BMC Complementary Medicine and Therapies

Xanthones are a group of oxygen-containing heterocyclic compounds with remarkable pharmacological effects such as anti-cancer, antioxidant, anti-inflammatory, and antimicrobial activities.

A xanthones extract (81% α-mangostin and 16% γ-mangostin), was prepared by crystallization of a toluene extract of G. mangostana fruit rinds and was analyzed by LC-MS. Anti-colon cancer effect was investigated on HCT 116 human colorectal carcinoma cells including cytotoxicity, apoptosis, anti-tumorigenicity, and effect on cell signalling pathways. The in vivo anti-colon cancer activity was also investigated on subcutaneous tumors established in nude mice.

The extract showed potent cytotoxicity (median inhibitory concentration 6.5 ± 1.0 μg/ml), due to induction of the mitochondrial pathway of apoptosis. Three key steps in tumor metastasis including the cell migration, cell invasion and clonogenicity, were also inhibited. The extract and α-mangostin up-regulate the MAPK/ERK, c-Myc/Max, and p53 cell signalling pathways. The xanthones extract, when fed to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells.

Our data suggest new mechanisms of action of α-mangostin and the G. mangostana xanthones, and suggest the xanthones extract of as a potential anti-colon cancer candidate.

Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960–1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with  alterations in glutamate/glutamine cycle and glutamate transporters.

Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1–2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated.

After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS.

The studies indicated that XYS may have therapeutic actions on depression-like behaviors induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine cycle and glutamate transporter GLT-1 in the hippocampus.

Sulfated polysaccharides from marine algae are known to possess antioxidative activities, however, their therapeutic role in metal-induced neurodegeneration has not been explored. In this study, the neuroprotective potentials of sulfated polysaccharides isolated from Ecklonia maxima (PKPM), Gelidium pristoides (PMNP), Ulva lactuca (PULV), Ulva rigida (PURL) and Gracilaria gracilis (PGCL) against Zn-induced neurodegeneration in rats’ hippocampal neuronal cells (HT-22) were assessed.

Cells were cultured and maintained at 37 °C. Control cells did not contain Zinc sulphate (ZnSO₄) while other experimental groups contain Zn (50 μM) alone or in combination with sulfated polysaccharides (0.4 or 0.8 mg/mL). Cell viability was assessed using MTT assay while apoptotic assay was also determined using acridine orange and ethidium bromide staining technique. Oxidative stress parameters (superoxide dismutase and catalase activities, glutathione and nitric oxide levels) and acetylcholinesterase activity were also assessed in neuronal cells treated with or without Zn.

Zn significantly reduced cell viability to about 50%. However, sulfated polysaccharides improved cell viability to about 95%. The sulfated polysaccharides also prevented late apoptosis and necrosis triggered by Zn. Furthermore, superoxide dismutase and catalase activities including glutathione content were significantly low in cells induced with Zn. Treatment with sulfated polysaccharides triggered a significant increase in antioxidant enzymes and glutathione content as well as a decrease in the activity of acetylcholinesterase in cells treated with Zn.

PKPM, PGCL, PURL, PULV and PMNP exhibit neuroprotective effects against neuronal damage induced by Zn and this may be attributed to inhibition of apoptosis, oxidative damage and acetylcholinesterase activity. These polysaccharides may be good therapeutic agents to protect neuronal cells against Zn - induced pathological processes associated with Alzheimer’s disease.

There is preliminary evidence to suggest curcumin can alleviate digestive symptoms in adults with self-reported digestive complaints and irritable bowel syndrome. However, in all these trials, curcumin was used as a component of a multi-herbal combination and there were consistent concerns associated with risk of bias in most studies. The goal of this study was to investigate the effects of a curcumin extract (Curcugen™) on gastrointestinal symptoms, mood, and overall quality of life in adults presenting with self-reported digestive complaints. Moreover, to determine the potential therapeutic mechanisms of action associated with curcumin, its effects on intestinal microbiota and small intestinal bowel overgrowth (SIBO) were examined.

