Antiviral and antibacterial properties of phloroglucinols: a review on naturally occurring and (semi)synthetic derivatives with potential therapeutic interest.

Phloroglucinol and derived compounds comprise a huge class of secondary metabolites widely distributed in plants and brown algae. A vast array of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer has been associated to this class of compounds. In this review, the available data on the antiviral and antibacterial capacity of phloroglucinols have been analyzed. Some of these compounds and derivatives show important antimicrobial properties in vitro. Phloroglucinols have been shown to be effective against viruses, such as human immunodeficiency virus (HIV), herpes or enterovirus, and preliminary data through docking analysis suggest that they can be effective against SARS-CoV-19. Also, some phloroglucinols derivatives have shown antibacterial effects against diverse bacteria strains, including Bacillus subtilis and Staphylococcus aureus, and (semi)synthetic development of novel compounds have led to phloroglucinols with a significantly increased biological activity. However, therapeutic use of these compounds is hindered by the absence of in vivo studies and scarcity of information on their mechanisms of action, and hence further research efforts are required. On the basis of this consideration, our work aims to gather data regarding the efficacy of natural-occurring and synthetic phloroglucinol derivatives as antiviral and antibacterial agents against human pathogens, which have been published during the last three decades. The recollection of results reported in this review represents a valuable source of updated information that will potentially help researchers in the development of novel antimicrobial agents.

Meta analysis of the effect of phloroglucinol combined with progesterone in the treatment of threatened miscarriage before 20 weeks of gestation: A protocol for a systematic review.

BACKGROUND: Threatened miscarriage (TM) is an important factor endangering the health of pregnant women. It not only affects women's physical and mental health, but also destroys family happiness. To treat this disease, it is necessary to find a treatment with better clinical efficacy and fewer side effects. The purpose of this systematic study was to evaluate the efficacy and safety of phloroglucinol (PHL) combined with progesterone in the treatment of TM before 20 weeks of pregnancy. METHODS: Electronic databases (EMBASE, PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Elsevier, China National Knowledge Infrastructure, Chongqing VIP, and WanFang Data) were searched from inception until September. 2022. Randomized controlled trials of PHL combined with progesterone in the treatment of TM before 20 weeks of gestation will be included, and all articles will be independently screened and collected by 2 reviewers. Revman 5.3.5 software will be used for meta-analysis. The specific process is described in the Cochrane Handbook for Systematic Reviews. RESULTS: The efficacy and safety of PHL combined with progesterone for the treatment of threatened abortion were comprehensively evaluated in terms of efficacy, efficiency, time of symptom relief, length of hospital stay, and incidence of adverse events. CONCLUSION: This study provides reliable evidence for the clinical application of PHL combined with progesterone for the treatment of TM.

Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses.

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of -4.9 and -5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (-67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (-77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

Efficacy of phloroglucinol in shortening the first stage of labor: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Protracted labor is associated with an elevated risk of maternal and fetal complications. Results of randomized controlled trials on the efficacy in labor of phloroglucinol (PHL), a pure antispasmodic drug, are uncertain. OBJECTIVES: To evaluate whether PHL is effective in shortening the first stage of labor. SEARCH STRATEGY: MEDLINE, EMBASE, LILACS, Scopus, ClinicalTrials.gov, and the Cochrane Library were searched from inception to July 2020. SELECTION CRITERIA: Randomized controlled trials (RCTs) concerning women with a singleton vertex pregnancy at term who were treated with PHL. DATA COLLECTION AND ANALYSIS: Relevant data were extracted and tabulated. Review Manager 5.3 was used for data analysis. Primary outcome evaluated was the mean reduction of the first stage of labor. MAIN RESULTS: Five RCTs, including 487 pregnant women, were analyzed. The first stage of labor duration was significantly shorter in the treatment arm compared to the control group [MD-113.21 min (95% CI-119.63,-106.79)]. A significant shortening of the second stage was achieved in the PHL group [MD-11.12 min (95% CI-12.64,-9.75)] while no differences were reported for the third stage. CONCLUSIONS: PHL might represent an effective treatment to shorten the duration of the first and second stage of labor. SYNOPSIS: A meta-analysis of 5 trials found that Phloroglucinol favorably impacts on the total duration of the labor in primiparae and multiparae women with a singleton pregnancy.

