Anti-Trypanosoma cruzi activity of Coptis rhizome extract and its constituents.

BACKGROUND: Current therapeutic agents, including nifurtimox and benznidazole, are not sufficiently effective in the chronic phase of Trypanosoma cruzi infection and are accompanied by various side effects. In this study, 120 kinds of extracts from medicinal herbs used for Kampo formulations and 94 kinds of compounds isolated from medicinal herbs for Kampo formulations were screened for anti-T. cruzi activity in vitro and in vivo. METHODS: As an experimental method, a recombinant protozoan cloned strain expressing luciferase, namely Luc2-Tulahuen, was used in the experiments. The in vitro anti-T. cruzi activity on epimastigote, trypomastigote, and amastigote forms was assessed by measuring luminescence intensity after treatment with the Kampo extracts or compounds. In addition, the cytotoxicity of compounds was tested using mouse and human feeder cell lines. The in vivo anti-T. cruzi activity was measured by a murine acute infection model using intraperitoneal injection of trypomastigotes followed by live bioluminescence imaging. RESULTS: As a result, three protoberberine-type alkaloids, namely coptisine chloride, dehydrocorydaline nitrate, and palmatine chloride, showed strong anti-T. cruzi activities with low cytotoxicity. The IC50 values of these compounds differed depending on the side chain, and the most effective compound, coptisine chloride, showed a significant effect in the acute infection model. CONCLUSIONS: For these reasons, coptisine chloride is a hit compound that can be a potential candidate for anti-Chagas disease drugs. In addition, it was expected that there would be room for further improvement by modifying the side chains of the basic skeleton.

Anti-SARS-CoV-2 activity of various PET-bottled Japanese green teas and tea compounds in vitro.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to global public health. The emergence of SARS-CoV-2 variants is a significant concern regarding the continued effectiveness of vaccines and antiviral therapeutics. Thus, natural products such as foods, drinks, and other compounds should be investigated for their potential to treat COVID-19. Here, we examined the in vitro antiviral activity against SARS-CoV-2 of various polyethylene terephthalate (PET)-bottled green Japanese teas and tea compounds. Six types of PET-bottled green tea were shown to inhibit SARS-CoV-2 at half-maximal inhibitory concentrations (IC50) of 121- to 323-fold dilution. Our study revealed for the first time that a variety of PET-bottled Japanese green tea drinks inhibit SARS-CoV-2 infection in a dilution-dependent manner. The tea compounds epigallocatechin gallate (EGCG) and epicatechin gallate showed virucidal activity against SARS-CoV-2, with IC50 values of 6.5 and 12.5 µM, respectively. The investigated teas and tea compounds inactivated SARS-CoV-2 in a dose-dependent manner, as demonstrated by the viral RNA levels and infectious titers. Furthermore, the green teas and EGCG showed significant inhibition at the entry and post-entry stages of the viral life cycle and inhibited the activity of the SARS-CoV-2 3CL-protease. These findings indicate that green tea drinks and tea compounds are potentially useful in prophylaxis and COVID-19 treatment.

The discovery of herbal drugs and natural compounds as inhibitors of SARS-CoV-2 infection in vitro.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2019 has led to a global health crisis. Mutations of the SARS-CoV-2 genome have impeded the development of effective therapeutics and vaccines against SARS-CoV-2. Natural products are important for discovering therapeutics to treat the 2019 coronavirus disease (COVID-19). In the present study, we investigated the antiviral activity of herbal drug extracts from Polygala Root, Areca, and Quercus Bark and natural compounds derived from herbal drug such as baicalin and glabridin, with IC50 values of 9.5 µg/ml, 1.2 µg/ml, 5.4 µg/ml, 8.8 µM, and 2.5 µM, respectively, against SARS CoV-2 infection in vitro. Certain herbal drug extracts and natural compounds were found to inhibit viral RNA levels and infectious titers of SARS-CoV-2 in a dose-dependent manner. Furthermore, viral protein analyses showed that herbal drug extracts and natural compounds effectively inhibited SARS-CoV-2 in the various entry treatments. Our study revealed that three herbal drugs are good candidates for further in vivo and clinical studies.