In this 8-week, parallel-group, double-blind, randomised controlled trial, 79 adults with self-reported digestive complaints were recruited and randomised to receive either a placebo or 500 mg of the curcumin extract, Curcugen™. Outcome measures included the Gastrointestinal Symptom Rating Scale (GSRS), intestinal microbial profile (16S rRNA), Depression, Anxiety, and Stress Scale – 21 (DASS-21), Short Form-36 (SF-36), and SIBO breath test.

Based on self-report data collected from 77 participants, curcumin was associated with a significantly greater reduction in the GSRS total score compared to the placebo. There was also a greater reduction in the DASS-21 anxiety score. No other significant between-group changes in self-report data were identified. An examination of changes in the intestinal microbial profile and SIBO test revealed curcumin had no significant effect on these parameters. Curcumin was well-tolerated with no significant adverse events.

The curcumin extract, Curcugen™, administered for 8 weeks at a dose of 500 mg once daily was associated with greater improvements in digestive complaints and anxiety levels in adults with self-reported digestive complaints. Compared to the placebo, there were no significant changes in intestinal microbiota or SIBO; however, further research using larger samples and testing methods that allow more detailed microbial analyses will be important. An investigation into other potential mechanisms associated with curcumin’s gastrointestinal-relieving effects will also be important such as examining its influence on the intestinal barrier function, inflammation, neurotransmitter activity, and visceral sensitivity.

Australian New Zealand Clinical Trials Registry, Trial ID.ACTRN12619001236189. Registered 6 September 2019.

To investigate the protective effects of Tualang honey against the toxicity effects induced by cadmium (Cd) on the ovary.

A total of 32 female Sprague Dawley rats were taken and randomly divided into four groups (n = 8). Throughout the experimental period of 6 weeks, negative control-NC (vehicle deionized water), positive control-CD (Cd at 5 mg/kg), Tualang honey followed by Cd exposure-TH (Tualang honey at 200 mg/kg and Cd at 5 mg/kg) and Tualang honey control-THC (Tualang honey at 200 mg/kg) groups, were administered orally on a daily basis.

Rats exposed to Cd were significantly higher in ovarian weight, number of antral and atretic follicles as compared to the NC group. The disruptive effects of Cd on ovarian follicles were associated with a disruption in gonadotropin hormones and decreases in follicular stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, a significant formation of oxidative stress in ovarian Cd-exposed rats has been proven by increasing the level of lipid peroxidation products (malondialdehyde) and decreasing the levels of enzymatic antioxidant (catalase). Interestingly, a daily supplementation of high antioxidant agents such as Tualang honey in these animals, caused significant improvements in the histological changes. Additionally, less atretic follicles were observed, restoring the normal level of LH and FSH (P < 0.001), and normalizing the ovarian malondialdehyde (P < 0.05) and catalase levels in comparison with CD group (P < 0.05).

Tualang honey has protective effects against Cd-induced ovarian toxicity by reducing morphological abnormalities, restoring the normal levels of gonadotropin hormones and stabilizing equilibrium levels of lipid peroxidation and antioxidant enzyme in ovaries of rats.

Coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2, and responsible for a global pandemic. Despite there being no known vaccines or medicines that prevent or cure COVID-19, many traditional, integrative, complementary and alternative medicines (TICAMs) have been touted as the solution, as well as researched as a potential remedy globally. This study presents a bibliometric analysis of global research trends at the intersection of TICAM and COVID-19.

SCOPUS, MEDLINE, EMBASE, AMED and PSYCINFO databases were searched on July 5, 2020, with results being exported on the same day. All publication types were included, however, articles were only deemed eligible if they made mention of one or more TICAMs for the potential prevention, treatment, and/or management of COVID-19 or a health issue indirectly resulting from the COVID-19 pandemic. The following eligible article characteristics were extracted: title; author names, affiliations, and countries; DOI; publication language; publication type; publication year; journal (and whether it is TICAM-focused); 2019 impact factor, and TICAMs mentioned.

