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Background: Depression is a crippling mental disorder with high prevalence around the world. The available clinical antidepressants have been effective to a certain degree, and different side effects have limited their application. This leads to the necessity of finding new treatments. Herbal plants are a substantial source of new drug leads. Terpenoid compounds are secondary metabolites representing an enormous category of structures found commonly in plants either as aglycones or attached to sugar moieties. These phytochemicals have been extensively studied for their various biological effects, and several have been investigated for potential therapeutic effects in the treatment of depression. Aim: This review aims to highlight the current knowledge on some terpenoids and triterpenoid saponins as potential antidepressant agents and their mechanisms of action, which may provide a better understanding of the potential antidepressant-like effects of these compounds and lead to the development of auspicious molecules with high efficiency and low side effects for depressive disorders treatment. Methods: A total of 16 plants containing antidepressant agents are reviewed in this article. 9 terpenoids and 23 triterpenoid saponins compounds have been reported to becommonly found in plant extracts, indicating potential use for depression. To enhance the datum of this review, the mechanism of action for the candidate compounds has been predicted via functional enrichment analysis. Results: The behavioural and neurochemical effects, as well as the possible mechanisms of action, have been evaluated in rodents by different predictive models of depression, mainly the acute stress models of the forced swimming test (FST) and tail suspension test (TST). The involved mechanisms include enhancing monoamine neurotransmitters, ameliorating brain-derived neurotrophic factor (BDNF), and normalizing the hypothalamus-pituitary-adrenal (HPA) axis. Preclinical studies support the potential antidepressant activities of some terpenoid compounds. Furthermore, the functional enrichment analysis has confirmed the previous pre-clinical findings and predicted further mechanisms of action, including cellular calcium ion homeostasis, cellular response to dopamine, endocrine resistance, and regulating GABAergic, serotonergic, glutamatergic, and dopaminergic synapse, bedsides neurotransmitter reuptake. Conclusion: Terpenoids and triterpenoid saponins provide a large number of natural compounds. This review sheds light on terpenoids and triterpenoid saponins compounds with antidepressant-like activity and their potential mechanisms of action. However, more evaluations are required to confirm that these compounds are promising for discovering antidepressant drugs.

The role of Carica papaya L. leaf juice in immune dysregulation caused by dengue virus infection remains unclear. This study aimed to investigate the immunomodulatory activities of the freeze-dried C. papaya leaf juice (FCPLJ) on AG129 mice infected with a clinical DENV-2 (DMOF015) isolate. The infected AG129 mice were orally treated with 500 and 1000 mg/kg/day of FCPLJ, for three days. Platelet, leukocyte, lymphocyte and neutrophil counts were microscopically determined. The level of plasma proinflammatory cytokines was measured by multiplex immunoassay. The levels of intracellular cytokines and viral RNA were determined by RT-qPCR technique. The results showed that the FCPLJ treatment increased the total white blood cell and neutrophil counts in the infected mice. The FCPLJ treatment decreased the level of GM-CSF, GRO-alpha, IL-1 beta, IL-6, MCP-1 and MIP-1 beta in the plasma of the infected mice. The intracellular IL-6 and viral RNA levels in the liver of infected mice were decreased by the FCPLJ treatment. In conclusion, this study supports the potential immunomodulatory role of the FCPLJ in a non-lethal, symptomatic dengue mouse model. Further studies on the action mechanism of the C. papaya leaf juice and its possible use as adjunctive dengue immunotherapy are warranted.