Phenylpropanoid-conjugated iridoid glucosides from leaves of Morinda morindoides.

Three phenylpropanoid-conjugated iridoid glucosides, acetylgaertneric acid (1), acetyldehydrogaertneroside (2), and dehydrogaertneric acid (10), together with nine known related iridoid glucosides (3-9, 11, and 12), two coumaroyl alkaloids, one benzenoid, and three flavonoid glucosides were isolated from leaves of Morinda morindoides (Rubiaceae). Structures of these isolated compounds were determined using spectroscopic analysis. Compounds 1-18 and previously isolated compounds (19-29) were evaluated for anti-trypanosomal activity against Trypanosoma cruzi Tulahuen strain (trypomastigote and amastigote) together with cytotoxicity against host cells, new-born mouse heart cells. Among them, molucidin (21) and prismatomerin (22) exhibited good anti-trypanosomal activity (IC50 of 4.67 and 5.70 µM, respectively), together with cytotoxicity (CC50 of 2.76 and 3.22 µM, respectively). Compounds 1-18 did not show anti-malarial activity against a chloroquine/mefloquine-sensitive strain of Plasmodium falciparum.

Phenylpropanoid conjugated iridoids with anti-malarial activity from the leaves of Morinda morindoides.

Two phenylpropanoid-conjugated iridoids, deglucosyl gaertneroside (1) and morindoidin (2), were isolated from the leaves of Morinda morindoides (Rubiaceae) by activity-guided fractionation using an anti-malarial activity assay. The known related iridoids molucidin (3) and prismatomerin (4), two lignans, abscisic acid, two megastigmanes, and two flavonol glycosides were also identified. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/mefloquine-sensitive strains of Plasmodium falciparum together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of 3 and 4 (IC50 of 0.96 and 0.80 µM, CC50 of 1.02 and 0.88 µM, and SI of 1.06 and 1.10, respectively) was shown, while new iridoids 1 and 2 and pinoresinol (5) displayed moderate activity (IC50 of 40.9, 20.6, and 24.2 µM) without cytotoxicity (CC50 > 50 µM). These results indicate that 1-5 may be promising lead compounds for anti-malarial drugs. In addition, our results imply the necessity of the quality control of the extract of M. morindoides leaves based on the contents of 1-5 in terms of the safety and efficacy.

Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds.

BACKGROUND: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities. METHODS: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity. RESULTS: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride. CONCLUSION: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Honey in Bronchial Asthma: From Folk Tales to Scientific Facts.

Bronchial asthma is one of the most common chronic inflammatory diseases. Complementary and alternative medicine is increasingly used for treating bronchial asthma. Ten electronic databases were searched to investigate whether honey alone or in combination with other ingredients can be considered as the potential treatment for bronchial asthma. Combinations of honey and Nigella sativa (NS) showed significant improvement in all pulmonary functions, including forced expiratory volume (FEV1) (MD = 0.52, P < .001), forced vital capacity (FVC) (MD = 0.55, P = .002), and peak expiratory flow rate (PEFR) (MD = 80.60, P < .001), in both moderate and severe, uncontrolled persistent asthma compared with baseline. Asthma control test scores also improved significantly (MD = 11.22, P < .001) in patients using combinations of honey and NS compared with baseline. Patients with a less severe grade of asthma showed a significant positive response in clinical parameters upon using honey. One study showed that using celery seeds and honey was associated with clinical improvement of both lung functions, FEV1 (MD = 18.09, P < .001) and FVC (MD = 24.23, P < .001), and respiratory parameters compared with baseline. In conclusion, honey alone has no strong evidence of being effective in controlling asthma. However, when used in combination with other substances, it showed a relatively high efficacy in patients with asthma. This finding may help in asthma control with lower cost alternatives and better outcomes.

Therapeutic efficacy and safety of chamomile for state anxiety, generalized anxiety disorder, insomnia, and sleep quality: A systematic review and meta-analysis of randomized trials and quasi-randomized trials.