2,4,6-Trihydroxy-3-geranyl acetophenone suppresses vascular leakage and leukocyte infiltration in lipopolysaccharide-induced endotoxemic mice.

CONTEXT: Lipopolysaccharide (LPS) exacerbates systemic inflammatory responses and causes excessive fluid leakage. 2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) has been revealed to protect against LPS-induced vascular inflammation and endothelial hyperpermeability in vitro. OBJECTIVE: This study assesses the in vivo protective effects of tHGA against LPS-induced systemic inflammation and vascular permeability in endotoxemic mice. MATERIALS AND METHODS: BALB/c mice were intraperitoneally pre-treated with tHGA for 1 h, followed by 6 h of LPS induction. Evans blue permeability assay and leukocyte transmigration assay were performed in mice (n = 6) pre-treated with 2, 20 and 100 mg/kg tHGA. The effects of tHGA (20, 40 and 80 mg/kg) on LPS-induced serum TNF-α secretion, lung dysfunction and lethality were assessed using ELISA (n = 6), histopathological analysis (n = 6) and survivability assay (n = 10), respectively. Saline and dexamethasone were used as the negative control and drug control, respectively. RESULTS: tHGA significantly inhibited vascular permeability at 2, 20 and 100 mg/kg with percentage of inhibition of 48%, 85% and 86%, respectively, in comparison to the LPS control group (IC50=3.964 mg/kg). Leukocyte infiltration was suppressed at 20 and 100 mg/kg doses with percentage of inhibition of 73% and 81%, respectively (IC50=17.56 mg/kg). However, all tHGA doses (20, 40 and 80 mg/kg) failed to prevent endotoxemic mice from lethality because tHGA could not suppress TNF-α overproduction and organ dysfunction. DISCUSSION AND CONCLUSIONS: tHGA may be developed as a potential therapeutic agent for diseases related to uncontrolled vascular leakage by combining with other anti-inflammatory agents.

High-throughput screening for natural compound-based autophagy modulators reveals novel chemotherapeutic mode of action for arzanol.

Autophagy is an intracellular recycling pathway with implications for intracellular homeostasis and cell survival. Its pharmacological modulation can aid chemotherapy by sensitizing cancer cells toward approved drugs and overcoming chemoresistance. Recent translational data on autophagy modulators show promising results in reducing tumor growth and metastasis, but also reveal a need for more specific compounds and novel lead structures. Here, we searched for such autophagy-modulating compounds in a flow cytometry-based high-throughput screening of an in-house natural compound library. We successfully identified novel inducers and inhibitors of the autophagic pathway. Among these, we identified arzanol as an autophagy-modulating drug that causes the accumulation of ATG16L1-positive structures, while it also induces the accumulation of lipidated LC3. Surprisingly, we observed a reduction of the size of autophagosomes compared to the bafilomycin control and a pronounced accumulation of p62/SQSTM1 in response to arzanol treatment in HeLa cells. We, therefore, speculate that arzanol acts both as an inducer of early autophagosome biogenesis and as an inhibitor of later autophagy events. We further show that arzanol is able to sensitize RT-112 bladder cancer cells towards cisplatin (CDDP). Its anticancer activity was confirmed in monotherapy against both CDDP-sensitive and -resistant bladder cancer cells. We classified arzanol as a novel mitotoxin that induces the fragmentation of mitochondria, and we identified a series of targets for arzanol that involve proteins of the class of mitochondria-associated quinone-binding oxidoreductases. Collectively, our results suggest arzanol as a valuable tool for autophagy research and as a lead compound for drug development in cancer therapy.

Efficacy of phloroglucinol for acceleration of labour: a systematic review and meta­analysis.