A total of 296 eligible articles were published by 1373 unique authors at 977 affiliations across 56 countries. The most common countries associated with author affiliation included China, the United States, India and Italy. The vast majority of articles were published in English, followed by Chinese. Eligible articles were published across 157 journals, of which 33 were TICAM-focused; a total of 120 journals had a 2019 impact factor, which ranged from 0.17 to 60.392. A total of 327 TICAMs were mentioned across eligible articles, with the most common ones including: traditional Chinese medicine (n = 94), vitamin D (n = 67), melatonin (n = 16), phytochemicals (n = 12), and general herbal medicine (n = 11).

This study provides researchers and clinicians with a greater knowledge of the characteristics of articles that been published globally at the intersection of COVID-19 and TICAM to date. At a time where safe and effective vaccines and medicines for the prevention and treatment of COVID-19 have yet to be discovered, this study provides a current snapshot of the quantity and characteristics of articles written at the intersection of TICAM therapies and COVID-19.

The hand, foot and mouth disease (HFMD) is a febrile and exanthematous childhood disease mainly caused by Enterovirus 71 (EV-A71). In severe HFMD, virulent EV-A71 strains can cause acute flaccid paralysis and cardiopulmonary edema leading to death. Currently, no FDA approved antiviral treatment or vaccine is available for EV-A71. Flavonoids such as silymarin and baicalein are known to possess in vitro antiviral properties against viruses. In this study, the cytotoxicity and antiviral activity of silymarin, baicalein and baicalin were investigated.

The cytotoxic effects of three flavonoids towards rhabdomyosarcoma (RD) cells were first examined using cell proliferation MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Compounds found to be non-cytotoxic in RD cells were evaluated for their in vitro antiviral properties against the EV-A71 subgenotype B4 strain 41 (5865/SIN/000009) using antiviral assays. Viral infectivity was determined by reduction of the formation of plaques in RD cells. For the measurement of RNA copy number, the real time quantitative reverse transcription PCR (qRT-PCR) was used. The most potent compound was further evaluated to determine the mode of action of inhibition by time course, virus attachment and entry assays in Vero cells.

Silymarin was shown to exert direct extracellular virucidal effects against EV-A71 at 50% inhibitory concentration (IC₅₀) of 15.2 ± 3.53 μg/mL with SI of 10.53. Similarly, baicalein exhibited direct extracellular virucidal effects against EV-A71 at a higher IC₅₀ value of 30.88 ± 5.50 μg/mL with SI of 13.64. Besides virucidal activity, silymarin was shown to block both viral attachment and entry of EV-A71 to inhibit infection in Vero cells.

Silymarin has a stronger inhibition activity against EV-A71 in comparison to baicalein. It could serve as a promising antiviral drug to treat EV-A71 infections.

Human respiratory system infected with influenza A virus (IAV) elicited a robust pro-inflammatory response that resulted in severe illness and even death. Currently, limited immunomodulator is available to counteract IAV-associated pneumonia in the clinic. Sinensetin, a polymethoxylated flavone with five methoxy groups, has been found to possess anti-agiogenesis, anti-inflammatory and anti-diabetic activities. However, the effects of sinensetin on IAV-triggered pro-inflammatory response remain unclear. In the present study, the anti-inflammatory effects and corresponding possible mechanism of sinensetin in IAV-infected A549 cells were subjected to investigations.

The cytotoxic effects of sinensetin towards A549 cells was detected by MTT and LDH assays. The antiviral activity of sinensetin against influenza A virus was assayed in A549 cells with an engineered replication-competent influenza A virus carrying Gaussia luciferase reporter gene infection. The effect of sinensetin on influenza A virus-triggered inflammatory reaction was determined by qRT-PCR, Luminex assays, ELISA and Western blot.

