Therapeutic potential of flavonoids and their mechanism of action against microbial and viral infections—A review

Limonium sinense and gallic acid suppress hepatitis C virus infection by blocking early viral entry

Dengue infections are still a worldwide burden, especially in Indonesia. There is no specific medication against the dengue virus. Recently, many types of research have been conducted to discover a new drug for dengue virus using natural resource extracts. Indonesia, as a tropical country, has a wide biodiversity. There are several medicinal plants in Indonesia that are believed to possess anti-dengue activity, such as Myristica fatua, Cymbopogon citratus, and Acorus calamus plants. We conducted an in vitro laboratory experiment of several extracts from Indonesian herbs combined with in silico analysis. The extracts were evaluated for safety and antiviral activity in Huh7it-1 cell lines, using a single dose of 20 µg/mL and dose-dependent (5, 10, 20, 40, 80 and 160 µg/mL) of plant extracts against dengue virus serotype 2 (DENV-2) NGC strain. The DMSO 0.1% was used as a negative control. The cytotoxic aspect was assessed by counting the cell viability, while the antiviral activity was calculated by counting the average inhibition. The selectivity index (SI) of plant extracts were performed from a ratio of CC50/EC50 value. In silico analysis was conducted to determine the free energy of binding between NS5 of dengue virus with bioactive compounds contained in Myristica fatua, Cymbopogon citratus and Acorus calamus extract plants. We determined that all extracts were not toxic against Huh7it-1 cell lines. The methanolic extracts of A. calamus, C. citratus, and M. fatua showed inhibition of DENV-2 at a dose of 20 µg/mL to 96.5%, 98.9%, and 122.7%, respectively. The dose-dependent effects showed that M. fatua has the best inhibition activity towards DENV-2. Molecular docking result showed that artesunic acid within M. fatua has the best free energy of binding (−7.2 kcal/mol), followed by homoegonol (−7.1 kcal/mol) which was slightly different from artesunic acid among others. The methanolic extracts of A. calamus, C. citratus, and M. fatua showed prospective anti-dengue activities both in vitro and in silico. Future research should be conducted to find the pure extracts of all useful herbs as a new candidate of antiviral drug.

https://www.mdpi.com/2076-0817/8/2/85/pdf

The Antiviral Effect of Indonesian Medicinal Plant Extracts Against Dengue Virus In Vitro and In Silico

Kalanchoe pinnata (KP) is popularly used for treating inflammatory diseases. This study investigated the antinociceptive, antiedematogenic, and anti-inflammatory potential of the subcutaneous administration of KP flower aqueous extract (KPFE), its ethyl acetate (EtOAcF) and butanol (BuOHF) fractions, and the main KP flavonoid [quercetin 3-O-α-L-arabinopyranosyl () α-L-rhamnopyranoside] (KPFV) in mice, as well as its possible mechanisms of action. KPFE (30–300 mg/kg) and KPFV (1–10 mg/kg) inhibited the acetic acid-induced writhing (ID50 = 164.8 and 9.4 mg/kg, resp.). KPFE (300 mg/kg), EtOAcF (12 mg/kg), BuOHF (15 mg/kg), or KPFV (0.3–3.0 mg/kg) reduced leukocyte migration on carrageenan-induced pleurisy (ID50 = 2.0 mg/kg for KPFV). KPFE (3–30 mg/kg) and KPFV (0.3–3.0 mg/kg) reduced the croton oil-induced ear edema (ID50 = 4.3 and 0.76 mg/kg, resp.). KPFE and KPFV reduced the TNF-α concentration in the pleural exudates on carrageenan-induced pleurisy test. Moreover, KPFV inhibited COX-1 (IC50 = 22.1 μg/mL) and COX-2 (IC50 > 50 μg/mL). The selectivity index (COX-/COX-) was <0.44. These results indicate that KPFE and KPFV produced antinociceptive, antiedematogenic, and anti-inflammatory activities through COX inhibition and TNF-α reduction, revealing that the main flavonoid in KP flowers and leaves plays an important role in the ethnomedicinal use of the plant.

