Alimentos funcionales y nutracéuticos en el tratamiento de la hipercolesterolemia: posicionamiento de la Sociedad Española de Arteriosclerosis 2023 / Functional foods and nutraceuticals in the treatment of hypercholesterolemia: Statement of the Spanish Society of Arteriosclerosis 2023

Para el tratamiento de la hipercolesterolemia, además de aconsejar una alimentación saludable, puede ser conveniente recomendar alimentos funcionales o nutracéuticos con efecto hipolipemiante. Dado el progresivo incremento en el número de estos productos y su creciente utilización por la población, la Sociedad Española de Arteriosclerosis (SEA) ha creído conveniente revisar la información disponible, seleccionar los resultados de los estudios científicamente más sólidos y posicionarse sobre la utilidad de los mismos, para recomendar a los profesionales sanitarios y a la población general su potencial utilidad en términos de eficacia y sus posibles beneficios y limitaciones. Se han identificado los siguientes escenarios clínicos en los que se podrían utilizar estos productos y que se analizarán con más detalle en este documento: 1. Tratamiento hipolipemiante en sujetos con intolerancia a estatinas. 2. Tratamiento hipolipemiante «a la carta» en personas en prevención primaria. 3. Prevención cardiovascular a largo plazo en personas sin indicación de tratamiento hipolipemiante. 4. Pacientes con tratamiento hipolipemiante optimizado que no alcanzan objetivos terapéuticos. (AU)

In the management of hypercholesterolemia, besides advising a healthy, plant-based diet, it may be useful to recommend functional foods or nutraceutical with cholesterol-lowering properties. Given the progressive increase in the number of these products and their rising use by the population, the Spanish Society of Arteriosclerosis (SEA) has considered it appropriate to review the available information, select the results of the scientifically more robust studies and take a position on their usefulness, to recommend to health professionals and the general population their potential utility in terms of efficacy and their possible benefits and limitations. The following clinical scenarios have been identified in which these products could be used and will be analyzed in more detail in this document: (1) Hypolipidemic treatment in subjects with statin intolerance. (2) Hypolipidemic treatment «a la carte» in individuals in primary prevention. (3) Long-term cardiovascular prevention in individuals with no indication for lipid-lowering therapy. (4) Patients with optimized lipid-lowering treatment who do not achieve therapeutic objectives. (AU)

Phytosterol supplementation in capsules or tablets as adjunctive treatment for hypercholesterolemia: A systematic review of randomized controlled trials.

BACKGROUND: The exploration of lipid-lowering resources, such as phytosterols, for the complementary nutritional treatment of hypercholesterolemia is relevant to reduce cardiovascular risk. The use of phytosterols in capsules or tablets can bring advantages in the context of diet therapy, but such format is still less studied when compared to fortified foods. OBJECTIVE: Systematically review randomized clinical trials on the effects of phytosterol supplementation, in capsules or tablets, on the lipid profile and its use in the treatment of hypercholesterolemia in adults. DESIGN: A systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, with a PROSPERO protocol registered under number CRD42021249539. The process was conducted by two independent reviewers. Only randomized clinical trials with phytosterol supplementation in adult individuals with hypercholesterolemia were included. The terms were searched in the databases: PubMed/MEDLINE, Cochrane Library/CENTRAL, Embase, LILACS and Web of Science, without restriction of time and language. The manual search was also performed through the list of references of articles included in this review. RESULTS: The searches resulted in 977 articles. 22 articles were selected, whose full text was read, and according to the eligibility criteria 10 were incorporated into the review. The studies were separated into groups according to the association of the intervention with changes in lifestyle and the characteristics extracted from the studies were summarized and displayed in tables. Most studies have revealed a positive association between phytosterol supplementation and cholesterol reduction, despite the short duration of interventions. CONCLUSION: The analyzed studies showed that phytosterol supplements can be useful to modulate the lipid profile, helping to reduce the plasma concentration of LDL cholesterol. However, more research with the aforementioned supplementation in such pharmaceutical formats should be encouraged.

Supplements for Lipid Lowering: What Does the Evidence Show?