Our results showed that sinensetin did not exhibit antiviral activity against A/PR/8/34 (H1N1). Meanwhile, sinensetin treatment significantly decreased IAV-induced expression of pro-inflammatory mediators at mRNA and protein levels, including IL-6, TNF-α, IP-10, IL-8 and MCP-1. Additionally, levels of cyclooxygenase (COX)-2 and the downstream product prostaglandin E₂ (PGE₂) up-regulated by IAV infection were dramatically suppressed by sinensetin. The mechanistic investigation revealed that sinensetin treatment suppressed the NF-κB transcriptional activity using the NF-κB reporter stable HEK293 cell line stimulated with TNF-α (20 ng/mL) or influenza H1N1 virus. Furthermore, sinensetin abrogated influenza H1N1 virus-induced activation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings.

Collectively, our results indicated that sinensetin has potential capacity to attenuate IAV-triggered pro-inflammatory response via inactivation of NF-κB, ERK1/2 MAPK and p38 MAPK signalings, which implied that sinensetin may be a promising candidate drug for influenza H1N1 virus infection therapeutics.

Acute myocardial infarction (AMI) is the most serious and lethal manifestation of coronary heart disease worldwide, presenting extremely high disability and mortality. Our previous studies have shown that Guanxin V (GXV) could significantly improve the cardiac function and the blood flow dynamics, and reduce serum levels of inflammatory factors in AMI rats, thus triggering ventricular remodeling (VR) at post-AMI.

An in vivo AMI model was established in Syrian hamsters by performing the ligation of the left anterior descending coronary artery. Syrian hamsters were randomly divided into four groups, namely Sham operation group (n = 12), AMI group (n = 12), GXV group (GXV 6 g/Kg/d, n = 12), and Tranilast group (Tra 105 mg/Kg/d, n = 12). Drug intervention was conducted for consecutive 8 weeks. Relative biological indicators were measured in the 4th and 8th week, respectively.

Cardiac functions were improved, and the infarcted size and heart weight index were limited in Syrian hamsters of GXV and Tra groups compared with those in AMI group. Furthermore, GXV was able to decrease the number of mast cells and chymase level in Syrian hamsters with AMI. Administration of GXV remarkably inactivated the renin-angiotension-aldosterone system, and alleviated myocardial fibrosis and cardiomyocyte apoptosis, thus slowing down VR at post-AMI.

GXV slows down the process of VR at post-AMI by reducing chymase level and mast cells number, as well as inactivating the reninangiotension-aldosterone system..

Dermal papilla cells (DPCs) play a key role in hair growth among the various cell types in hair follicles. Especially, DPCs determine the fate of hair follicle such as anagen to telogen transition and play a pivotal role in androgenic alopecia (AGA). This study was performed to elucidate the hair growth promoting effects of Polygonum multiflorum extract (PM extract) in cultured human DPCs and its underlying mechanisms.

The effects of PM extract on cultured DPCs were investigated. Cell viability and mitochondrial activity were measured by CCK-8 and JC-1 analysis, respectively. Western blotting, dot blotting, ELISA analysis, immunocytochemistry and real-time PCR analysis were also performed to elucidate the changes in protein and mRNA levels induced by PM extract. 3D cultured DPC spheroids were constructed for mimicking the in vivo DPs. The hair growth stimulatory effect of PM extract was evaluated using human hair follicle organ culture model.

PM extract increased the viability and mitochondrial activity in cultured human DPCs in a dose dependent manner. The expression of Bcl2, an anti-apoptotic protein expressed dominantly in anagen was significantly increased and that of BAD, a pro-apoptotic protein expressed in early catagen was decreased by PM extract in cultured DPCs and/or 3D DPC spheroid culture. PM extract also decreased the expression of catagen inducing protein, Dkk-1. Growth factors including IGFBP2, PDGF and VEGF were increased by PM extract, revealed by dot blot protein analysis. We also have found that PM extract could reverse the androgenic effects of dihydrotestosterone (DHT), the most potent androgen. Finally, PM extract prolonged the anagen of human hair follicles by inhibiting catagen entry in human hair follicle organ culture model.

Our data strongly suggest that PM extract could promote hair growth by elongating the anagen and/or delaying the catagen induction of hair follicles through activation of DPCs.