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Flavonoids of Artocarpus heterophyllus Lam. heartwood inhibit the innate immune responses of human phagocytes

Septama AW, Jantan I, Panichayupakaranant P

J Pharm Pharmacol, 2018 Sep;70(9):1242-1252.
PMID: 29943393 DOI: 10.1111/jphp.12952

OBJECTIVES: To investigate the effects of flavonoids isolated from Artocarpus heterophyllus. heartwood on chemotaxis, phagocytosis, reactive oxygen species (ROS) production and myeloperoxidase (MPO) activity of human phagocytes.
METHODS: Chemotaxis was evaluated using a modified Boyden chamber and phagocytosis was determined by flowcytometer. Respiratory burst was investigated by luminol-based chemiluminescence assay while MPO activity was determined by colorimetric assay.
KEY FINDINGS: Artocarpanone and artocarpin strongly inhibited all steps of phagocytosis. Artocarpanone and artocarpin showed strong chemotactic activity with IC50 values of 6.96 and 6.10 μm, respectively, which were lower than that of ibuprofen (7.37 μm). Artocarpanone was the most potent compound in inhibiting ROS production of polymorphonuclear leucocytes and monocytes with IC50 values comparable to those of aspirin. Artocarpin at 100 μg/ml inhibited phagocytosis of opsonized bacteria (28.3%). It also strongly inhibited MPO release with an IC50 value (23.3 μm) lower than that of indomethacin (69 μm). Structure-activity analysis indicated that the number of hydroxyl group, the presence of prenyl group and variation of C-2 and C-3 bonds might contribute towards their phagocytosis.
CONCLUSIONS: Artocarpanone and artocarpin were able to suppress strongly the phagocytosis of human phagocytes at different steps and have potential to be developed into potent anti-inflammatory agents.
Dietary polyphenols suppress chronic inflammation by modulation of multiple inflammation-associated cell signaling pathways

Jantan I, Haque MA, Arshad L, Harikrishnan H, Septama AW, Mohamed-Hussein ZA

J Nutr Biochem, 2021 07;93:108634.
PMID: 33794330 DOI: 10.1016/j.jnutbio.2021.108634

The high failure rate of the reductionist approach to discover effective and safe drugs to treat chronic inflammatory diseases has led scientists to seek alternative ways. Recently, targeting cell signaling pathways has been utilized as an innovative approach to discover drug leads from natural products. Cell signaling mechanisms have been identified playing key role in diverse diseases by inducing proliferation, cell survival and apoptosis. Phytochemicals are known to be able to modulate the cellular and molecular networks which are associated to chronic diseases including cancer-associated inflammation. In this review, the roles of dietary polyphenols (apigenin, kaempferol, quercetin, curcumin, genistein, isoliquiritigenin, resveratrol and gallic acid) in modulating multiple inflammation-associated cell signaling networks are deliberated. Scientific databases on suppressive effects of the polyphenols on chronic inflammation via modulation of the pathways especially in the recent five years are gathered and critically analyzed. The polyphenols are able to modulate several inflammation-associated cell signaling pathways, namely nuclear factor-kappa β, mitogen activated protein kinases, Wnt/β-catenin and phosphatidylinositol 3-kinase and protein kinase B via selective actions on various components of the networks. The suppressive effects of the polyphenols on the multiple cell signaling pathways reveal their potential use in prevention and treatment of chronic inflammatory disorders. Understanding the mechanistic effects involved in modulation of the signaling pathways by the polyphenols is necessary for lead identification and development of future functional foods for prevention and treatment of chronic inflammatory diseases.
Fulltext Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review

Jantan I, Arshad L, Septama AW, Haque MA, Mohamed-Hussein ZA, Govender NT

Phytother Res, 2023 Mar;37(3):1036-1056.
PMID: 36343627 DOI: 10.1002/ptr.7671

The worldwide spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to health, economic, environmental, and social aspects of human lives. Currently, there are no approved treatments that can effectively block the virus although several existing antimalarial and antiviral agents have been repurposed and allowed use during the pandemic under the emergency use authorization (EUA) status. This review gives an updated overview of the antiviral effects of phytochemicals including alkaloids, flavonoids, and terpenoids against the COVID-19 virus and their mechanisms of action. Search for natural lead molecules against SARS-CoV-2 has been focusing on virtual screening and in vitro studies on phytochemicals that have shown great promise against other coronaviruses such as SARS-CoV. Until now, there is limited data on in vivo investigations to examine the antiviral activity of plants in SARS-CoV-2-infected animal models and the studies were performed using crude extracts. Further experimental and preclinical investigations on the in vivo effects of phytochemicals have to be performed to provide sufficient efficacy and safety data before clinical studies can be performed to develop them into COVID-19 drugs. Phytochemicals are potential sources of new chemical leads for the development of safe and potent anti-SARS-CoV-2 agents.
Antibacterial, bacteriolytic, antibiofilm, and synergistic effects of the peel oils of Citrus microcarpa and Citrus x amblycarpa with tetracycline against foodborne Escherichia coli

Septama AW, Yuandani Y, Khairunnisa NA, Nasution HR, Utami DS, Kristiana R, et al.