PURPOSE: To assess the efficacy of phloroglucinol for acceleration of labour. METHODS: Randomized controlled trials (RCTs) comparing phloroglucinol with placebo were searched in PubMed, Embase and the Cochrane Library. Literatures were collected up to April 2020. Primary outcomes were the duration of labour and average blood loss. Finally, a total of 4 RCTs, 377 patients were included in this meta-analysis. The included RCTs were analyzed by the software Rev Man 5. 3. RESULTS: In the phloroglucinol group, the duration of the first stage was reduced by 116.04 min (95% CI 107.71 to 124.68), and the duration of the second stage was reduced by 10.75 min (95% CI 8.79 to 12.70). The average blood loss was reduced by 16.07 ml, which was statistically different from the control group. CONCLUSION: The application of phloroglucinol is proved to be effective for accelerating the labour process, reducing the risk of maternal and neonatal complications.

Phloroglucinol and dieckol isolated from Ecklonia cava suppress impaired diabetic angiogenesis; A study of in-vitro and in-vivo.

Abnormalities in angiogenesis that are associated with diabetes may contribute to vascular complications and result in disabilities and death. Furthermore, an imbalance in angiogenesis in different tissues, including the retina and kidney, can play a role in the pathogenesis of diabetic microvascular complications. Phlorotannins, such as phloroglucinol (PG) and dieckol (DK), which are found in Ecklonia cava exhibit antioxidant and anti-inflammatory activities that improve endothelial function in hypertension. However, reports on the effects of these compounds on diabetes-induced angiogenesis in vivo and in vitro are scarce. In this study, we assessed the antiangiogenic effects of PG and DK on endothelial cells treated with a high concentration of glucose to mimic angiogenesis. In addition, we sought to determine the effects of these compounds on cell proliferation, cell migration, and capillary formation. In silico docking of PG and DK into VEGFR-2 revealed their potential as therapeutic agents against angiogenesis. Further, both compounds were identified to inhibit the formation of the retinal vessel in transgenic zebrafish (flk:EGFP) embryos under high glucose conditions. These findings suggested that PG and DK derived from E. cava are potential inhibitors of angiogenesis in diabetic vascular complications and could, therefore, be used to develop angiogenic agents.

The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.

Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

Hyperforin alleviates the psychiatric disorders of adult rats suffered from early maternal separation via activating autophagy.

Rodent animals exposed to early maternal separation (EMS) show abnormal behaviors. Our previous study reported that autophagy is inhibited in the hippocampus of EMS rats, and hyperforin (HYP) alleviates depressive-like and anxious-like behaviors induced by EMS. However, the underlying mechanism of HYP is still unclear. In this study, we tested whether HYP alleviates the psychiatric disorders of EMS rats via activating autophagy. Pups were randomly divided into the control (CON) group, the EMS group, the EMS +3 mg/kg/day HYP (EMS + HYP) group and the EMS + treatment with 3 mg/kg/day fluoxetine (EMS + FT) group. Pups were separated from their mothers for 6 h every day from postnatal day 1 (PD1) to PD21 except pups of the CON group. Besides, HYP and FT were administered from PD22 to PD35 in the EMS + HYP group and the EMS + FT group respectively. Data showed that HYP not only reduced the level of glutamate, decreased the expression of N-methyl-d-aspartate receptor subunit 2B and postsynaptic density-95, but also increased the expression of synaptophysin of EMS rats. Interestingly, the expression of beclin-1 and the ratio of LC3II/LC3I were up-regulated in the EMS + HYP group. Moreover, HYP reduced the expression of the Notch1 receptor and the acetylation of H3K9 of EMS rats. In conclusion, our findings demonstrated that HYP ameliorates the depressive-like and anxious-like behaviors via activating autophagy in the hippocampus of EMS rats.

IC261 suppresses progression of hepatocellular carcinoma in a casein kinase 1 δ/ε independent manner.