PURPOSE: In this review, the regulation, proposed hypolipidemic mechanism, and efficacy of common dietary supplements (DSs) marketed for cardiovascular health are discussed. RECENT FINDINGS: Data demonstrate modest but inconsistent lipid-lowering effects with common DSs such as probiotics, soluble fibers, plant sterols, green tea, berberine, guggul, niacin, and garlic. Furthermore, data is limited regarding turmeric, hawthorn, and cinnamon. Red yeast rice has shown to be a beneficial DS, but its safety and efficacy are dependent upon its production quality and monacolin K content, respectively. Finally, soy proteins and omega-3 fatty acid-rich foods can have significant health benefits if used to displace other animal products as part of a healthier diet. Despite the rising use of DSs, data demonstrate unpredictable results. Patients should be educated on the difference between these DSs and evidence-based lipid-lowering medications proven to improve cardiovascular outcomes.

The elucidation of structure-activity and structure-permeation relationships for the cutaneous delivery of phytosterols to attenuate psoriasiform inflammation.

Phytosterols have been reported to exert anti-inflammatory activity. This study aimed to investigate the capacity of campesterol, ß-sitosterol, and stigmasterol on the mitigation of psoriasiform inflammation. We also tried to establish structure-activity and structure-permeation relationships for these plant sterols. To support this study, we first approached the in silico data of the physicochemical properties and the molecular docking of phytosterols with stratum corneum (SC) lipids. The anti-inflammatory activity of the phytosterols was explored in the activated keratinocytes and macrophages. Using the activated keratinocyte model, a significant inhibition of IL-6 and CXCL8 overexpression by phytosterols was detected. A comparable inhibition level was found for the three phytosterols tested. The macrophage-based study showed that the anti-IL-6 and anti-CXCL8 activities of campesterol were greater than those of the other compounds, which indicated that a phytosterol structure without a double bond on C22 and with methyl moiety on C24 was more effective. The conditioned medium of phytosterol-treated macrophages decreased STAT3 phosphorylation in the keratinocytes, suggesting the inhibition of keratinocyte hyperproliferation. ß-sitosterol was the penetrant with the highest pig skin absorption (0.33 nmol/mg), followed by campesterol (0.21 nmol/mg) and stigmasterol (0.16 nmol/mg). The therapeutic index (TI) is a parameter measured by multiplying the cytokine/chemokine suppression percentage with skin absorption for anticipating the anti-inflammatory activity after topical delivery. ß-sitosterol is a potential candidate for treating psoriatic inflammation due to having the greatest TI value. In this study, ß-sitosterol attenuated epidermal hyperplasia and immune cell infiltration in the psoriasis-like mouse model. The psoriasiform epidermis thickness could be reduced from 92.4 to 63.8 µm by the topical use of ß-sitosterol, with a downregulation of IL-6, TNF-α, and CXCL1. The skin tolerance study manifested that the reference drug betamethasone but not ß-sitosterol could generate barrier dysfunction. ß-sitosterol possessed anti-inflammatory activity and facile skin transport, showing the potential for development as an anti-psoriatic agent.

Curcumin and Teupolioside attenuate signs and symptoms severity associated to hirsutism in PCOS women: a preliminary pilot study.

OBJECTIVE: Hirsutism affects 5-15% of women of reproductive age, with approximately 80% of these women having polycystic ovary syndrome (PCOS). The etiopathogenesis of PCOS remains unclear, the clinical characteristics of PCOS include hyperandrogenism, generally manifested as hirsutism and acne, and both these clinical symptoms are treated with oral contraceptive pills (OCPs), topical medications or antiandrogens. Curcumin (diferuloylmethane) and Plant sterols, such as a phenylpropanoid glycosides of Ajuga reptans, known as Teupolioside, have attracted considerable attention due to their pharmacological properties. Taking into consideration wide-ranging pharmacological and biological properties and the safety of herbal extracts, we proposed a combination of curcumin and teupolioside to evaluate the anti-androgenic properties in women with PCOS and clinical signs of hyperandrogenism. PATIENTS AND METHODS: Six hyperandrogenic PCOS women with a hirsutism score (HS) > 20, according to Ferriman-Gallwey scoring system, were involved in the study. These women were treated with a galenical preparation mixture containing curcumin and teupolioside and clinical features were assessed after 12 weeks. RESULTS: The nutraceutical combination containing curcumin/teopolioside ameliorated clinical manifestations associated to hyperandrogenism in women with PCOS after a 12-weeks treatment. CONCLUSIONS: This pilot study suggests that a curcumin/teopolioside nutraceutical combination is beneficial for improving various clinical manifestations associated to abnormal hormonal parameters in PCOS women, as well as signs and symptoms associated to hyperandrogenism.

