, phenols, emetine alkaloids, flavonoids, saponins, volatile and fixed oils, vitamins, carbohydrates, reducing sugars, and minerals. Further, studies of disease models and clinical trials have demonstrated anti- inflammatory, analgesic, cough suppressant, expectorant, anticancer, antimicrobial, anticoagulant, and smooth muscle relaxant activities. Conclusion: This review summarizes the bioactive constituents of H. helix leaves and their underlying pharmacological mechanisms, clinical efficacies, and safety profiles. We also suggest potential therapeutic uses for COVID-19.

Background: The presence of condensed tannins, flavonones, flavonols, flavones, xantones, catechins and alkaloids in the ethanolic extract of Lantana undulata leaves has been associated with cytotoxicity and virucidal effect on suid herpesvirus. Objective: To evaluate cellular toxicity, antimicrobial and antioxidant activities, and anti-phlogistic property of the ethanolic extract leaves of Lantana undulata, a plant from the Verbenaceae family. Methods: Cytotoxicity was evaluated on Madin Darby bovine kidney (MDBK) cells and erythrocytes and through leukocyte DNA damage. Antibacterial and antifungal activities were performed using the agar diffusion technique and broth microdilution. The inhibition percentage and viral inhibition index were established against bovine herpesvirus. The antioxidant effect (EC50) was determined by the DPPH technique and the mouse ear edema model was used to determine the anti-phlogistic activity. Results: The maximum nontoxic concentration for MDBK cells was 650 μg/ml. The ethanolic extract of L. undulata was considered non-hemolytic from 2 to 16 μg/ml and not genotoxic at the concentration tested (<8 μg/ml). High concentrations (3500 μg/ml) were needed to inhibit bacteria and yeasts, and the action of the extract was bacteriostatic or fungistatic. The IIV was of 0.37 and the IP was of 57.34% against bovine herpesvirus. The antioxidant EC50 was 540.87 μg/ml and the reduction of oedema occurred at 10, 30 and 100 mg/kg in the mouse model used. Conclusion: Although the ethanolic extract of L. undulataleaves showed to be potentially toxic and to have a reduced spectrum of action on microorganisms, the outstanding antiphlogistic action puts the therapeutic potential of this plant into perspective.

Background: Dryobalanops rappa is a plant species belonging to the family of Dipterocarpaceae. Nevertheless, the active compounds present in D. rappa have never been investigated. Objective: The aim of this research is to isolate and characterize compounds from Dryobalanops rappa and to study its bioactivity against human MCF-7 breast cancer and A549 lung cancer cell lines and several bacterial strains. Methods: The isolation step was carried out using a combination of chromatographic techniques. The structure of the isolated compounds was elucidated mainly using NMR spectroscopy. The cytotoxic activity of isolated compounds was determined with MTT assay, and the antimicrobial was screened using a modified resazurin microtiter-plate assay. Results: Isolation and purification of methanolic extract of D. rappa stem bark yielded 14 known oligomeric resveratrol types of compounds (1-14). Results showed that isolated ampelopsin E (5) and vaticanol C (14) displayed moderate activity against human MCF-7 breast cancer and A549 lung cancer cell lines with IC50 values 14.3 and 10.7 μg/mL, respectively. Interestingly, acetate derivative of isolated laevifonol (2) and ampelopsin F (3) was found to possess potent activities towards MCF-7 cancer cell line with IC50 values 2.8 and 3.3 μg/mL, respectively, in comparison to the parental compounds that demonstrated weak activities (IC50 > 50 μg/mL). For the antibacterial assay, compounds 10 and 12 showed moderate activities towards Gram-positive bacterial strains (MIC ≤ 50 μM). Conclusion: 14 known oligomeric resveratrol types of compounds have been isolated. The activity of 14 against A549 cell line, 5 against MCF-7 cell line, and 10 and 12 against Gram-positive bacterial strains were the most promising results of this study. While the strong cytotoxicity of acetate derivative (2 and 3) against MCF-7 cell line has revealed the potential of resveratrol oligomers to be used as a template for designing new anticancer drugs.