This systematic review and meta-analysis aimed to study the efficacy and safety of chamomile for the treatment of state anxiety, generalized anxiety disorders (GADs), sleep quality, and insomnia in human. Eleven databases including PubMed, Science Direct, Cochrane Central, and Scopus were searched to retrieve relevant randomized control trials (RCTs), and 12 RCTs were included. Random effect meta-analysis was performed by meta package of R statistical software version 3.4.3 and RevMan version 5.3. Our meta-analysis of three RCTs did not show any difference in case of anxiety (standardized mean difference = -0.15, 95% CI [-0.46, 0.16], P = 0.4214). Moreover, there is only one RCT that evaluated the effect of chamomile on insomnia and it found no significant change in insomnia severity index (P > 0.05). By using HAM-A scale, there was a significant improvement in GAD after 2 and 4 weeks of treatment (mean difference = -1.43, 95% CI [-2.47, -0.39], P = 0.007), (MD = -1.79, 95% CI [-3.14, -0.43], P = 0.0097), respectively. Noteworthy, our meta-analysis showed a significant improvement in sleep quality after chamomile administration (standardized mean difference = -0.73, 95% CI [-1.23, -0.23], P < 0.005). Mild adverse events were only reported by three RCTs. Chamomile appears to be efficacious and safe for sleep quality and GAD. Little evidence is there to show its effect on anxiety and insomnia. Larger RCTs are needed to ascertain these findings.

Efficacy of ethyl-EPA as a treatment for Huntington disease: a systematic review and meta-analysis.

OBJECTIVE: After MRI studies suggested the efficacy of ethyl-EPA in reducing the progressive brain atrophy in Huntington disease (HD), trials were conducted to test its efficacy as a treatment for HD. Trials that continued for 6 months did not find any significant improvement, urging discontinuation of the drug. However, trials that continued for 12 months indicated improvement of motor functions in these patients. METHODS: We searched 12 electronic databases to find randomised clinical trials relevant to our inclusion criteria. After screening, only five papers were included. Continuous and binary variables were analysed to compute the pooled mean difference (MD) and risk ratio (RR), respectively. Quality effect model meta-analysis was used as a post hoc analysis for studies at 12 months. FINDINGS: Meta-analysis indicated that ethyl-eicosapentaenoic acid (EPA) has no significant effect on any scale of HD at 6 months. At 12 months, two studies suggested significant improvements of the Total Motor Score and Total Motor Score-4 in both fixed and quality effect models [MD = -2.720, 95% CI (-4.76, -.68), p = 0.009; MD = -2.225, 95% CI (-3.842, -0.607), p = 0.007], respectively. Maximal chorea score showed significant results [MD = -1.013, 95% CI (-1.793, -0.233), p = 0.011] in only fixed-effect model, while no improvement was detected for Stroop colour naming test or symbol digit modality. CONCLUSION: Meta-analysis indicated a significant improvement of motor scores only after 12 months. These results should be interpreted cautiously because only two studies had assessed the efficacy of ethyl-EPA after 12 months with one of them having a 6-month open-label phase.

Ginsenoside Rh1: A Systematic Review of Its Pharmacological Properties.

Ginsenoside Rh1 is one of major bioactive compounds extracted from red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. The objective of this study was to review the pharmacological effects of ginsenoside Rh1 in a systematic manner. We performed searches on eight electronic databases including MEDLINE (Pubmed), Scopus, Google Scholar, POPLINE, Global Health Library, Virtual Health Library, the System for Information on Grey Literature in Europe, and the New York Academy of Medicine Grey Literature Report to select the original research publications reporting the biological and pharmacological effects of ginsenoside Rh1 from in vitro and in vivo studies regardless of publication language and study design. Upon applying the inclusion and exclusion criteria, we included a total of 57 studies for our systemic review. Ginsenoside Rh1 exhibited the potent characteristics of anti-inflammatory, antioxidant, immunomodulatory effects, and positive effects on the nervous system. The cytotoxic effects of ginsenoside Rh1 were dependent on different types of cell lines. Other pharmacological effects including estrogenic, enzymatic, anti-microorganism activities, and cardiovascular effects have been mentioned, but the results were considerably diverged. A higher quality of evidence on clinical trial studies is highly recommended to confirm the consistent efficacy of ginsenoside Rh1.