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Mechanisms Underlying the Antinociceptive, Antiedematogenic, and Anti-Inflammatory Activity of the Main Flavonoid from Kalanchoe pinnata

The species Kalanchoe laciniata (L.) DC. and Bryophyllum pinnatum (Lam) Pers. are native from Brazil and Madagascar, respectively. Both belonging to the Crassulaceae family and being widely used by population as a natural anti-inflammatory agent. These species have similar leaf morphology and for this reason, they are known by the same popular name as “saiao” or “coirama”. Several studies have been published involving different parts and preparations of these species. Therefore, this review aims to provide an update overview about the traditional uses, chemical constitution, pharmacology and toxicology of K. laciniata and B. pinnatum species. An extensive literature review was conducted in different scientific databases. Various chemical constituents have been identified in extracts from different parts of K. laciniata and B. pinnatum, being flavonoids the major compounds. They have been traditionally used to treat inflammation, microbial infection, pain, respiratory diseases, gastritis, ulcers, diabetes and cancer tumors. Non-clinical in vitro assays evaluated mainly the antimicrobial and antioxidant activities, while in vivo assays evaluated the leishmanicide, anti-inflammatory and immunomodulatory activities. Regarding toxicity, few studies have been conducted for the two species. The information reported in this work might contribute to the recognition of the importance of K. laciniata and B. pinnatum species, as well as to direct further studies.

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Kalanchoe laciniata and Bryophyllum pinnatum: an updated review about ethnopharmacology, phytochemistry, pharmacology and toxicology

Objective: The aim of this study was to examine extracts from Indonesian plants to identify a compound(s) responsible for antiviral activity against hepatitis C virus (HCV). Methods: Huh7it-1 cells, a clone of human hepatocellular carcinoma-derived Huh7 cells, were infected with the HCV genotype 2a strain JFH1 in the presence of crude methanol extracts from the plants. The extracts were further fractionated and purified by anti-HCV bioactivity-guided analysis using a combination of various column chromatography techniques. The isolated compounds were examined for anti-HCV activity and cytotoxicity, and their structures determined by nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry. Results: Screening of Indonesian plants revealed that a crude methanol extract from Kalanchoe pinnata exhibited anti-HCV activity with a 50%inhibitory concentration (IC50) of 17.2 μg/ml. An ethyl acetate fraction was found to possess strong anti-HCV activity, from which three compounds, i.e., quercetin, gallic acid and quercitrin, were isolated. Anti-HCV activity assay revealed that quercetin and gallic acid, but not quercitrin, inhibited HCV production in a dose-dependent manner, with IC50 values of 1.5 and 6.1 μg/ml, respectively, without exhibiting cytotoxicity. A time-of-addition study demonstrated that quercetin acted at the post-entry step whereas gallic acid at both the entry and post-entry steps. Conclusion: An extract from K. pinnata and its constituents, quercetin and gallic acid, could be potentially used as a supplement for the treatment of HCV infection.

Isolation and identification of substances with anti-hepatitis c virus activities from kalanchoe pinnata

Dengue hemorrhagic fever (DHF) is major public health problem in tropical and subtropical areas of the world with lack of approved vaccines and effective antiviral therapies. With no current treatment for illness attributed to dengue virus (DENV) infection other than supportive care, therapeutic strategies that use natural extract was developed. Indonesia have many plants that potential for antiviral drµgs such as Pterocarpus indicus Willd ( P . indicus ). The objective of this study was to determine the effect of P. indicus to inhibit DENV replication. We used a well-differentiated hepatocytes-derived cellular carcinoma cell line (Huh-7 it-1 cells) to determine and select antiviral activity. The toxicity effects were determined by MTT assay. Then, the suppression of DENV replication was determined by Focus assay. Dengue infected cells with DMSO were used as control. We found that crude extract (Pi), hexane (Pi.1) and ethyl acetate (Pi.2) extract showed strong inhibition with high selectivity index (SI) of 1,392; 285.36 and 168.56 respectively.  Sub fraction of Pi.1 and Pi.2 still showed strong inhibition with high SI.  Further sub-sub fraction of Pi.2 such as Pi.2.12 and Pi.2.12.1 still showed inhibition of DENV replication but there was reduction of SI value. The mechanism experiment of Pi.2.12, we found that Pi 2.12 more profound to inhibit in the post infection stage that entry or pre-infection. We conclude that the sub-fraction of Pi.2.12 has potential antiviral activity against DV infection in vitro. Further studies are still needed to investigate the pure compound of Pi.2.12 that inhibit and have advantages in the future as alternative for treatment of DENV infection.

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Mei Ria Santi

Papers

Isolation and identification of substances with anti-hepatitis c virus activities from kalanchoe pinnata

Antiviral Effect of Pterocarpus indicus Willd Leaves Extract Against Replication of Dengue Virus (DENV) In Vitro

AntiHepatitis C Virus Activity of Alectryon serratus Leaves Extract