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide that responds poorly to existing therapies. The Casein kinase 1 (CK1) isoforms CK1δ and CK1ε are reported to be highly expressed in several tumor types, and both genetic and pharmacological inhibition of CK1δ/ε activity has deleterious effects on tumor cell growth. IC261, an CK1δ/ε selectively inhibitor, shows anti-tumor effect against pancreatic tumor and glioblastoma, but its role in HCC remains poorly characterized. In our research, IC261 displayed time- and dose-dependent inhibition of HCC cell proliferation, and induced G2/M arrest and cell apoptosis in vitro. However, the anti-tumor effects of IC261 was independent of CK1δ/ε. Additionally, IC261 was verified to induce centrosome fragmentation during mitosis independent of CK1δ status, and intraperitoneal injection of IC261 to HCCLM3 xenograft models inhibited tumor growth. Taken together, our data indicated that IC261 has therapeutic potential for HCC.

Phloroglucinol derivative compound 21 attenuates cuprizone-induced multiple sclerosis mice through promoting remyelination and inhibiting neuroinflammation.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease in the central nervous system. The myelin loss is mainly caused by dysfunction of oligodendrocytes and inflammatory responses of microglia and astrocytes further aggravate the demyelination. Current therapies for MS focus on suppressing the overactivated immune response but cannot halt the disease progress, so effective drugs are urgently needed. Compound 21 is a phloroglucinol derivative that has been proved to have an outstanding anti-inflammatory effect. The purpose of the present study is to investigate whether this novel compound is effective in MS. The cuprizone-induced model was used in this study to mimic the pathological progress of MS. The results showed that Compound 21 significantly improved the neurological dysfunction and motor coordination impairment. Luxol Fast Blue staining and myelin basic protein immunostaining demonstrated that Compound 21 remarkably promoted remyelination. In addition, Compound 21 significantly promoted oligodendrocytes differentiation. Furthermore, we found that Compound 21 decreased microglia and astrocytes activities and the subsequent neuroinflammatory response, indicating that the anti-inflammatory effect of Compound 21 was also involved in its neuro-protection. All the data prove that Compound 21 exerts protective effect on MS through promoting remyelination and suppressing neuroinflammation, indicating that Compound 21 might be a potential drug candidate for MS treatment.

Attenuation of Inflammation and Leptin Resistance by Pyrogallol-Phloroglucinol-6,6-Bieckol on in the Brain of Obese Animal Models.

Obesity induces inflammation both in the adipose tissue and the brain. Activated macrophage infiltration, polarization of macrophages to a more inflammatory type (M1), and increased levels of pro-inflammatory cytokines are related to brain inflammation, which induces leptin resistance in the brain. Pyrogallol-phloroglucinol-6,6-bieckol (PPB), a compound from Ecklonia cava, has anti-inflammatory effects. In this study, we evaluated the effects of PPB effect M1 polarization and inflammation and its ability to restore the effects of leptin, such as a decrease in appetite and body weight. We administered PPB to diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice, evaluated macrophage activation, polarization, and changes of inflammatory cytokine level in adipose tissue and brain, and determined the effect of PPB on leptin resistance or leptin sensitivity in the brain. The levels of activated macrophage marker, M1/M2, and pro-inflammatory cytokines were increased in the adipose tissue and brain of DIO and ob/ob mice than control. TLR4 expression, endoplasmic reticulum (ER) stress, and NF-κB expression in the brain of DIO and ob/ob mice were also increased; this increase was related to the upregulation of SOCS3 and decreased phosphorylated STAT3, which decreased leptin sensitivity in the brain. PPB decreased inflammation in the brain, restored leptin sensitivity, and decreased food intake and weight gain in both DIO and ob/ob mice.

Comparison of the efficacy and safety of phloroglucinol and magnesium sulfate in the treatment of threatened abortion: A meta-analysis of randomized controlled trials.