The Role of Phytosterols in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease is now recognized as the most common cause of chronic liver disease with an increasing prevalence in both adults and children. Although the symptoms are absent or poorly expressed in most cases, some patients may progress to end-stage liver disease. The pathogenesis of NAFLD is known to be multifactorial. Current therapeutic recommendations focus on lifestyle changes in order to reduce the incidence of risk factors and drugs targeting major molecular pathways potentially involved in the development of this disease. Given that a pharmacological treatment, completely safe and effective, is not currently known in recent years more research has been done on the effects that some bio-active natural compounds, derived from plants, have in preventing the onset and progression of NAFLD. Numerous studies, in animals and humans, have shown that phytosterols (PSs) play an important role in this pathology. Phytosterols are natural products that are found naturally in plant. More than 250 phytosterols have been identified, but the most common in the diet are stigmasterol, ß-sitosterol, and campesterol. Consumption of dietary PSs can reduce serum cholesterol levels. Due to these properties, most studies have focused on their action on lipid metabolism and the evolution of NAFLD. PSs may reduce steatosis, cytotoxicity oxidative stress, inflammation, and apoptosis. The purpose of this review is to provide an overview of the importance of dietary phytosterols, which are a window of opportunity in the therapeutic management of NAFLD.

A Comprehensive Review on Therapeutic Perspectives of Phytosterols in Insulin Resistance: A Mechanistic Approach.

Natural products in the form of functional foods have become increasingly popular due to their protective effects against life-threatening diseases, low risk of adverse effects, affordability, and accessibility. Plant components such as phytosterol, in particular, have drawn a lot of press recently due to a link between their consumption and a modest incidence of global problems, such as Type 2 Diabetes mellitus (T2DM), cancer, and cardiovascular disease. In the management of diet-related metabolic diseases, such as T2DM and cardiovascular disorders, these plant-based functional foods and nutritional supplements have unquestionably led the market in terms of cost-effectiveness, therapeutic efficacy, and safety. Diabetes mellitus is a metabolic disorder categoriszed by high blood sugar and insulin resistance, which influence major metabolic organs, such as the liver, adipose tissue, and skeletal muscle. These chronic hyperglycemia fallouts result in decreased glucose consumption by body cells, increased fat mobilisation from fat storage cells, and protein depletion in human tissues, keeping the tissues in a state of crisis. In addition, functional foods such as phytosterols improve the body's healing process from these crises by promoting a proper physiological metabolism and cellular activities. They are plant-derived steroid molecules having structure and function similar to cholesterol, which is found in vegetables, grains, nuts, olive oil, wood pulp, legumes, cereals, and leaves, and are abundant in nature, along with phytosterol derivatives. The most copious phytosterols seen in the human diet are sitosterol, stigmasterol, and campesterol, which can be found in free form, as fatty acid/cinnamic acid esters or as glycosides processed by pancreatic enzymes. Accumulating evidence reveals that phytosterols and diets enriched with them can control glucose and lipid metabolism, as well as insulin resistance. Despite this, few studies on the advantages of sterol control in diabetes care have been published. As a basis, the primary objective of this review is to convey extensive updated information on the possibility of managing diabetes and associated complications with sterol-rich foods in molecular aspects.

Khasianine ameliorates psoriasis-like skin inflammation and represses TNF-α/NF-κB axis mediated transactivation of IL-17A and IL-33 in keratinocytes.