The role of Carica papaya L. leaf juice in immune dysregulation caused by dengue virus infection remains unclear. This study aimed to investigate the immunomodulatory activities of the freeze-dried C. papaya leaf juice (FCPLJ) on AG129 mice infected with a clinical DENV-2 (DMOF015) isolate. The infected AG129 mice were orally treated with 500 and 1000 mg/kg/day of FCPLJ, for three days. Platelet, leukocyte, lymphocyte and neutrophil counts were microscopically determined. The level of plasma proinflammatory cytokines was measured by multiplex immunoassay. The levels of intracellular cytokines and viral RNA were determined by RT-qPCR technique. The results showed that the FCPLJ treatment increased the total white blood cell and neutrophil counts in the infected mice. The FCPLJ treatment decreased the level of GM-CSF, GRO-alpha, IL-1 beta, IL-6, MCP-1 and MIP-1 beta in the plasma of the infected mice. The intracellular IL-6 and viral RNA levels in the liver of infected mice were decreased by the FCPLJ treatment. In conclusion, this study supports the potential immunomodulatory role of the FCPLJ in a non-lethal, symptomatic dengue mouse model. Further studies on the action mechanism of the C. papaya leaf juice and its possible use as adjunctive dengue immunotherapy are warranted.

Environmental conditions influence specialized plant metabolism. However, many studies aiming to understand these modulations have been conducted with model plants and/or under controlled conditions, thus not reflecting the complex interaction between plants and environment. To fully grasp these interactions, we investigated the specialized metabolism and genetic diversity of a native plant in its natural environment. We chose Myrcia bella due to its medicinal interest and occurrence in Brazilian savanna regions with diverse climate and soil conditions. An LC-HRMS-based metabolomics approach was applied to analyze 271 samples harvested across seven regions during the dry and rainy season. Genetic diversity was assessed in a subset of 40 samples using amplified fragment length polymorphism. Meteorological factors including rainfall, temperature, radiation, humidity, and soil nutrient and mineral composition were recorded in each region and correlated with chemical variation through multivariate analysis (MVDA). Marker compounds were selected using a statistically informed molecular network and annotated by dereplication against an in silico database of natural products. The integrated results evidenced different chemotypes, with variation in flavonoid and tannin content mainly linked to soil conditions. Different levels of genetic diversity and distance of populations were found to be correlated with the identified chemotypes. These observations and the proposed analytical workflow contribute to the global understanding of the impact of abiotic factors and genotype on the accumulation of given metabolites and, therefore, could be valuable to guide further medicinal exploration of native species.

Ficus deltoidea Jack (Moraceae) is a plant used in Malaysia for various diseases including as a supplement in diabetes management. Morphology distinction of the 7 main varieties (var. angustifolia, var. bilobata, var. deltoidea, var. intermedia, var. kunstleri, var. motleyana and var. trengganuensis) is challenging due to the extreme leaf heterophylly and unclear varietal boundaries, making it difficult for quality control of F. deltoidea products. We aimed to compare the phytochemical composition of 7 varieties growing in different conditions at various geographical locations. We also aimed to establish the quality control markers for the authentication of these varieties. We applied untargeted UHPLC-TOFMS metabolomics to discriminate 100 leaf samples of F. deltoidea collected from 6 locations in Malaysia. A genetic analysis on 21 leaf samples was also performed to validate the chemotaxonomy differentiation. The PCA and HCA analysis revealed the existence of 3 chemotypes based on the differentiation in the flavonoid content. The PLS-DA analysis identified 15 glycosylated flavone markers together with 1 furanocoumarin. These markers were always consistent for the respective varieties, regardless of the geographical locations and growing conditions. The chemotaxonomy differentiation was in agreement with the DNA sequencing. In particular, var. bilobata accession which showed divergent morphology was also differentiated by the chemical fingerprints and genotype. Chemotype differentiation based on the flavonoid fingerprints along with the proposed markers provide a powerful identification tool to complement morphology and genetic analyses for the quality control of raw materials and products from F. deltoidea.

