Immunomodulatory Role of Plants and Their Constituents on the Management of Metabolic Disorders: An Evidence-Based Review.

The relationship between the immune system and metabolic diseases is complex and increasingly recognized as critical to understanding conditions like obesity, diabetes, and cardiovascular diseases. Modulation of the immune system in patients with metabolic disorders can offer several potential benefits. While the salutary impact of plant-derived bioactive compounds on metabolic and immune functions is acknowledged, there is a paucity of comprehensive reviews on the multifaceted and synergistic mechanisms through which these effects are mediated. This review elucidates the therapeutic potential of phytochemical formulations in ameliorating metabolic disorders and delineates their mechanistic implications on relevant biomarkers and immune modulation. Our analysis reveals a predominance of plant species, including Boswellia serrata, Cinnamomum cassia, Citrus bergamia, Coffea arabica, Ficus racemosa, Momordica charantia, Morus Alba, and Trigonella foenum-graecum, that have undergone clinical evaluation and have been substantiated to confer both metabolic and immunological benefits. The phytoconstituents contained in these plants exert their effects through a range of mechanisms, such as improving glucose regulation, reducing inflammatory responses, and modulating immune system. As such, these findings hold considerable promise for clinical and therapeutic translation and necessitate further empirical validation through randomized controlled trials and mechanistic elucidations to affirm the safety and efficacy of herbal formulations.

Clinical Toxicology of Vitamin D in Pediatrics: A Review and Case Reports.

Intoxication of vitamin D is not a common case in pediatrics. Vitamin D supplements are sold as OTC drugs; however, there is a lack of public education about the permissible limits of vitamin D intake which may lead to vitamin D toxicity (VDT). This review aims to give insights to readers or practitioners about the clinical toxicology of vitamin D in pediatrics, which includes the mechanism of VDT, case reports, and the management of vitamin D poisoning. VDT refers to serum 25(OH)D levels, particularly when the level exceeds 100 ng/mL (250 nmol/L) or is defined as hypervitaminosis D. Hypercalcemia is a common condition of vitamin D toxicity. Vitamin D and its metabolites in moderate levels can induce hypercalcemia, as indicated by the elevation of osteoclastic bone resorption, the presence of calcium in renal tubules, intestinal calcium intake (through increased production of calcium-binding protein in enterocytes), and the decrease of parathyroid hormone synthesis. VDT in pediatrics can be managed by discontinuing vitamin D intake; using activated charcoal, furosemide, prednisone, and calcitonin; rehydration using intravenous sodium chloride 0.9%; and dextrose fluid therapy. It is important for parents to be more careful when providing vitamin D to their children.

Efficacy and Safety of Add-On Plant-Based Drugs for COVID-19 Patients: A Review of the Randomized Control Trials.

COVID-19 caused by the infection of SARS-CoV-2 is still a global concern. WHO reported that from 13 March to 9 April 2023, there were 3 million new cases and approximately 23,000 deaths, mostly occurring in the South-East Asia and Eastern Mediterranean regions, which is predicted due to the new Omicron variant, Arcturus XBB.1.16. Many studies have reported the potency of medicinal plants in enhancing the function of the immune system to combat virus infection. The literature review aimed to describe the efficacy and safety of add-on plant-based drugs for COVID-19 patients. The articles were explored on the PubMed and Cochrane Library databases, and published during 2020-2023. Twenty-two varieties of plants were used as add-on therapy for COVID-19 patients. These plants were Andrographis paniculata, Viola odorata, Withania somnifera, Zingiber officinale, Curcuma longa, Ferula foetida, Centella asiatica, Thymus vulgaris, Citrus sinensis, Eugenia caryophyllus, Boswellia carterii, Elettaria cardamomum, Salvia rosmarinus, Piper nigrum, Alstonia scholaris, Picrorhiza kurroa, Swertia chirata, Caesalpinia crista, Cucurbita maxima, Tinospora cordifolia, Ocimum sanctum, and Allium sativum. The best efficacy of an add-on therapy for COVID-19 patients was found in A. paniculata herbs as a single component in pharmaceutical dosage form or in combination with other plants. The safety of the plant has been confirmed. A. paniculata does not show interaction with remdesivir or favipiravir, however, caution and therapy drug monitoring is needed if A. paniculata is used in combination with lopinavir or ritonavir because a strong noncompetitive inhibition of CYP3A4 may occur.