The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials.

Rheumatoid arthritis is an autoimmune disease in which probiotics appears to have an immune modulating action along with decreased inflammatory process. Therefore, we aim to investigate the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis. A comprehensive literature search was performed using nine databases including PubMed and Web of Science. Interesting data was extracted and meta-analyzed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD 42016036769). We found nine studies involving 361 patients who met our eligibility criteria. Our meta-analysis indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group (standardized mean difference = - 0.708; 95% confidence interval (CI) - 1.370 to 0.047, P = 0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P = 0.940). Probiotics lowered pro-inflammatory cytokines IL-6 in RA; however, its clinical effect is still unclear. Hence, many high-quality randomized controlled trials (RCTs) are still needed to prove this effect.

Medicinal plants for in vitro antiplasmodial activities: A systematic review of literature.

The increasing resistance of malaria to drugs raise the need to new antimalarial agents. Antiplasmodial herbs and their active compounds are the most promising source the new antimalarial agents. This study aimed to identify the medicinal plants with very good in vitro antiplasmodial activities, with half-maximal inhibitory concentration (IC50)≤1µg/ml, and to determine trends in the process of screening their antiplasmodial activities. A total of 58 reports published in the English language were retrieved from the bibliographical databases. Screening and data extraction were performed by two independent reviewers. The herbs were categorized as very good, good, moderate and inactive if the IC50 values were <0.1µg/ml, 0.1-1µg/ml, >1-5µg/ml and >5µg/ml respectively. We documented 752 medicinal plants belonging to 254 genera. The majority of the plants were reported from Africa followed by Asia. The traditional use for malaria treatment was the most common reason for the selection of the plants for investigation. About 80% of the plants experimented were reported to be inactive. Among plants identified as having very good to good antiplasmodial crude extracts are Harungana madagascariensis, Quassia africana, and Brucea javanica, while Picrolemma spruce, Aspidosperma vargasi, Aspidosperma desmanthum, and Artemisia annua were reported to have individual compound isolates with very good antiplasmodial activities. In conclusion, the number of plant species assessed so far is still small compared with the stock in nature's plant library. A mechanism of systematically approaching and exploring the untouched plant genera needs to be designed.

Exploratory, Phase II Controlled Trial of Shiunko Ointment Local Application Twice a Day for 4 Weeks in Ethiopian Patients with Localized Cutaneous Leishmaniasis.

The clinical efficacy and safety of Shiunko ointment (phase II clinical trial) was investigated in 40 Ethiopian patients with cutaneous leishmaniasis. Patients were randomized to receive treatment with Shiunko ointment or placebo (n = 20, each), applied on the lesion twice a day for 4 weeks. Clinicoparasitological assessments were performed before treatment, weekly for 4 weeks, and then 4, 8, and 12 weeks after the end of treatment. A marked reduction in lesion size was observed on week 16 of treatment in the Shiunko compared with placebo group (69% and 22% reduction, resp.). The overall rate of lesion reduction during the four weeks of treatment was significantly faster in the Shiunko group. Shiunko provided significant effect on wound closure in patients with ulcerated lesion. The clinical efficacy and tolerability of Shiunko were comparable to placebo with regard to its clinicoparasitological response (cure rate and parasitological clearance). Results of this preliminary study may suggest that Shiunko could be useful as adjuvant or as complementary treatment, not as alternatives to current treatment. Its attractive action includes fast lesion healing with a significantly smaller lesion at week 16 of treatment compared with placebo. In addition, its action was promoted in ulcerative lesions.

Anticancer Activity of Atractylodes lancea (Thunb.) DC in a Hamster Model and Application of PET-CT for Early Detection and Monitoring Progression of Cholangiocarcinoma.

Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is an important cancer in the Great Mekong region, particularly in Thailand. Limitations of treatment options and the lack of an effective diagnostic tool for early detection of CCA are major concerns for the control of this type of cancer. The aim of the study was to investigate anti-CCA activity of the ethanolic extract of Atractylodes lancea (Thunb.) DC., and the applicability of positron emission tomography-computed tomography (PET-CT) as a tool for detection and monitoring the progression of CCA in Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN)-induced CCA hamsters. Male Syrian hamsters were used for toxicity tests and anti-CCA activity evaluation. Development of CCA was induced by initial feeding of 50 metacercariae of OV, followed by drinking water containing 12.5 ppm of DMN in hamsters. The ethanolic extract of A. lancea (Thunb.) DC. was administered orally for 30 days. PET-CT was performed every 4 weeks after initiation of CCA using 18F-fluorodeoxyglucose (18F-FDG). Results from the present study suggest that the ethanolic extract of A. lancea (Thunb.) DC. rhizome exhibited promising anti-CCA activity and safety profile in the OV/DMN-induced hamster model. To successfully apply PET-CT as a tool for early detection of tumor development and progression, modification of radiolabeling approach is required to improve its specificity for CCA cells.

Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia.

BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA) regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG), and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region) mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD), and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease.

Prevention of cadmium accumulation in retinal pigment epithelium with manganese and zinc.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly. Risk factors include old age, female gender, obesity, smoking, low dietary intakes of antioxidants and increased exposure to the toxic metal cadmium (Cd(2+)). Supplementation with high-dose zinc (80 mg) provides some protection, but the mechanism(s) underlying such protection has not been fully elucidated. The present study had a focus on the human retinal pigment epithelial (RPE) cell line ARPE-19 in an attempt to demonstrate a reduction in intracellular Cd(2+) effect associated with heme oxygenase-1 (HO-1) expression by co-exposure with zinc (Zn(2+)) or manganese (Mn(2+)), which is known to be a more potent inhibitor of Cd(2+) uptake than Zn(2+). Our results indicated that co-exposure of 10 microM Cd(2+) with 5 microM Mn(2+) reduced the intracellular Cd(2+) effect by 50-60%, possibly by limiting the amounts of Cd(2+) entering cells through Mn(2+) transporter protein (ZIP8). A similar reduction in a Cd(2+) effect was achieved by co-exposure with 20 microM Zn(2+) while co-exposure with 5 and 10 microM Zn(2+) ions was ineffective. Mn(2+) ions as low as 2.5 microM were found to cause an increase in HO-1 mRNA expression levels in ARPE-19 cells, demonstrating for the first time that Mn(2+) is an inducer of HO-1. Mn(2+) ions at 1 microM induced HO-1 mRNA expression in the HEK293 human embryonic kidney cells. In contrast, Zn(2+) in 5, 10 or 20 microM concentrations did not induce expression of HO-1 in ARPE-19 cells or any other cells tested. These data suggest the superiority of Mn(2+) over Zn(2+) in preventing Cd(2+) uptake and accumulation in RPE to toxic levels. Further, induction of HO-1 by Mn(2+) could provide RPE with some resistance to enhanced oxidative stress arising from Cd(2+) accumulation in RPE as HO-1 is one of the frontline cellular antioxidant defense mechanisms.

Trypanocidal activity of extracts and compounds from the stem bark of Anogeissus leiocarpus and Terminalia avicennoides.

The antitrypanosomal activity of methanolic extracts of Anogeissus leiocarpus and Terminalia avicennoides were evaluated in vitro against four strains of Trypanosoma species with minimum inhibitory concentration (MIC) value range of 12.5-50 mg/ml. Successive fractionations of the two plant extracts in water, butanol and ethyl acetate gave a range of activity (MIC, 20 to > or =50 microg/ml). Activity-guided and chromatographic analysis of butanolic fractions on Sephadex LH-20 column followed by high-performance liquid chromatography, nuclear magnetic resonance analysis and both ultraviolet and thin layer chromatography revealed hydrolysable tannins with a range of activity (MIC, 7.5-27.5 microg/ml or 14-91 microM). Effect of the compounds on fibroblasts did not reveal serious toxicity at moderate concentration but is concentration dependent.