Lett Appl Microbiol, 2023 Nov 01;76(11).
PMID: 37898554 DOI: 10.1093/lambio/ovad126

Citrus essential oils (EOs) have shown significant antibacterial activity. The present study was undertaken to evaluate the antibacterial activity of the peel oils of Citrus microcarpa and C. x amblycarpa against Escherichia coli. The minimum inhibition concentration (MIC) was determined by using the broth microdilution assay. The checkerboard method was used to identify synergistic effects of the EOs with tetracycline, while bacteriolysis was assessed by calculating the optical density of the bacterial supernatant, crystal violet assay was used to assess their antibiofilm. Ethidium bromide accumulation test was employed to assess efflux pump inhibition. Electron microscope analysis was performed to observe its morphological changes. The EOs of C. microcarpa and C. x amblycarpa were found to contain D-limonene major compound at 55.78% and 46.7%, respectively. Citrus microcarpa EOs exhibited moderate antibacterial against E. coli with a MIC value of 200 μg/mL. The combination of C. microcarpa oil (7.8 μg/mL) and tetracycline (62.5 μg/mL) exhibited a synergy with FICI of 0.5. This combination inhibited biofilm formation and disrupt bacterial cell membranes. Citrus microcarpa EOs blocked the efflux pumps in E. coli. Citrus microcarpa EOs demonstrated promising antibacterial activity, which can be further explored for the development of drugs to combat E. coli.
Fulltext Transcriptomics-driven drug repositioning for the treatment of diabetic foot ulcer

Adikusuma W, Zakaria ZA, Irham LM, Nopitasari BL, Pradiningsih A, Firdayani F, et al.

Sci Rep, 2023 Jun 20;13(1):10032.
PMID: 37340026 DOI: 10.1038/s41598-023-37120-1

Diabetic foot ulcers (DFUs) are a common complication of diabetes and can lead to severe disability and even amputation. Despite advances in treatment, there is currently no cure for DFUs and available drugs for treatment are limited. This study aimed to identify new candidate drugs and repurpose existing drugs to treat DFUs based on transcriptomics analysis. A total of 31 differentially expressed genes (DEGs) were identified and used to prioritize the biological risk genes for DFUs. Further investigation using the database DGIdb revealed 12 druggable target genes among 50 biological DFU risk genes, corresponding to 31 drugs. Interestingly, we highlighted that two drugs (urokinase and lidocaine) are under clinical investigation for DFU and 29 drugs are potential candidates to be repurposed for DFU therapy. The top 5 potential biomarkers for DFU from our findings are IL6ST, CXCL9, IL1R1, CXCR2, and IL10. This study highlights IL1R1 as a highly promising biomarker for DFU due to its high systemic score in functional annotations, that can be targeted with an existing drug, Anakinra. Our study proposed that the integration of transcriptomic and bioinformatic-based approaches has the potential to drive drug repurposing for DFUs. Further research will further examine the mechanisms by which targeting IL1R1 can be used to treat DFU.
Antibacterial, bacteriolytic, and antibiofilm activities of the essential oil of temu giring (Curcuma heyneana Val.) against foodborne pathogens

Septama AW, Tasfiyati AN, Rahmi EP, Jantan I, Dewi RT, Jaisi A

Food Sci Technol Int, 2023 May 22.
PMID: 37218156 DOI: 10.1177/10820132231178060

Foodborne pathogens may cause foodborne illness, which is among the major health problems worldwide. Since the therapeutic options for the treatment of the disease are becoming limited as a result of antibacterial resistance, there is an increasing interest to search for new alternatives of antibacterial. Bioactive essential oils from Curcuma sp become potential sources of novel antibacterial substances. The antibacterial activity of Curcuma heyneana essential oil (CHEO) was evaluated against Escherichia coli, Salmonella typhi, Shigella sonnei, and Bacillus cereus. The principal constituents of CHEO are ar-turmerone, β-turmerone, α-zingiberene, α-terpinolene, 1,8-cineole, and camphor. CHEO exhibited the strongest antibacterial activity against E. coli with a MIC of 3.9 µg/mL, which is comparable to that of tetracycline. The combination of CHEO (0.97 µg/mL) and tetracycline (0.48 µg/mL) produced a synergistic effect with a FICI of 0.37. Time-kill assay confirmed that CHEO enhanced the activity of tetracycline. The mixture disrupted membrane permeability of E. coli and induced cell death. CHEO at MIC of 3.9 and 6.8 µg/mL significantly reduced the formation of biofilm in E. coli. The findings suggest that CHEO has the potential to be an alternative source of antibacterial agents against foodborne pathogens, particularly E. coli.
A synergistic interaction between Citrus hystrix peel essential oil and tetracycline and evaluation of their antibacterial mechanism of action in vitro and in silico against Escherichia coli

Khairunnisa NA, Yuandani YA, Nasution HR, Utami DS, Frimayanti N, Jantan I, et al.