A Review of Herbal Medicine-Based Phytochemical of Garcinia as Molecular Therapy for Breast Cancer.

Data from globocan statistic in 2020 indicate that breast cancer has become highest incidence rate of cancer. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are known immunohistochemistry (IHC) markers that mediate cell growth and survival signaling. Furthermore, regulator proteins, receptors, and their downstream signaling pathways have emerged as critical components in breast cancer formation and proliferation, and have become well-established therapeutic targets and the core focus of breast cancer therapy research. Garcinia is a big genus in the Clusiaceae family that contains a wide spectrum of biologically active metabolites for the chemical composition of their isolated fruits, stem barks, seeds, leaves, and roots, have resulted including polyisoprenylated benzophenones, polyphenols, bioflavonoids, xanthones, lactones, and triterpenes. This review article aimed to analyze the potential of Garcinia phytochemicals as a molecular therapy of breast cancer. The results showed that phytochemicals of Garcinia (i.e., α-mangostin, Cambogin, Gambogic Acid [GA], Garcinol, Griffipavixanthone, Friedolanostane triterpenoid, Hexane, Neobractatin, 7-Epiclusianone, xanthochymol - guttiferone E, and isoxanthochymol - cycloxanthochymol) have anticancer properties, including apoptosis, inhibition of proliferation, and metastasis. This review is important to provide information regarding phytochemicals of Garcinia as an alternative treatment for breast cancer patients. This article selected 28 article researches based on inclusion criteria with the keyword "Garcinia" and "Breast cancer", in English, and available in full text and abstract searching on PubMed.

Phytochemical Analysis and Immunomodulatory Potential on Diabetic-Infected Tuberculosis by Fruit Etlingera rubroloba A.D. Poulsen.

<b>Background and Objective:</b> <i> Etlingera rubroloba</i> (<i>E. rubroloba</i>) A.D. Poulsen is an endemic plant in South-East Sulawesi and is a newly discovered species. This plant is expected to have the potential as an immunomodulator in patients with diabetes mellitus (DM), which can prevent tuberculosis infection by increasing the phagocytic function of macrophage cells and interleukin-12 (IL-12) levels. <b>Materials and Methods:</b> Phytochemical analysis of the ethanolic extract of the fruit of <i>E. rubroloba</i> A.D. Poulsen using Liquid Chromatography-Mass Spectrometry (LC-MS/MS) was carried out. The immunomodulatory potential <i>in vivo</i> on BALB/c mice model DM was carried out by oral induction of TB antigen with extract dose, control positive, negative and normal groups. Furthermore, the phagocytic activity of macrophage cells can be seen with a microscope and the levels of IL-12 with the Elisa kit. <b>Results:</b> The results showed the ethanol extract of the fruit of <i>E. rubroloba</i> contained eight chemical compounds and had potential as immunomodulators in BALB/c DM mice induced by TB antigen by increasing the phagocytic activity of macrophage cells and levels of IL-12, which were significantly different from the negative control (p<0.05). <b>Conclusion:</b> The chemical composition of the ethanol extract of the fruit of <i>E. rubroloba</i> has the potential as an immunomodulator in TB antigen-induced DM <i>in vivo</i>.

Phytochemical Screening, Toxicity Activity and Antioxidant Capacity of Ethanolic Extract of Etlingera alba Rhizome.

