Therapeutic potential of low-molecular weight lignin model polymer fractions for treating skin lesions in animals: a pilot study.

Bacterial infections and resistance to antibiotics are increasingly severe problems. In recent years, Staphylococcus species have emerged as important pathogens in animals and humans. Current therapeutic methods against these species have serious disadvantages; therefore new agents with antibacterial potential, such as plant-based substances, are very important in therapy. We report a pilot study with new method of fractioning the dehydrogenate polymer DHP obtained from coniferyl alcohol and application of the low-MW fractions of 200-3000 Da for antibacterial activity in healing animal lesions. In vivo experiments were conducted on the dogs having a skin lesion. Dogs were treated with the suspension containing the low-MW DHP fractions as the active ingredient, in combination with alginate for 7 days. Cytological smears and microbiological analyses of the affected area were performed. Staphylococcus spp. was isolated from lesions in all dogs from our research. The results show that the low-MW DHP suspension in alginate promotes skin healing and reduction of the infection of the lesions in the affected animals. Pharmaceutical composition containing the low-MW DHP fractions exerts a soothing effect on the subject in wound treatment. Reduction in the number of bacteria by 30% and more were noticed in 6 dogs, while in 4 dogs this percentage is above 50%. No side effects were noticed. Synthesized lignin oligomers may have a significant place as antimicrobial and skin healing agents, especially since an increasing number of multidrug-resistant staphylococci are found on the skin lesions in animals.

Effects of Flaxseed Interventions on Circulating Inflammatory Biomarkers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There have been various clinical studies on the effect of flaxseed-derived products on circulating inflammatory biomarkers, but the findings from these are contradictory. The aim of the present study was to clarify any association. A comprehensive literature search was conducted from inception to May 2018. From the eligible trials, 32 articles describing studies conducted on adults aged 18-70 y were selected for the meta-analysis. Meta-analyses using the random-effects model were performed to investigate the data and results showed significant effects of flaxseed intake on circulating high-sensitivity CRP (hs-CRP) [weighted mean difference (WMD) = -0.75; 95% CI: -1.19, -0.30; P < 0.001] and TNFα (WMD = -0.38; 95% CI: -0.75,-0.01; P = 0.04). However, no significant changes were found in IL6 concentration (WMD = -0.24; 95% CI: -0.70, 0.21; P = 0.28) and C-reactive protein (CRP) (WMD = -0.34; 95% CI:-0.89, 0.20; P = 0.22). Moreover, by eliminating 1 of the studies from the sensitivity analysis, changes in IL6 concentration were significant (WMD = -0.44; 95% CI: -0.81, -0.08). The changes in inflammatory biomarkers were dependent on study design (parallel or crossover), supplement type (flaxseed, flaxseed oil, or lignan), study quality (high or low), and participants' age and BMI. According to this meta-analysis, flaxseed significantly reduced circulating concentrations of hs-CRP and TNFα, but did not affect IL6 and CRP. Further research is needed to examine the effect of different doses and long-term benefits of flaxseed and its derivatives on inflammatory factors.

Lignosulfonic acid attenuates NF-κB activation and intestinal epithelial barrier dysfunction induced by TNF-α/IFN-γ in Caco-2 cells.

Lentinula edodes mycelia solid culture extract (MSCE) is used as a medical food ingredient and provides beneficial effects to patients with cancer and chronic type C hepatitis. Low molecular weight lignin (LM-lignin), which is an active component of MSCE, exhibits hepatoprotective, antitumor, antiviral, and immunomodulatory effects. In this study, we investigated the effect of LM-lignin/lignosulfonic acid on intestinal barrier function. Lignosulfonic acid enhanced transepithelial membrane electrical resistance in human intestinal Caco-2 cell monolayers. In Caco-2 cells treated with lignosulfonic acid, expression of claudin-2, which forms high conductive cation pores in tight junctions (TJs), was decreased. Lignosulfonic acid also attenuated the barrier dysfunction that is caused by tumor necrosis factor (TNF)-α and interferon (IFN)-γ in Caco-2 cells. TNF-α- and IFN-γ-induced activation of NF-κB, such as translocation of NF-κB p65 into the nucleus and induction of gene expression, was inhibited by lignosulfonic acid treatment. Furthermore, lignosulfonic acid decreased the TNF-α- and IFN-γ-induced increase in interleukin (IL)-1ß and IL-6 expression in Caco-2 cells. These results suggest that lignosulfonic acid not only enhances TJ barrier function but also restores TJ barrier integrity impaired by inflammatory cytokines. Therefore, lignosulfonic acid may be beneficial for the treatment of inflammation-induced intestinal barrier dysfunction observed in inflammatory bowel disease.

Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts.

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-ß-stimulated cell viability, migration, and invasion and decreased TGF-ß-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.

Dietary phyto-oestrogens and the risk of ovarian and endometrial cancers: findings from two Australian case-control studies.

Phyto-oestrogens have been suggested to have a protective effect on hormone-sensitive cancers. However, few studies have investigated the association between dietary phyto-oestrogens and gynaecological cancers. In the present study, we analysed data from two population-based case-control studies of ovarian (1366 cases and 1414 controls) and endometrial (1288 cases and 1435 controls) cancers. Dietary intake information was obtained using a 135-item FFQ, and phyto-oestrogen intake was estimated using published food composition databases. Unconditional logistic regression was used to estimate adjusted OR and 95% CI. In multivariable analyses, there was a suggestive pattern of inverse associations between increasing intakes of total phyto-oestrogens, isoflavones and enterolignans and the risk of ovarian cancer. However, the results only reached statistical significance for the lignan compounds matairesinol and lariciresinol, where the OR for the highest v. the lowest intake category was 0.72 (95% CI 0.54, 0.96; P for trend = 0.02) for matairesinol and 0.72 (95% CI 0.55, 0.96; P for trend = 0.03) for lariciresinol. When the risk of ovarian cancer was assessed by subtype, there was an indication that increasing intakes of phyto-oestrogens may be associated with a decreased risk of mucinous (cases n 158) ovarian tumours (OR for the highest v. the lowest intake category: 0.47 (95% CI 0.24, 0.93); P for trend = 0.04). However, there were no significant associations with other histological subtypes. In contrast, dietary phyto-oestrogens (total or any subclass) were unrelated to the risk of endometrial cancer cases overall or by subtype.

Health effects with consumption of the flax lignan secoisolariciresinol diglucoside.

Flaxseed is the richest source of the lignan secoisolariciresinol diglucoside (SDG). After ingestion, SDG is converted to secoisolariciresinol, which is further metabolised to the mammalian lignans enterodiol and enterolactone. A growing body of evidence suggests that SDG metabolites may provide health benefits due to their weak oestrogenic or anti-oestrogenic effects, antioxidant activity, ability to induce phase 2 proteins and/or inhibit the activity of certain enzymes, or by mechanisms yet unidentified. Human and animal studies identify the benefits of SDG consumption. SDG metabolites may protect against CVD and the metabolic syndrome by reducing lipid and glucose concentrations, lowering blood pressure, and decreasing oxidative stress and inflammation. Flax lignans may also reduce cancer risk by preventing pre-cancerous cellular changes and by reducing angiogenesis and metastasis. Thus, dietary SDG has the potential to decrease the incidence of several chronic diseases that result in significant morbidity and mortality in industrialised countries. The available literature, though, makes it difficult to clearly identify SDG health effects because of the wide variability in study methods. However, the current evidence suggests that a dose of at least 500 mg SDG/d for approximately 8 weeks is needed to observe positive effects on cardiovascular risk factors in human patients. Flaxseed and its lignan extracts appear to be safe for most adult populations, though animal studies suggest that pregnant women should limit their exposure. The present review discusses the potential health benefits of SDG in humans, with supporting evidence from animal studies, and offers suggestions for future research.

A clinical pilot study of lignin--ascorbic acid combination treatment of herpes simplex virus.

Antiviral drugs as well as natural remedies have been used to reduce symptoms and the rate of recurrences of herpes simplex virus type 1 (HSV-1) infection, a common disease. To evaluate anti-HSV-1 activity of a pine cone lignin and ascorbic acid treatment, a clinical pilot study was carried out. Forty-eight healthy patients of both genders between 4 and 61 years old (mean: 31+/-16 years), with active lesions of HSV-1, took part in the study. According to the HSV-1 stage at the presentation, the patients were classified into the prodromic (16 patients), erythema (11 patients), papule edema (1 patient), vesicle/pustule (13 patients) and ulcer stages (7 patients). One mg of lignin-ascorbic acid tablet or solution was orally administered three times daily for a month. Clinical evaluations were made daily the first week and at least three times a week during the second week after the onset and every six months during the subsequent year to identify recurrence episodes. The patients who began the lignin-ascorbic acid treatment within the first 48 hours of symptom onset did not develop HSV-1 characteristic lesions, whereas those patients who began the treatment later experienced a shorter duration of cold sore lesions and a decrease in the symptoms compared with previous episodes. The majority of the patients reported the reduction in the severity of symptoms and the reduction in the recurrence episodes after the lignin-ascorbic acid treatment compared with previous episodes, suggesting its possible applicability for the prevention and treatment of HSV-1 infection.