ETHNO-PHARMACOLOGICAL RELEVANCE: Khasianine is recently identified as a bioactive compound from Solanum nigrum L. (SNL) which is a traditional Chinese herb (named LongKui in China) and has been clinically applied for treating psoriasis in China but with limited knowledge about the active ingredients. AIM OF THE STUDY: This study tried to explore the bioactivity of Khasianine and showed that Khasianine possessed highly anti-inflammatory bioactivity which rapidly alleviated psoriasis-like mice skin inflammation. MATERIALS AND METHODS: Imiquimod induced psoriasis-like mouse model, and human keratinocytes were employed in this study. In vivo, immunohistochemistry and immunofluorescence were performed to evaluate the pathological improvement in psoriatic lesions after Khasianine treatment. In vitro, tumor necrosis factor α (TNF-α) treated HaCaT cells with or without Khasianine, were used to analyze the expression and cellular location of NF-κB p65, the expression of IL-17A and IL-33, and the binding intensity of NF-κB p65 on the promoter of IL-17A and IL-33 to understand the molecular mechanism of Khasianine mediated anti-inflammatory effect. RESULTS: Khasianine reduced infiltration of CD4+ T helper cells (Th cells) and macrophages in mice psoriatic lesions. Immunohistochemistry analysis revealed that Khasianine reduced TNF-α levels in lesions and suppressed NF-κB p65 activation as well as expression of IL-17A and IL-33 in mice epidermal keratinocytes. Further studies in human keratinocytes demonstrated that Khasianine inhibited TNF-α-induced transcriptional activation (transactivation) of NF-κB p65 such as evicting NF-κB p65 binding from the promoter regions of IL-17A and IL-33 and preventing NF-κB nuclear translocation. CONCLUSIONS: Our results suggested that Khasianine is a potent anti-inflammatory compound with the bioactivity of NF-κB inhibition and is a promising candidate for psoriasis topical therapy.

Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases.

Phytosterols constitute a class of natural products that are an important component of diet and have vast applications in foods, cosmetics, and herbal medicines. With many and diverse isolated structures in nature, they exhibit a broad range of biological and pharmacological activities. Among over 200 types of phytosterols, stigmasterol and ß-sitosterol were ubiquitous in many plant species, exhibiting important aspects of activities related to neurodegenerative diseases. Hence, this mini-review presented an overview of the reported studies on selected phytosterols related to neurodegenerative diseases. It covered the major phytosterols based on biosynthetic considerations, including other phytosterols with significant in vitro and in vivo biological activities.

Formulation and Characterization of Phytostanol Ester Solid Lipid Nanoparticles for the Management of Hypercholesterolemia: An ex vivo Study.

BACKGROUND: Phytostanols are naturally occurring compounds that reduce blood cholesterol levels significantly. However, their aqueous insolubility poses formulation challenges. AIM: To formulate and characterize solid lipid nanoparticle carriers for phytostanol esters to enhance the bioavailability of phytostanols. METHODS: Phytostanol ester solid lipid nanoparticles were formulated by the microemulsion method. They were characterized for particle size distribution, polydispersity index, shape, surface charge, entrapment efficiency, stability, chemical structure, and thermal properties. The uptake of the formulation by cell lines, HepG2 and HT-29, and its effect on cell viability were evaluated. RESULTS: The formulation of solid lipid nanoparticles was successfully optimised by varying the type of lipids and their concentration relative to that of surfactants in the present study. The optimised formulation had an average diameter of (171 ± 9) nm, a negative surface charge of (-23.0 ± 0.8) mV and was generally spherical in shape. We report high levels of drug entrapment at (89 ± 5)% in amorphous form, drug loading of (9.1 ± 0.5)%, nanoparticle yield of (67 ± 4)% and drug excipient compatibility. The biological safety and uptake of the formulations were demonstrated on hepatic and intestinal cell lines. CONCLUSION: Phytostanol ester solid lipid nanoparticles were successfully formulated and characterized. The formulation has the potential to provide an innovative drug delivery system for phytostanols which reduce cholesterol and have a potentially ideal safety profile. This can contribute to better management of one of the main risk factors of cardiovascular diseases.

Effect of phytosterols on reducing low-density lipoprotein cholesterol in dogs.

Hyperlipidemia is described as an increase in serum and/or plasma levels of triglycerides, cholesterol, or both. This disturbance can be primary in some cases, or combined with other comorbidities such as endocrinopathies, liver diseases, or specific drug use. Among the various ways to control dyslipidemia are specific diets, omega-3 fatty acid supplementation, or hypolipemiant treatment. Herbal medicine has been used in the human clinical routine to reduce cholesterol circulation. With an aim to expand its application in veterinary medicine, we analyzed the use of phytosterols in dogs as a potential alternative to control hypercholesterolemia. We performed lipidogram analysis in healthy dogs to examine the possible adverse effects during the treatment. Eight Beagle dogs received orally two 650 mg capsules of phytosterols (Collestra, Aché), for 15 consecutive d, along with the 2 usual meals. All animals remained clinically stable during the trial. There were significant alterations in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels during the trial. LDL was reduced (86.8 ± 29.89 mg/dL [D0], 74.45 ± 31.58 mg/dL [D8], and 58.91 ± 18.65 mg/dL [D15]; P = 0.0442) and HDL was elevated (83.40 ± 12.05 mg/dL [D0], 86.46 ± 13.05 mg/dL [D8], and 101.5 ± 10.52 [D15]; P = 0.0141), while total cholesterol and triglyceride concentrations remained constant and within the normal range for canine species. Thus, a 1300 mg dose of phytosterols, administrated orally and fractionated along with the 2 usual meals, was capable of reducing LDL and increasing HDL concentration in healthy nondyslipidemic dogs, which makes them candidates to be included on the list of hypolipemiant drugs for clinical use in dogs with hypercholesterolemia.