<b>Background and Objective:</b> <i>Etlingera alba </i>(Blume) A.D. Poulsen is one of the plants of the genus <i>Etlingera</i> which is commonly found in Southeast Sulawesi. The research is still lacking, thus, we assumed other species related to <i>E. alba,</i> specifically from the genus<i> Etlingera</i> that provides antioxidant and radical scavenging activity, namely <i>Etlingera elatior</i> (Jack) R.M. Smith. Thus, this study aimed to assess the antioxidant and toxicity activity as well as its secondary metabolites. <b>Materials and Methods:</b> <i>Etlingera alba</i> rhizome was extracted with 96% ethanol. The radical scavenging activity was assayed with 1,1-diphenyl-2-picrylhydrazyl (DPPH) and antioxidant activity was assayed with 2,2'-azino-bis-[3-ethylbenzothiazoline sulphonate (ABTS) assay for radical cation decolourization<i> in vitro</i>. Both Ascorbic Acid (AA) and Trolox were used as positive control. The secondary metabolites were identified by Thin Layer Chromatography (TLC) and LSMS/MS analyzed the difference between compounds. According to results performed with TLC and LCMS/MS. <b>Results:</b> The extract exhibited antioxidant properties using both DPPH and ABTS method. The LC₅₀ of the extract was 608.42±18.31 mg L¹.<i> Etlingera alba </i>rhizome extract contains alkaloids, flavonoids, terpenoids and steroids. The compounds detected in the extract were E-p-Coumaric acid aschantin, 2-Methoxyanofinic acid, Chavicol-ß-D-glucoside, Myristicanol B, ent-16α,17-Hydroxy-19-kaurenoic acid, 5-Hydroxy-7,8,2'-trimethoxyflavone, Methyl ursolate and Spinasterol. <b>Conclusion:</b> <i>Etlingera alba</i> rhizome contains several compounds that might be responsible for antioxidant activity and the extract itself classified as medium toxic.

Antiproliferation Activity and Apoptotic Mechanism of Soursop (Annona muricata L.) Leaves Extract and Fractions on MCF7 Breast Cancer Cells.

INTRODUCTION: Breast cancer is the second most common cancer in women globally, and the incidence rate has increased annually. Traditional medicine is frequently used as a cancer treatment, and soursop or Annona muricata L (A. muricata) is a traditional medicinal plant that has been widely used as an anticancer treatment and requires more thorough study. METHODS: In this research, we prepared ethanol extract and three solvents, ie, ethyl acetate, n-hexane and water fractions of A. muricata leaves and assessed their antiproliferation and cytotoxic activity on MCF7 breast cancer cells compared with that on CV1 normal kidney cells; observation of cell morphology by stained with mixture of propidium iodide and 4',6-diamidino-2-phenylindole indicated that this treatment induced an ongoing process of apoptotic cell death in MCF7 cells. To clarify the cell death mechanism via apoptosis, we assessed the mRNA expression in the caspase cascade of caspase-9, caspase-3, and PARP-1, and anti-apoptotic, Bcl-2 which mediated cytotoxic activity of extracts and ethyl acetate fractions of A. muricata leaves against MCF7 cells. RESULTS: The ethanol extract, ethyl acetate, n-hexane, and water fractions of A. muricata leaves had IC50 values of 5.3, 2.86, 3.08, and 48.31 µg/mL, respectively, in MCF7 cells but had no activity in CV1 cells. The high cytotoxic activity of A. muricata leaves was reflected by changes in the morphology of cancer cells that appeared after 6 h exposure to A. muricata leaf extract and ethyl acetate fraction; the membrane and nucleus of cells undergoing apoptosis were characterized by the rupture and loss of membranes and nuclei. The mechanism that mediates this cytotoxic activity in MCF7 cells was mediated through a decrease in the expression of Bcl-2 mRNA and an increase in caspase-9 and caspase-3 mRNA expression. CONCLUSION: Therefore, the leaves of the medicinal plant A. muricata contained compounds that on extraction exerted a highly effective activity as an anticancer treatment for breast cancer via induced apoptotic cell death.

Pharmacokinetics of 10-gingerol and 6-shogaol in the plasma of healthy subjects treated with red ginger (Zingiber officinale var. Rubrum) suspension.