Pilot evaluation of flaxseed for the management of hot flashes.

The objective of this study was to evaluate, in a phase 2 pilot study, tolerability and the effect of 6 weeks of flaxseed therapy on hot flash scores in women not wishing to receive estrogen therapy. Eligibility included 14 hot flashes per week for at least 1 month. In the baseline week, participants took no study medication and documented the characteristics of their hot flashes. Thereafter, crushed flaxseed was administered at 40 g daily. Participants provided weekly toxicity reports and health-related quality of life information. The primary end point was a change in hot flash score prospectively reported in a daily hot flash diary. Thirty women were enrolled between June 17 and November 8, 2005. The mean decrease in hot flash scores after flaxseed therapy was 57% (median decrease 62%). The mean reduction in daily hot flash frequency was 50% (median reduction 50%), from 7.3 hot flashes to 3.6. Fourteen of the 28 participants (50%) experienced mild or moderate abdominal distention. Eight participants (29%) experienced mild diarrhea, one experienced flatulence, and six (21%) withdrew because of toxicities. This study suggests that dietary therapy decreases hot flash activity in women not taking estrogen therapy. This reduction is greater than what would be expected with placebo.

Lig-8, a highly bioactive lignophenol derivative from bamboo lignin, exhibits multifaceted neuroprotective activity.

Lignin is a durable aromatic network polymer that is second only to cellulose in natural abundance. Lig-8, a lignophenol derivative from bamboo lignin, is a highly potent neuroprotectant. It protects human neuroblastoma cells (SH-SY5Y) from hydrogen peroxide (H2O2)-induced apoptosis by preventing caspase-3 activation via either caspase-8 or caspase-9. It exerts this antiapoptotic effect by protecting mitochondrial membrane permeability from damage by H2O2 or the peripheral benzodiazepine receptor ligand PK11195. Lig-8 has been also shown to scavenge the reactive oxygen or nitrogen species in vitro. Furthermore, lig-8 suppresses apoptosis induced by oxygen-glucose deprivation, tunicamycin (endoplasmic reticulum [ER]-stress inducer), or proteasome inhibitor in pheochromocytoma cells. In addition, in vivo, lig-8 reduced intravitreal N-methyl-D-aspartate-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness) in mice. Lig-8 prevents neuronal damage partly by inhibiting excessive endoplasmic reticulum stress. In this article, we review the protective effects of lig-8 against apoptosis induced by various stimuli. Apoptosis is an active, energy-dependent process through which living cells initiate their own death. It can be induced by a variety of physiological and pharmacological stimuli. Apoptotic cell death is associated with neurodegenerative disorders such as Alzheimer, Parkinson, or Huntington disease as well as glaucoma. We believe that the elucidation of the mechanism of antiapoptotic action of lig-8 may help in finding new approaches to the treatment of neurodegenerative disorders.

Chemical properties, mode of action, and in vivo anti-herpes activities of a lignin-carbohydrate complex from Prunella vulgaris.

The chemical nature, the mode of action, and the in vitro and in vivo anti-HSV activities of the polysaccharide from Prunella vulgaris were characterized. The polysaccharide was isolated by ethanol precipitation, dialysis, CTAB precipitation, and gel exclusion chromatography. The isolated compound (PPS-2b) was a lignin-carbohydrate complex with a molecular weight of 8500. The carbohydrate moiety was composed of glucose, galactose, mannose, galacturonic acid, rhamnose, xylose, and arabinose with glucose as the major sugar. In plaque reduction assay, PPS-2b showed activities against HSV-1 and HSV-2. The anti-HSV activity could be abolished by periodate oxidation. Mechanism studies showed that PPS-2b inactivated HSV-1 directly, blocked HSV-1 binding to Vero cells, and inhibited HSV-1 penetration into Vero cells. A similar inhibition was observed with a gC-deficient strain of HSV-1. The in vivo activities of a Prunella cream formulated with a semi-purified fraction was assessed in a HSV-1 skin lesion model in guinea pigs and a HSV-2 genital infection model in BALB/c mice. Guinea pigs that received the Prunella cream treatment showed a significant reduction (P<0.01) in skin lesions. Mice that received the Prunella cream treatment showed a significant reduction (P<0.01) in mortality. In conclusion, the anti-HSV compound from P. vulgaris is a lignin-polysaccharide complex with potent activity against HSV-1 and HSV-2. Its mode of action appears to be inhibiting viral binding and penetration into host cells.