Background: Lotus maritimus L. (Fabaceae) is a perennial herb species with yellow flowers, growing in Europe, Asia, Middle East and Maghreb. Some flavones and flavonols have been identified in their leaves and flowers. Their leaf extract was used as a cellulolytic and antiaging cosmetic ingredient. Objective: The aim of this work was to perform antioxidant, anti-tyrosinase and anti-elastase properties of L. maritimus aerial parts and their chemical profile. Methods: A ¹³C NMR-based dereplication method combined with a bio-guided purification was used for metabolite identification. Chemical structures were determined by NMR and ESI-MS spectroscopic methods. The antioxidant properties of the fractions and purified compounds were measured using CUPRAC, DPPH and hydroxyl radical scavenging assays. Their inhibitory activities against the fungal tyrosinase and human neutrophil elastase enzymes were also evaluated. Results: EtOAc and n-BF fractions were characterized as the most active parts. Twenty-two compounds were identified from these fractions by using a ¹³C NMR-based dereplication method. This process was completed by the purification of minor compounds in the n-BuOH fraction. Eight known compounds were isolated, including many mono-glycosylated flavonoids with variable substitutions on the B-ring, allowing structure-activity relationships. Conclusion: Twenty-two compounds, including phenolic acids, flavonoids and glycoside derivatives, were firstly described in L. maritimus. Three quercetin and myricetin-type flavonoids exhibited good antioxidant activities and all flavonoids tested have moderate effects on elastase inhibition.

Background: Indonesian herbal medicine has become target of new drugs against diseases, including cancer. The high incidence and mortality rate of cancer, anticancer resistance, and side effects of chemotherapy contribute to the urgency of researching novel anticancer drugs. A natural product from Schima wallichii Korth., an Indonesian herbal medicine empirically used for many diseases, has shown anticancer activity in MCF-7 and LNCaP cells. Objective: In this study, we investigated the antiproliferative mechanism of the active compound of S. wallichii, kaempferol-3-O-rhamnoside, against Jurkat cells. Methods: Treated cells were analyzed using a proliferation assay and real time-reverse transcriptase polymerase chain reaction for IL-2 mRNA measurement. The mechanism of antiproliferative activity was assesed by western blotting analysis for Mitogen Activated Protein Kinases (MAPKs). Results: Kaempferol-3-O-rhamnoside has an antiproliferative activity at IC50 of 76.3 μM and slightly inhibited IL-2 mRNA expression. The mechanism to inhibit Jurkat cells proliferation was through the stimulation of phosphorylated Jun amino-terminal kinase. Conclusion: The present study observed the molecular mechanism of antiproliferative activity of kaempferol-3-O-rhamnoside.

Background: Cancer is one of the major problems at present, to which vast research is being dedicated to find an effective remedy. Medicinal plants are endowed with numerous molecules that could be effective in multiple diseases including cancer. Thymus linearis, being rich in phenols, terpenoid, and flavonoids have the potential to provide anti-cancer entities. Methods: The extracts of Thymus linearis were investigated for in vitro anticancer activity using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay on a panel of cancer cell lines. The cellular and nuclear morphology was studied using microscopic techniques. Agarose gel electrophoresis was used for DNA fragmentation analysis. Protein expression was determined by western blotting. LC-MS was used for phytochemical identification. Results: Among all the extracts, Thymus linearis methanolic (TLM) extract was found to exhibit antiproliferative activity on cell lines to varying degrees. TLM was found to be most potent against HCT-116 with an IC50 of 158μg/ml after 48hrs treatment while being nontoxic to HEK-293 and FR-2 cells under similar concentrations. TLM decreased clonogenic potential of HCT-116 cells. It induced cell shrinkage, membrane blebbing and nuclear fragmentation characteristic of apoptotic in a dose dependent manner in HCT-116 cells. Prominent internucleosomal DNA cleavage was observed in HCT-116 cells after 48hrs TLM treatment. Western blot analysis revealed the up regulation of expression of Bax, caspases 9 and caspases 3 and downregulation of Bcl-2 proteins. The LC-MS data revealed the presence of Salvianolic acid H, Synparvolide C, Thymuside A and Jasmonic acid; 12-Hydroxy, O-β-D-glucopyranoside and polyphenolic flavonoids to which antiproliferative activity can be attributed. Conclusion: The results suggest that Thymus linearis methanolic extract could be valuable source of anti-cancer agents.