Semi-preparative HPLC is one of the main techniques used for the purification of natural products (NPs). Generally, the sample has to be solubilized in organic solvent and injected on column through a loop valve. Since the solubility of crude natural extracts is often limited, a high solvent volume is needed for injection. This significantly compromises the resolution and increases the risk of overpressure in the system. To overcome this problem, a dry load injection procedure was developed to ensure optimum resolution even at high sample loading. The approach was first validated with a representative mixture of NPs standards, and successfully applied to two representative crude plant extracts: the dichloromethane extract of Annacardium occidentale and the methanolic extract of Hypericum perforatum. In all cases, the dry loading injection setup enabled an efficient introduction of the samples in the semi-preparative HPLC system. Different overload conditions of the columns were tested and the results demonstrated the robustness of the method and the possibility of applying it with a limited loss of resolution compared to liquid injection and without increasing pressure. The chromatographic resolutions were close to those obtained at the analytical level and separation were of much better quality when compared to liquid injection. This approach is especially relevant when purifying compounds isolated with high resolution from extracts that are poorly soluble in low volume of injection solvent due to the presence of lipophilic compounds and are thus not compatible for loop injection in typical reversed phase conditions. In addition, the dry load setup was also found to be useful when relatively polar components have to be separated in reversed phase conditions. In this case, loop injection with methanol generates strong peak distortion and broadening, while the dry load injection affords symmetrical peaks.

Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

article i nfo Camellia sinensis DPPH assay Methanolic extract Total flavonoid content Total phenolic content Background: Tea (Camellia sinensis), a well-known beverage is consumed frequently worldwide due to its high antioxidant properties. The present study determines the amount of phytochemicals and antioxidant activities among 12 high yielding tea clones cultivated in Iran. Results: Among the 12 clones studied, tea clone Iran 100 had the highest total phenolic content and total flavonoid content with values of 8.44 ± 1.03 mg gallic acid equivalents per gram dry weight and 4.50 ± 0.16 mg rutin equivalents per gram dry weight respectively. High performance Liquid Chromatography (HPLC) analysis of phenolics and flavonoids in 12 clones revealed the presence of (+)-catechin, (−)-epicatechin, (−)-epigallocatechin, (−)-epigallocatechin-gallate, (−)-epicatechingallate, gallic acid and caffeine. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay showed the existence of variation in the antioxidant activity ranging from 22.67 to 65.36%. The highest antioxidant activity with IC50 value of 218.24 μg/mL was observed in the leaf extract of the clone Iran 100, while the lowest was found in the clone Iran 482 with IC50 value of 234.44 μg/mL. The antioxidant activity had a positive correlation with total phenolic content, total flavonoid content, (−)-epigallocatechin-gallate, (−)-epicatechingallate and caffeine (0.59 ≤ r ≤ 0.97, P b 0.05). Conclusion: From the study it can be concluded that the clone Iran 100 has a superior quality compared to any other clones studied due to occurrence of more phenolic compounds and a greater antioxidant activity. Hence, we recommend the use of tea clone Iran 100 for commercial planting.

Background The development of resistant to current antimalarial drugs is a major challenge in achieving malaria elimination status in many countries. Therefore there is a need for new antimalarial drugs. Medicinal plants have always been the major source for the search of new antimalarial drugs. The aim of this study was to screen selected Malaysian medicinal plants for their antiplasmodial properties. Methods Each part of the plants were processed, defatted by hexane and sequentially extracted with dichloromethane, methanol and water. The antiplasmodial activities of 54 plant extracts from 14 species were determined by Plasmodium falciparum Histidine Rich Protein II ELISA technique. In order to determine the selectivity index (SI), all plant extracts demonstrating a good antiplasmodial activity were tested for their cytotoxicity activity against normal Madin-Darby Bovine Kidney (MDBK) cell lines by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Results Twenty three extracts derived from Curcuma zedoaria (rhizome), Curcuma aeruginosa (rhizome), Alpinia galanga (rhizome), Morinda elliptica (leaf), Curcuma mangga (rhizome), Elephantopus scaber (leaf), Vitex negundo (leaf), Brucea javanica (leaf, root and seed), Annona muricata (leaf), Cinnamomun iners (leaf) and Vernonia amygdalina (leaf) showed promising antiplasmodial activities against the blood stage chloroquine resistant P. falciparum (EC50