Plant sterol ester of α-linolenic acid ameliorates high-fat diet-induced nonalcoholic fatty liver disease in mice: association with regulating mitochondrial dysfunction and oxidative stress via activating AMPK signaling.

The present study was designed to explore the beneficial mitochondrial effects and anti-oxidative activities of plant sterol ester of α-linolenic acid (PS-ALA) through AMP-activated protein kinase (AMPK) signaling in the treatment of nonalcoholic fatty liver disease (NAFLD) using in vivo and in vitro models. The mitochondrial function was evaluated and the oxidative stress index was measured. The protein expression was analyzed by immunohistochemical, immunofluorescence, and western blotting methods. The results showed that PS-ALA significantly suppressed NAFLD and alleviated steatosis in HepG2 cells induced by oleic acid (OA). In addition, PS-ALA promoted mitochondrial biogenesis, enhanced mitochondrial fatty acid oxidation capacity, improved mitochondrial dynamics, and restored mitochondrial membrane potential. Moreover, PS-ALA reduced reactive oxygen species production both in the liver tissue of HFD-fed mice and OA-loaded HepG2 cells. At the molecular level, PS-ALA accelerated the phosphorylation of AMPK and increased the protein expression of peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and nuclear NF-E2-related factor 2 (Nrf2). Furthermore, the stimulating effects of PS-ALA on the PGC-1α/Nrf1/Tfam pathway and Nrf2/HO-1 pathway as well as its mitochondrial biogenesis promotion effects and anti-oxidative activities were abrogated by the AMPK inhibitor in OA-treated HepG2 cells. In conclusion, the protective effects of PS-ALA on NAFLD appear to be associated with improving mitochondrial function and oxidative stress via activating AMPK signaling.

Sex hormone-like Effects of Icariin on T-cells immune modulation in spontaneously hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium brevicornu Maxim as a Chinese herb, is recommended for the treatment of menopausal women with hypertension for 50 years. Icariin, as the main hydrophilic ingredient of Epimedium brevicornu Maxim, has been proven to be a plant sex hormone and lower blood pressure down. Here, we hypothesized that Icariin can regulate T cells differentiation which leads to the blood pressure decrease in castrated SHR rats. AIM OF THE STUDY: The present study aimed to investigate the effects of the exogenous estrogen, androgen and Icariin on T-cell modulation in hypertension. MATERIALS AND METHODS: Two weeks after castration, both male and female SHR rats were given estradiol, testosterone, and Icariin intervention respectively. Body weight, blood pressure, and heart rate were tested weekly. After six weeks, proportion of T helper cells (Th), cytotoxic T cells (Tc), and regulatory T cells (Tregs) in both peripheral blood mononuclear cells (PBMCs) and splenocytes were tested by flowcytometry. Serum levels of estrogen, testosterone, AngII, TNF-α, IL-17 were tested by Elisa. Aortic arches were isolated for HE and Masson staining. The expressions of ERß and AR in aorta were tested by Western-blot. RESULTS: In both male and female SHR rats, we found that Icariin and estradiol lower blood pressure, but testosterone elevates blood pressure. Similar as testosterone, Icariin can attenuate Tc and Th proportions and elevate Tregs proportion in both peripheral blood and splenocyte in male SHR, which can be blunt by flutamide. Besides, Icariin performs similar function as estradiol that attenuates Tc proportions and elevates Tregs proportion in both peripheral blood and splenocytes in female SHR, which leads to the lower blood pressure and can be partly blunt by fulvestrant. Testosterone increases AngII and TNF-α levels in serum, leading to the higher blood pressure in both male and female SHR rats. CONCLUSION: These results verified that Icariin, as a plant sex hormone, can regulate T cells differentiation related to blood pressure decrease in SHR rats.