Background and Aim: Obesity has reached epidemic proportions around the world, resulting in severe health effects and financial costs, which have led to prompt actions and the advancement of phytochemistry technologies as new treatment techniques. This study aimed to assess and compare the anti-obesity, antioxidant, and anti-inflammatory effects of some common and safe doses of natural products like bitter orange, flax seeds, and ginger in adult male albino rats fed a high-fat diet. Methods: Fifty adult male albino rats were divided into five groups (n=10): a negative control group that received a balanced normal diet, a positive control group that received a high-fat diet (HFD) for eight weeks, and other 3 groups were fed HFD for eight weeks receiving daily 20 mg/kg/day of bitter orange fruit aqueous extract (standardized at 10% p- synephrine) or 250 mg/kg/- day of flax seeds ethanol extract or 200 mg/kg/day of ginger rhizomes ethanol extract for the last 4 weeks. All rats were sacrificed at the end of the study to obtain blood, liver, and kidney samples for biochemical and histopathological analyses. Results: The herbal extracts reduced body weight, lipid profile, inflammatory markers alpha-fetoprotein (AFP) and C reactive protein (CRP), malondialdehyde (MDA), and liver enzymes, all of which had been increased by the HFD. Furthermore, treatment with herbal extracts resulted in a significant reduction and improvement of the proliferated inflammatory infiltration, congested veins, and fatty vacuolated vesicles induced by HFD in liver and kidney tissues. Bitter orange exhibited the strongest anti-obesity effects, while flaxseed and ginger showed the strongest antioxidant and anti-inflammatory effects in response to the HFD. Conclusion: In obese rats, the use of these herbal extracts displayed a variety of possible protective and therapeutic effects. As a result, they are recommended for obese people, and further research is needed to determine the effects of a combination of various biochemical components found in these plant extracts on obesity and related disorders.

Background: Dillenia suffruticosa (Griff.) Mart. has been traditionally used to promote wound healing, relieve rheumatism, fever and some cancerous growths. The leaves of the local variety of D. suffruticosa lack scientific studies on its biological applications in the context of antibacterial, antioxidant and cytotoxic activities. Objective: The objective of this study is to evaluate the antioxidant, antibacterial and cytotoxic properties of the leaves of D. suffruticosa from Brunei Darussalam. Methods: The leaves were extracted using 80% (v/v) methanol, 80% (v/v) ethanol and aqueous. The antioxidant capacities were determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging and ferric ion reducing antioxidant power (FRAP) assays. The Folin-Ciocalteu and aluminium chloride colorimetric assays were also used to evaluate the total phenolic and flavonoid contents. The antibacterial and cytotoxic activities of the extracts were determined using the Kirby-Bauer disc diffusion and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assays. Results: The methanolic extract of the D. suffruticosa leaves displayed the highest antioxidant activity despite having comparable phenol content when extracted using the ethanol extraction solvent. The methanolic extract also demonstrated antibacterial activity on Staphylococcus aureus at a concentration of 50 mg/mL or above. The cytotoxicity of the methanolic extract was higher against the CaSki cell line than the A549 lung cancer cell line in the first 24 h but became more cytotoxic against A549 than CaSki at 48 h and 72 h. Conclusion: Our findings suggest that the methanolic extract of the leaves of D. suffruticosa from Brunei Darussalam has significant antioxidant and antibacterial activity against S. aureus and moderate cytotoxicity against A549 and CaSki cell lines.