Red ginger (Zingiber officinale var. Rubrum) is among the most widely consumed medicinal herbs in Indonesia. Ginger rhizome contains phenol compounds including gingerol and shogaol. 10-gingerol has been reported to exhibit the greatest anti-inflammatory and anti-oxidant activities compared with those of other gingerols. Pharmacokinetic studies on ginger have been reported, but there is a lack of such study on red ginger. The present work studied the pharmacokinetics of 10-gingerol and 6-shogaol in the plasma of healthy subjects treated with a single dose of red ginger suspension. Healthy subjects (n=19) were given a single dose of red ginger suspension (2 g/15 ml), and blood samples were taken at baseline (0 min), 30, 60, 90, 120, and 180 min. Analysis of 10-gingerol and 6-shogaol was performed by dissolving 200 µl of the subjects' plasma in 800 µl acetonitrile. The mixture was vortexed and centrifuged at 20,440 × g for 15 min at room temperature. The supernatant was filtered using Millipore membrane (pore size 0.2 µm) and injected into an RP-C18 column for liquid chromatography-mass spectrometry. A mixture of 0.1% (v/v) formic acid in water and acetonitrile (38:62) was used as the mobile phase. The maximum plasma concentration (Cmax) and time to reach Cmax of 10-gingerol and 6-shogaol were 160.49 ng/ml (38 min) and 453.40 ng/ml (30 min), respectively. The elimination half-lives were 336 and 149 min for 10-gingerol and 6-shogaol, respectively. Thus, 10-gingerol and 6-shogaol were absorbed after per oral single dose of red ginger suspension and could be quantified in the plasma of the healthy subjects. Additionally, the red ginger analytes exhibited relatively slow elimination half-lives.

Inhibition of Phosphorylated c-Jun NH(2)-terminal Kinase by 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone Isolated from Eugenia aquea Burm f. Leaves in Jurkat T-cells.

BACKGROUND: Indonesian medicinal plants have been used for their anticancer activity for decades. However, the therapeutic effects of medicinal plants have not been fully examined scientifically. As cancer is a major health problem worldwide, searching for a new anticancer compound has attracted considerable attention. Our previous study found that 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone, an active compound isolated from leaves of Indonesian medicinal plants Eugenia aquea Burm f. (Myrtaceae), had anticancer activity in MCF-7 human breast cancer cells through induction of apoptosis. OBJECTIVE: To investigate the molecular mechanism of 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone antiproliferative activity. MATERIALS AND METHODS: Leaves of E. aquea were extracted by ethanol, fractionated by ethyl acetate, n-hexane, or water, and isolated for its active compound. Jurkat T-cells were treated with 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone for 12 and 24 h, and a cell viability assay and real-time-reverse transcriptase polymerase chain reaction for interleukin-2 (IL-2) mRNA measurement were performed. The effects of active compound to mitogen-activated protein kinases were also examined to investigate the mechanism of its antiproliferative activity. RESULTS: 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone inhibited Jurkat T-cell proliferation with a half maximal inhibitory concentration of 59.5 mM. Although IL-2 mRNA expression was slightly increased after treatment, it inhibited c-Jun N-terminal kinase expression but not p38 and extracellular signal-regulated kinase expression. CONCLUSIONS: Our study indicated that the molecular mechanism mediating the antiproliferative activity of 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone may be attributed to the stimulation of an immunological microenvironment in the cells. SUMMARY: 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone was isolated from Eugenia aquea. The antiproliferative activity of 2',4'-dihydroxy-6- methoxy-3,5-dimethylchalcone significantly showed in Jurkat T-cells with a half maximal inhibitory concentration of 59.5 mM through inhibition of c-Jun N-terminal kinase phosphorylation. Interleukin-2 mRNA expression was also slightly increased after treatment with the compound, and this result may be indicated to the stimulation of the immunological microenvironment in T-cells. Abbreviations used:E. aquea: Eugenia aquea, IL-2: Interleukin-2, MAPK: Mitogen-activated protein kinase, ERKs: Extracellular signal-regulated kinases, JNKs: c-Jun N-terminal kinases, p38: p38 MAPK, PI3K: Phosphatidylinositol-3 kinase, IC50: Half maximal inhibitory concentration.