Almond as a nutraceutical and therapeutic agent in Persian medicine and modern phytotherapy: A narrative review.

Sweet almond (Prunus dulcis (Mill.) D.A.Webb) is a known nut, which has long been used in several ethnomedical systems, especially in Persian medicine (PM) for its nutritional and therapeutic activities. In this study, we aimed to provide a summary on traditional uses, phytochemistry, and pharmacological activities of sweet almond. Thus, we reviewed textbooks of PM and electronic literature on traditional medicine. Moreover, the available data on the usage of sweet almond were searched in electronic databases to find articles on its pharmacological properties and phytochemistry. According to phytochemical investigations, this plant contains macronutrients, micronutrients, essential oils, various phenolic compounds, and phytosterols. Current pharmacological studies represent that Prunus dulcis has several biological activities including prebiotic, antimicrobial, antioxidant, antiinflammatory, anticancer, hepatoprotective, cardiometabolic protection, nootropic, anxiolytic, sedative-hypnotic, and nervous-improving effects. Further clinical trials and meta-analysis are required to draw a definitive conclusion on the efficacy and therapeutic activities of almond.

A double blind, placebo-controlled randomized comparative study on the efficacy of phytosterol-enriched and conventional saw palmetto oil in mitigating benign prostate hyperplasia and androgen deficiency.

BACKGROUND: The present clinical trial was conducted to evaluate the efficacy and tolerability of a standardized saw palmetto oil containing 3% ß-sitosterol in the treatment of benign prostate hyperplasia (BPH) and androgen deficiency. METHODS: Subjects aged 40-65 years with symptomatic BPH were randomized to 12-week double-blind treatment with 500 mg doses of ß-sitosterol enriched saw palmetto oil, conventional saw palmetto oil and placebo orally in the form of capsules (n = 33 in each group). BPH severity was determined using the International Prostate Symptom Score (IPSS), uroflowmetry, serum measurement of prostate specific antigen (PSA), testosterone and 5α-reductase. During the trial, the androgen deficiency was evaluated using Aging Male Symptoms (AMS) scale, the Androgen Deficiency in the Aging Male (ADAM) questionnaire, serum levels of free testosterone. RESULTS: Subjects treated with ß-sitosterol enriched saw palmetto oil showed significant decrease in IPSS, AMS and ADAM scores along with reduced postvoiding residual volume (p < 0.001), PSA (p < 0.01) and 5α-reductase from baseline to end of 12-week treatment as compared to placebo. There was also a significant increment in the maximum and average urine flow rate (p < 0.001), and serum free testosterone level of subjects treated with enriched saw palmetto oil as compared to placebo. CONCLUSION: This study demonstrates the efficacy of ß-sitosterol enriched saw palmetto oil superior to conventional oil thus extending the scope of effective BPH and androgen deficiency treatment with improved quality of life through the intake of functional ingredients. TRIAL REGISTRATION: CTRI/2018/12/016724 dated 19/12/2018 prospectively registered. URL: http://ctri.nic.in/Clinicaltrials/advsearch.php.

Phytosterols demonstrate selective inhibition of COX-2: In-vivo and in-silico studies of Nicotiana tabacum.