BACKGROUND: To compare the clinical efficacy and safety of phloroglucinol (PHL) and magnesium sulfate (MS) in the treatment of threatened abortion through systematic review. METHODS: Foreign databases, such as the Cochrane Library, PubMed and EMBASE, and Chinese databases, including the China Biology Medicine disc (SinoMed), China National Knowledge Infrastructure (CNKI), Chongqing VIP (VIP) and WanFang Data, were searched. Published randomized controlled trials (RCTs) documents obtained from these databases were included if they were associated with the research objective. The search timeframe was from the beginning of the establishment of each database to May 2018. Document selection, data abstraction and document quality evaluation were independently performed by 2 investigators. A combined analysis of the data was performed for those documents that fulfilled the study requirements; Rev Man 5.3 and Stata 12.0 software were used to compare and analyze the 2 drugs in terms of the total effective rate (TER), rate of adverse events, time required to relieve uterine contractions, onset time, time of complete relief of uterine contraction symptoms, medication duration and length of hospital stay. RESULTS: A total of 21 RCT trials were included in the present research, according to the inclusion criteria. However, the quality of the included studies was low. The meta-analysis suggested that the TER and drug onset time of PHL were higher than those for MS, while the rate of adverse events, the time required to relieve uterine contractions, time to complete relief of uterine contraction symptoms, drug continuous treatment time and length of hospital stay were shorter than those for MS. CONCLUSION: The clinical efficacy of PHL is better than that of MS, and PHL obviously results in fewer adverse reactions than MS. However, due to poor quality of evidence, high quality, multi-center RCTs with large samples are required for further verification.

Potential of phloroglucinol to improve erectile dysfunction associated with streptozotocin-induced diabetes in rats.

OBJECTIVE: Diabetes is a common metabolic disease with several complications in its patients. Often, people living with diabetes develop erectile dysfunction (ED). The primary aim of this work was to investigate the effect of phloroglucinol in diabetes-induced ED in rats. METHODS: Male Wistar rats were given 52 mg/kg of streptozotocin, by intraperitoneal injection, to induce diabetes and ED. Subsequently, animals were grouped into three groups: group 1, diabetic control; group 2, low-dose phloroglucinol (150 mg/kg body weight); and group 3, high-dose phloroglucinol (250 mg/kg body weight). A group of six normal rats served as a normal control. The rats were treated with phloroglucinol for six weeks and then were assessed for treatment effects. Sexual behavior, glycosylated hemoglobin A1c (HbA1c) values, serum testosterone, serum nitric oxide (NO), blood pressure and sperm count were measured after the end of treatment. RESULTS: After a 6-week treatment period, the high dose of phloroglucinol significantly decreased HbA1c values in diabetic rats. Rats treated with phloroglucinol had increased serum testosterone, NO and sperm count. Animals treated with 250 mg/kg phloroglucinol performed similar to normal rats in the sexual behavioral study, suggesting the reversal of complications of ED. Conversely, a decrease in the blood pressure in treated groups was observed. CONCLUSION: The results highlight the protective effect of phloroglucinol in diabetes-induced ED in rats warranting further studies.

Hyperforin improves post-stroke social isolation­induced exaggeration of PSD and PSA via TGF-ß.

Stroke survivors often experience social isolation, which can lead to post­stroke depression (PSD) and post­stroke anxiety (PSA) that can compromise neurogenesis and impede functional recovery following the stroke. The present study aimed to investigate the effects and mechanisms of post­stroke social isolation­mediated PSD and PSA on hippocampal neurogenesis and cognitive function. The effects of the natural antidepressant hyperforin on post­stroke social isolation­mediated PSD and PSA were also investigated. In the present study, a model of PSD and PSA using C57BL/6J male mice was successfully established using middle cerebral artery occlusion combined with post­stroke isolated housing conditions. It was observed that PSD and PSA were more prominent in the isolated mice compared with the pair­housed mice at 14 days post­ischemia (dpi). Mice isolated 3 dpi exhibited decreased transforming growth factor­ß (TGF­ß) levels and impairment of hippocampal neurogenesis and memory function at 14 dpi. Intracerebroventricular administration of recombinant TGF­ß for 7 consecutive days, starting at 7 dpi, restored the reduced hippocampal neurogenesis and memory function induced by social isolation. Furthermore, intranasal administration of hyperforin for 7 consecutive days starting at 7 dpi improved PSD and PSA and promoted hippocampal neurogenesis and memory function in the isolated mice at 14 dpi. The inhibition of TGF­ß with a neutralizing antibody prevented the effects of hyperforin. In conclusion, the results revealed a previously uncharacterized role of hyperforin in improving post­stroke social isolation­induced exaggeration of PSD and PSA and, in turn, promoting hippocampal neurogenesis and cognitive function via TGF­ß.