The subchronic toxicity effect of the leaf extract ofCarica papayaLinn. in Sprague Dawley (SD) rats was investigated in this study. The extract was prepared by dissolving the freeze dried extract of the leaves in distilled water and was administered orally to SD rats (consisted of 10 rats/sex/group) at 0 (control), 0.01, 0.14, and 2 g/kg body weight (BW) for 13 weeks. General observation, mortality, and food and water intake were monitored throughout the experimental period. Hematological and biochemical parameters, relative organ weights, and histopathological changes were evaluated. The study showed that leaf extract when administered for 13 weeks did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. There were no significant differences observed in hematology parameters between treatment and control groups; however significant differences were seen in biochemistry values, for example, LDH, creatinine, total protein, and albumin. However, these changes were not associated with histopathological changes. In conclusion, the results suggested that daily oral administration of rats withC. papayaleaf extract for 13 weeks at a dose up to fourteen times the levels employed in traditional medicine practice did not cause any significant toxic effect.

The study was conducted to investigate the platelet increasing property ofCarica papayaleaves juice (CPLJ) in patients with dengue fever (DF). An open labeled randomized controlled trial was carried out on 228 patients with DF and dengue haemorrhagic fever (DHF). Approximately half the patients received the juice, for 3 consecutive days while the others remained as controls and received the standard management. Their full blood count was monitored 8 hours for 48 hours. Gene expression studies were conducted on the ALOX 12 and PTAFR genes. The mean increase in platelet counts were compared in both groups using repeated measure ANCOVA. There was a significant increase in mean platelet count observed in the intervention group (P<0.001) but not in the control group 40 hours since the first dose of CPLJ. Comparison of mean platelet count between intervention and control group showed that mean platelet count in intervention group was significantly higher than control group after 40 and 48 hours of admission (P<0.01). The ALOX 12 (FC = 15.00) and PTAFR (FC = 13.42) genes were highly expressed among those on the juice. It was concluded that CPLJ does significantly increase the platelet count in patients with DF and DHF.

Aim of the study Orthosiphon stamineus, Benth, also known as Misai Kucing in Malaysia and Java tea in Indonesia, is traditionally used in Southeastern Asia to treat kidney dysfunctions, diabetes, gout and several other illnesses. Recent studies of Orthosiphon stamineus pharmacological profile have revealed antioxidant properties and other potentially useful biological activities thereby lending some scientific support to its use in folk medicine. So far the genotoxicity of Orthosiphon stamineus extracts has not been evaluated. In this study the genotoxic potential of Orthosiphon stamineus aqueous extract was investigated by the Salmonella/microsome mutation assay and the mouse bone marrow micronucleus test. Materials and methods Chemical composition of Orthosiphon stamineus aqueous extract was analyzed by High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD). The Salmonella/microsome assay (TA97a, TA98, TA100 and TA1535; plate incorporation method) was performed in the presence or in the absence of extrinsic metabolic activation (S9 mixture). In the mouse micronucleus assay, Orthosiphon stamineus extract was administered by gavage (0, 500, 2000 and 4000 mg/kg body weight/day for 3 days) to male and female Swiss Webster mice (N = 6 per dose per sex) and bone marrow cells were harvested 24 h after the last dose. Ethoxy-resorufin-O-dealkylase (EROD) and benzyloxy-resorufin-O-dealkylase (BROD) activities were determined in mouse liver microsomes. Results The chemical analysis revealed that the Orthosiphon stamineus extract contained flavonoids (sinensetin, eupatorin), caffeic acid, and rosmarinic acid (44.00 ± 1.879 μg/mg), the latter seemed to be one of its major constituent. Tested at doses up to 5000 μg/plate, the Orthosiphon stamineus extract was not toxic to Salmonella tester strains and did not increase the number of revertant colonies over the background incidence. In the mouse bone marrow assay, the extract did not alter the polychromatic:normochromatic erythrocytes (PCE:NCE) ratio, nor did it increase the incidence of micronucleated polychromatic erythrocytes (MNPEs). No overt toxicity and no change of CYP1A (EROD) and 2B9/10 (BROD) activities were noted. Conclusions Based on the aforementioned findings, it is concluded that the use of Orthosiphon stamineus in the traditional medicine poses no genotoxic risk.