The inhibition of cyclooxygenase-1 (COX-1) enzyme by Nonsteroidal anti-inflammatory drugs (NSAIDs) exposes the gastrointestinal mucosa to peptic injuries. Selective inhibition of COX-2 generates surpassing anti-inflammatory drug candidates with reduced side effects over current NSAIDs. Phytosterols consumption is reported to decrease the risk of cardiovascular problems. Reports on the selective inhibition of COX-2 by phytosterols are scarce. The present study assesses the anti-inflammatory potentials of phytosterols from Nicotiana tabacum (of the family Solanaceae) through selective inhibition of COX-1 and/or COX-2. Virtual High Throughput Screening (vHTS) and Molecular Docking of phytochemicals from Nicotiana tabacum against the catalytic pockets of COX-1 and COX-2 were used to identify the lead bioactive(s) components of the plant. The hit phytosterols were isolated, histopathological examination of the stomach, in-vivo COX-1/COX-2 mRNAs expression patterns in the liver through reverse transcription-polymerase chain reactions, and enzymes activities of Nicotiana tabacum phytosterol isolates (NTPI) in HCl/ethanol-induced inflammation in Wistar rats were all investigated. Formation of hydrogen bonds favour selective inhibition of COX-2 while hydrophobic interactions favour selective inhibition of COX-1. NTPI demonstrates inhibition of COX-2 by down-regulate the expression of COX-2 mRNA and were ineffective against the expression COX-1 mRNA. NTPI demonstrates hepatoprotective abilities by improving the antioxidant defense system of the liver. Histopathological analyses show NTPI at 50 mg/kg bodyweight regenerates the parietal cells and maintain the gastrointestinal architecture. Drug likeness prediction and ADME toxicity screening show that phytosterols possess good oral bioavailability with no side effects. Phytosterols are selective inhibitors of COX-2, they are hepatoprotective, regenerate parietal cells, and non-toxic.

Antidiabetes constituents, cycloartenol and 24-methylenecycloartanol, from Ficus krishnae.

Ficus krishnae stem bark and leaves are used for diabetes treatment in traditional medicines. Stem bark of F. krishnae was sequentially extracted with hexane, methanol and water, and these extracts were tested for their antihyperglyceamic activity by oral glucose tolerance test (OGTT) in overnight fasted glucose loaded normal rats. Hexane extract showed significant glucose lowering activity in OGTT, and the triterpene alcohols (cycloartenol+24-methylenecycloartanol) (CA+24-MCA) were isolated together from it by activity guided isolation and characterized by NMR and mass spectroscopy. The ratio of the chemical constituents CA and 24-MCA in (CA+24-MCA) was determined as 2.27:1.00 by chemical derivatization and gas chromatographic quantification. (CA+24-MCA) in high fat diet-streptozotocin induced type II diabetic rats showed significant antidiabetes activity at 1 mg/kg and ameliorated derailed blood glucose and other serum biochemical parameters. Cytoprotective activity of (CA+24-MCA) from glucose toxicity was evaluated in cultured RIN-5F cells by MTT assay and fluorescent microscopy. (CA+24-MCA) in in vitro studies showed enhanced cell viability in RIN-5F cells and significant protection of beta cells from glucose toxicity. Both in in vivo and in vitro studies (CA+24-MCA) showed enhancement in insulin release from the beta cells. In short term toxicity studies in mice (CA+24-MCA) did not show any conspicuous toxic symptoms. The combination of the phytosterols (CA+24-MCA) obtained through activity guided isolation of the stem bark of F. krishnae showed significant activity, and therefore is a promising candidate for new generation antidiabetes drug development.

Inhibitory effect of ergosterol on bladder carcinogenesis is due to androgen signaling inhibition by brassicasterol, a metabolite of ergosterol.

We previously revealed that Choreito, a traditional Kampo medicine, strongly inhibits bladder carcinogenesis promotion. We have also shown that Polyporus sclerotium, which is one of the crude drugs in Choreito, has the strongest bladder carcinogenesis inhibitory effect and that the ergosterol contained in Polyporus sclerotium is the main active component. In this study, we analyzed the mechanism by which ergosterol inhibits bladder carcinogenesis. Rats were given an N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) solution ad libitum, and then a promoter [saccharin sodium (SS), DL-tryptophan, or BHBN] was administered together with ergosterol or its metabolite, brassicasterol. The bladders were removed from rats, and the inhibitory effect on carcinogenesis promotion was evaluated by an agglutination assay with concanavalin A (Con A). Although the oral administration of ergosterol inhibited the promotion of bladder carcinogenesis with SS, the intraperitoneal administration of brassicasterol showed a stronger effect. The effect of brassicasterol on carcinogenesis promotion was observed regardless of the type of promoter. Administration of testosterone to castrated rats increased the number of cell aggregates caused by Con A. In contrast, intraperitoneal administration of brassicasterol to castrated rats treated with testosterone significantly decreased the number of cell aggregates, confirming the inhibition of bladder carcinogenesis promotion. The inhibitory effect of ergosterol on bladder carcinogenesis is due to brassicasterol, a metabolite of ergosterol. The action of brassicasterol via androgen signaling may play a role in the inhibitory effect on bladder carcinogenesis promotion.