Protective Effect of Hyperforin on ß Amyloid Protein Induced Apoptosis in PC12 Cells and Colchicine Induced Alzheimer's Disease: An Anti-oxidant and Anti-inflammatory Therapy.

The current investigation aimed to scrutinize the neuro-protective effect of hyperforin on ß­amyloid peptide (Aß)1-42 and H2O2 induced injury in PC12 cells and colchicine induced Alzheimer's disease (AD). PC12 cells were treated with H2O2 and (Aß)1-42 in the presence of hyperforin. The cell viability was determined via suing the MTT assay; malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels were also scrutinized. Colchicine induced the destruction of memory and learning which was exhibited in neurobehavioral theory (passive avoidance and Morris water maze) connected with reduced activity of acetylcholinesterase (AChE). Anti­oxidant and inflammatory parameters also estimated. Hyperforin dose dependently increased the cell viability and reduced the MDA and LDH release via PC12 cell injured with H2O2 and (Aß)1-42. Hyperforin treatment lead to a considerable enhance in TLT in the retention trials as comparisian to acquisition trial suggesting as boosting memory and learning in rats. Hyperforin treatments significantly increase the AChE and reduced the superoxide dismutase, glutathione, MDA, protein carbonyl, glutathione peroxdiase, catalase, NF­kB and IL­1ß at dose dependent manner. In summary, the model of H2O2 and (Aß)1-42 induced PC12 cell injury was successfully developed and dose dependently treatment of hypoforin showed the neuroprotective effect against the H2O2 and (Aß)1-42 induced cell damage. These finding clearly exhibited that hyperforin reverted the colchicine induced neuro­chemical and behavioural alteration via potent anti­inflammatory and anti­oxidant activity.

Protective Effect of Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava on Monocyte-Associated Vascular Dysfunction.

Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum.

Fifteen new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperforatones A-O (1-15), along with 3 structurally related analogues (16-18), were isolated from the stems and leaves of Hypericum perforatum. Their structures and absolute configurations were established by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD), modified Mosher's methods, Rh2(OCOCF3)4- and [Mo2(OAc)4]-induced ECD, X-ray crystallography, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Compound 5 was found to be the first PPAP decorated by a rare 2,2,4,4,5-(pentamethyltetrahydrofuran-3-yl)methanol moiety and an oxepane ring. Furthermore, the isolates were screened for their acetylcholinesterase (AChE) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities. Compounds 5, 10, 11, and 15 showed desirable AChE inhibitory activities (IC50 6.9-9.2 µM) and simultaneously inhibited BACE1 (at a concentration of 5 µM) with inhibition rates of 50.3%, 34.3%, 47.2%, and 34.6%, respectively. Interestingly, compound 5 showed the most balanced inhibitory activities against both AChE and BACE1 of all the tested compounds, which means that 5 could serve as the first valuable dual-targeted PPAP for the treatment of Alzheimer's disease. Preliminary molecular docking studies of 5 with BACE1 and AChE were also performed.

Efficacy of phloroglucinol for treatment of abdominal pain: a systematic review of literature and meta-analysis of randomised controlled trials versus placebo.

AIM: Phloroglucinol is a musculotropic anti-spasmodic drug. It is frequently prescribed in many European countries with a considerable cost for health services. The purpose of this study was to review the existing randomised controlled trials (RCT) comparing the efficacy of phloroglucinol treating abdominal pain versus placebo. METHODS: A literature search was carried out up to May 2017 to select RCT comparing the effect of phloroglucinol versus placebo with intensity of abdominal pain as an endpoint. Studies concerning obstetric or gynaecologic-related pain were not included. RESULTS: Three RCT were included and then analysed for risk of bias and meta-analysed. Only one RCT found that phloroglucinol was superior to placebo, although with a high risk of bias. The meta-analysis found a risk ratio of 1.10 (95% CI 0.95, 1.27) with no statistical significance. DISCUSSION: There is insufficient data to justify the wide-spread prescription of phloroglucinol for alleviating abdominal pain.