[New approaches to cholelithiasis prevention in young patients].

The purpose of the study was to evaluate efficacy of poliphepan and hepabene as components of complex therapy in patients with chronic cholecystitis (CC). The subjects were 33 CC patients with biliary tract (BT) dyskinesia and biliar sludge. Application of the drugs led to significant improvement of clinical symptoms and the parameters of BT functional condition, as well as to decrease of bile lithogenicity and improvement of life quality.

Estrogenic activity of phenylpropanoids from Sarcomelicope megistophylla and structure determination of a new norneolignan.

Bioassay-guided fractionation of the neutral extract of the bark of Sarcomelicope megistophylla resulted in the isolation of the new nor-neolignan sarcomeginal ( 1), together with the known ailanthoidol ( 2) and (+/-)-seco-isolariciresinol ( 3). The structure of 1 was determined by spectroscopic means. Estrogenic activity of the isolated compounds was tested using estrogen receptor-positive MCF7 and estrogen receptor-negative MDA-MB-231 human mammary adenocarcinoma cell lines. Compound 3 displayed significant estrogenic activity.

Antitumor, antiviral and immunopotentiating activities of pine cone extracts: potential medicinal efficacy of natural and synthetic lignin-related materials (review).

Several antitumor substances that effectively inhibited the growth of ascites and solid tumor cells transplanted in mice were isolated from pine cone NaOH extract by acid- and ethanol-precipitation. These antitumor substances were also potent antiviral agents against human immunodeficiency virus, herpes simplex virus and influenza virus; they induced antimicrobial activity against Staphylococcal aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Candida albicans, and induced antiparasite activity against Hymenolepis nana in mice. Chemical analysis of these substances by IR, UV, NMR, ESR and partition chromatography on cellulose-TLC plate disclosed that they had lignin-related structures complexed with sugars or polysaccharides. Chlorinated decomposition of the lignin portion significantly reduced their antiviral activity. In agreement with this, the antiviral activity of synthesized lignins prepared by polymerization of phenylpropanoid precursors was comparable to that of the undecomposed counterparts of the pine cone extract. Acid hydrolysis of the polysaccharide portion significantly reduced the ability of the substances to induce antitumor and antimicrobial activities in mice. With an appropriate eliciting agent, intravenous administration of natural lignified substances transiently induced endogenous production of a cytotoxic factor (possibly tumor necrosis factor) in normal mice. Their priming activity was significantly higher than that of their component units or degradation products. These data suggest the importance of conjugating lignins with polysaccharides for in vivo expression of various kinds of immunopotentiating activity. As possible explanations for their induction of a variety of immunopotentiating activities, these natural and synthetic lignins stimulated macrophage NBT-reducing activity, polymorphonuclear cell (PMN) iodination and splenocyte DNA synthesis and inhibited poly (ADP-ribose) glycohydrolase, RNA-dependent DNA polymerase (reverse transcriptase) and RNA-dependent RNA polymerase activities.

Bioactivity of neolignans from fructus Schizandrae.

Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Induction of antiparasite activity by pine cone lignin-related substances.

Pretreatment with two distinct lignin-related antitumor substances extracted from pine cone of Pinus parviflora Sieb. et Zucc. protected infant mice from Hymenolepis nana (Cestoda) infection. Subcutaneous administration of these fractions (10 mg/kg) to 1 week old mice evoked strong protective immunity against oral infection by Hymenolepis nana eggs. Significant antiparasite effects were also induced in 4 week old mice by intraperitoneal or oral administration of these fractions. These fractions had more potent antiparasite activity than pine cone extracts with lower antitumor and antiviral activity, and various polysaccharides derived from plants and bacteria.

Potential anticancer agents II: antitumor and cytotoxic lignans from Linum album (Linaceae).

A phytochemical study of Linum album (Linaceae), guided by bioassay with the 9KB cell culture, resulted in the isolation of podophyllotoxin and a new lignan, 3'-demethylpodophyllotoxin; alpha-and beta-peltatins were identified by comparative TLC.