Catechin Isolated from Garcinia celebica Leaves Inhibit Plasmodium falciparum Growth through the Induction of Oxidative Stress.

BACKGROUND: Resistance of antimalarial drugs to Plasmodium falciparum has become a major concern in malaria eradication. Although it is also affected by several socioeconomic factors, a new antiplasmodial agent is needed for a global malaria control program. OBJECTIVE: In this study, we attempted to uncover the antiplasmodial properties of Garcinia celebica, an Indonesian medicinal plant, along with the responsible compound and its possible mechanism. MATERIALS AND METHODS: The G. celebica leaves were ethanol extracted and fractionated based on their polarity using n-hexane, ethyl acetate, and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant P. falciparum at 100 µg/ml for 72 h. The active compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. RESULTS: The IC50 of (+)-catechin, the characterized compound, against P. falciparum was 198 µM in 24 h and experiment. The isolated catechin inhibited P. falciparum growth in both trophozoite and schizont stages. An additional experiment also suggests that the antiplasmodial property of catechin occurs through the induction of the oxidative stress to P. falciparum. CONCLUSION: This result shows that the potential of catechin and its antimalarial properties should be explored further. SUMMARY: Garcinia celebica leaf extract and fractions inhibit Plasmodium falciparum growthCatechin, the active compound of Garcinia celebica leaf extract, inhibits Plasmodium falciparum growth in a time- and dose-dependent manner Abbreviations used: RBC: Red Blood Cells; IC50: Inhibition Concentrattino 50; MeOH: Methanol; RPMI: Roswell Park Memorial Institute; EI: Electron Ionization.

ANTIBACTERIAL PROPERTIES OF SELECTED PLANTS CONSUMED BY PRIMATES AGAINST ESCHERICHIA COLI AND BACILLUS SUBTILIS.

Bacterial antimicrobial resistance is a major health problem worldwide. Plants consumed by non-human primates are potentially safe for humans. In this study, we examined the potential antibacterial properties of plants consumed by non-human primates in Indonesia. We studied the antibacterial properties of the leaf extracts of 34 primate-consumed plants against Escherichia coli and Bacillus subtilis in vitro. The plants were collected from the Pangandaran Conservation Area, West Java Province, Indonesia. The leaves were dried and then powdered by crushing and the potential active ingredients were extracted with 95% ethanol at room temperature for 24 hours. The obtained solvent was then dried at 50ºC under reduced pressure. The antibacterial properties of each product were then tested to determine the minimum inhibitory and minimum bactericidal concentrations using the broth microdilution technique and a disc diffusion test was also performed. The results show Kleinhovia hospita, Dillenia excelsa and Garcinia celebica had the best antibacterial properties against Escherichia coli and Ficus benjamina, Ficus altissima, and Elaeocarpus glaber had the best antibacterial properties against Bacillus subtilis. Some of the studied leaf extracts in our study have the potential to be developed into antibacterial medications and need to be studied further.

Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum.

Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported to have several biological activities. The ethanol extract of S. wallichii was fractionated based on polarity using n-hexane, ethyl acetate and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant Plasmodium falciparum (P. falciparum) at 100 µg/ml for 72 h. The major compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. The characterized compound was also tested against chloroquine-resistant P. falciparum in culture to evaluate its antiplasmodial activity. The ethanol extract of S. wallichii at 100 µg/ml exhibited a significant parasite shrinkage after 24 h of treatment. The ethyl acetate fraction at 100 µg/ml was the most active fraction against chloroquine-resistant P. falciparum. Based on the structural characterization, the major compound isolated from the ethyl acetate fraction was kaempferol-3-O-rhamnoside, which showed promising antiplasmodial activity against chloroquine-resistant P. falciparum with an IC50 of 106 µM after 24 h of treatment. The present study has provided a basis for the further investigation of kaempferol-3-O-rhamnoside as an active compound for potential antimalarial therapeutics.