Chem Biodivers, 2024 Sep 09.
PMID: 39246102 DOI: 10.1002/cbdv.202401291

Citrus hystrix essential oil (CHEO) have shown various pharmacological properties including antibacterial activity. This EO also possessed antibacterial effect against foodborne pathogens. There is less information available about the synergy interaction between CHEO and tetracycline, as well as their mechanism of action. Therefore, this study was conducted to evaluate the synergistic effect of CHEO and tetracycline against clinical isolate of Escherichia coli. Antibiofilm, bacteriolytic, and efflux pump inhibitor activities were also performed. The chemical composition of CHEO was analysed using GC-MS. Three major compounds, D-limonene (25.02%), β-pinene (23.37%), and β-sabinene (22.20%) were identified. CHEO exhibited moderate antibacterial activity with MIC value of 250 μg/mL. The combination of CHEO (7.8 μg/mL) and tetracycline (62.5 μg/mL) produced a synergistic effect on E. coli with fractional inhibitory concentration index of 0.5. This mixture inhibited biofilm formation in E. coli. The combination of 7.8 μg/mL CHEO and 62.5 μg/mL tetracycline demonstrated bacteriolytic activity. In addition, the CHEO at 250 μg/mL showed a significant effect in inhibiting efflux pump. D-limonene has a binding free energy value of -20.13 kcal/mol with ompA transmembrane domain of E. coli. This finding indicates that CHEO has a potency to be developed as natural antibacterial against E. coli.
Fulltext Immunomodulatory effects and mechanisms of the extracts and secondary compounds of Zingiber and Alpinia species: a review

Yuandani, Jantan I, Haque MA, Rohani AS, Nugraha SE, Salim E, et al.

Front Pharmacol, 2023;14:1222195.
PMID: 37533631 DOI: 10.3389/fphar.2023.1222195

Zingiber and Alpinia species (family: Zingiberaceae) are popularly used in food as spices and flavoring agents and in ethnomedicine to heal numerous diseases, including immune-related disorders. However, their ethnomedicinal uses have not been sufficiently supported by scientific investigations. Numerous studies on the modulating effects of plants and their bioactive compounds on the different steps of the immune system have been documented. This review aimed to highlight up-to-date research findings and critically analyze the modulatory effects and mechanisms of the extracts and secondary compounds of several Zingiber and Alpinia species, namely, Zingiber officinale Roscoe, Z. cassumunar Roxb., Z. zerumbet (L.) Roscoe ex Sm., Alpinia galanga Linn., A. conchigera Griff, A. katsumadai Hayata, A. oxyphylla Miq., A. officinarum Hance, A. zerumbet (Pers.) Burtt. et Smith, and A. purpurata (Viell.) K. Schum. on the immune system, particularly via the inflammation-related signaling pathways. The immunomodulating activities of the crude extracts of the plants have been reported, but the constituents contributing to the activities have mostly not been identified. Among the extracts, Z. officinale extracts were the most investigated for their in vitro, in vivo, and clinical effects on the immune system. Among the bioactive metabolites, 6-, 8-, and 10-gingerols, 6-shogaol, and zerumbone from Zingiber species and cardamomin, 1'-acetoxychavicol acetate, yakuchinone, rutin, 1,8-cineole, and lectin from Alpinia species have demonstrated strong immunomodulating effects. More experimental studies using cell and animal models of immune-related disorders are necessary to further understand the underlying mechanisms, together with elaborate preclinical pharmacokinetics, pharmacodynamics, bioavailability, and toxicity studies. Many of these extracts and secondary metabolites are potential candidates for clinical development in immunomodulating agents or functional foods to prevent and treat chronic inflammatory disorders.
Mechanistic insights into anti-inflammatory and immunosuppressive effects of plant secondary metabolites and their therapeutic potential for rheumatoid arthritis

Yuandani, Jantan I, Salim E, Septama AW, Rullah K, Nainu F, et al.

Phytother Res, 2024 Apr 10.
PMID: 38600726 DOI: 10.1002/ptr.8147

The anti-inflammatory and immunosuppressive activities of plant secondary metabolites are due to their diverse mechanisms of action against multifarious molecular targets such as modulation of the complex immune system associated with rheumatoid arthritis (RA). This review discussed and critically analyzed the potent anti-inflammatory and immunosuppressive effects of several phytochemicals and their underlying mechanisms in association with RA in experimental studies, including preliminary clinical studies of some of them. A wide range of phytochemicals including phenols, flavonoids, chalcones, xanthones, terpenoids, alkaloids, and glycosides have shown significant immunosuppressive and anti-inflammatory activities in experimental RA models and a few have undergone clinical trials for their efficacy and safety in reducing RA symptoms and improve patient outcomes. These phytochemicals have potential as safer alternatives to the existing drugs in the management of RA, which possess a wide range of serious side effects. Sufficient preclinical studies on safety and efficacy of these phytochemicals must be performed prior to proper clinical studies. Further studies are needed to address the barriers that have so far limited their human use before the therapeutic potential of these plant-based chemicals as anti-arthritic agents in the treatment of RA is fully realized.