Treatment response in primary biliary cholangitis: The role of autoimmune hepatitis features.

INTRODUCTION AND AIM: Primary biliary cholangitis is a rare disease with scarce epidemiological data in Southern Europe. The authors aimed to evaluate treatment response in a cohort of patients. MATERIALS AND METHODS: This retrospective observational single-centre study included patients with diagnostic criteria of primary biliary cholangitis. Data on disease presentation, laboratory results, treatment and clinical endpoints were collected and analyzed. RESULTS: Fifty-three patients were included, 89% women, with mean age of 62±15 years at diagnosis. The majority was asymptomatic (49%), tested positive for antimitochondrial antibodies (96%) and had increased alkaline phosphatase (median=214U/L). 75% of the patients had liver histology and the majority were in Ludwig's stage I (42%). Autoimmune hepatitis (AIH) features were found in seven patients (13%). All were treated with ursodeoxycholic acid (UDCA) and 56% achieved biochemical response at one year; patients with AIH features exhibited steeper decreases in alkaline phosphatase (p=0.007) and reached the endpoint of 40% decrease in alkaline phosphatase more frequently (p=0.017). CONCLUSION: In conclusion a significant proportion of patients failed to achieve an adequate response to UDCA treatment. The response rate of patients with AIH features was better, which could be related to a different phenotype or to the potential impact of immunosuppressive agents.

Pigmented hepatocellular adenoma with ß-catenin activation: case report and literature review.

 Hepatocellular adenomas (HCAs) are benign liver tumors recently characterized into 4 different types according to genetic, pathological and clinical features. The prognosis is not well established yet and malignant transformation has been recently associated with ß-catenin activation. We aimed to describe a case of a pigmented HCA with ß-catenin nuclear expression and inflammatory features and to review the cases of pigmented HCAs in the literature. We report a case of a young female patient without contraceptive use, with a liver tumor diagnosis. Liver biopsy revealed diffuse expression of ß-catenin and a partial hepatic resection was performed. The histologic analysis revealed a hepatocellular tumor composed of uniform trabeculae of hepatocytes and solid areas, the later with a significant amount of black pigment highlighted by Masson-Fontana stain. Immunohistochemistry showed co-expression of C-reactive protein and serum amyloid A in the tumor. Literature review revealed that pigmented HCAs, previously reported as dark adenomas, are rare tumors. In HCAs, the presence of ß-catenin activation should be searched for due to the higher risk of malignant transformation in hepatocarcinoma. We describe a pigmented HCA with ß-catenin nuclear expression and inflammatory features being the fifth case reported so far.

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro.

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium berghei in mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

Anti-malarial activity of indole alkaloids isolated from Aspidosperma olivaceum.

BACKGROUND: Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum. METHODS: The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei. RESULTS: All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 µg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active. CONCLUSION: Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.

A comprehensive review of Pfaffia glomerata botany, ethnopharmacology, phytochemistry, biological activities, and biotechnology.

ETHNOPHARMACOLOGICAL RELEVANCE: Pfaffia glomerata (Spreng.) Pedersen, Amaranthaceae, is found in South America, mainly in Brazil, where it is considered a species of great medicinal interest owing to its popular use as a tonic, aphrodisiac, anti-inflammatory, and analgesic. These properties can be attributed to the presence of the phytosteroid, 20-Hydroxyecdysone (ß-ecdysone), the main compound found in its roots. AIM OF THE REVIEW: This review aims to provide information about the botanical characteristics, ethnomedicinal uses, the phytochemistry, the biological activities, and the biotechnology of P. glomerata, an important species to local communities and groups researching medicinal plants of South America. MATERIALS AND METHODS: The information available on P. glomerata was collected from scientific databases (ScienceDirect, PubMed/MEDLINE, SciELO, and Scopus) until June 7, 2023, using the search terms "Pfaffia glomerata", "Pfaffia glomerata (Spreng.) Pedersen", and "Brazilian ginseng". The review includes studies that evaluated the botanical, ethnopharmacological, and phytochemical aspects, biological properties, nutraceutical uses, and the application of biotechnology for improving the biosynthesis of metabolites of interest. RESULTS: A total of 207 studies were identified, with 81 articles read in full. Seventy-six studies were included for qualitative synthesis. Overall, 40 compounds belonging to different classes are presented in this review, including ecdysteroids, triterpenes, saponins, flavonoids, anthraquinones, tannins, coumarins, alkaloids, and polysaccharides. Among them, flavonoids, anthraquinones, tannins, coumarins, and alkaloids were only putatively identified. ß-Ecdysone, triterpenes, saponins, and polysaccharides are the chemical components most frequently identified and isolated from P. glomerata and possibly responsible for ethnopharmacological use and the biological activities of this species, with important in vitro and in vivo activities, such as anti-inflammatory, antidepressant, aphrodisiac, analgesic, gastroprotective, antioxidant, and prebiotic. CONCLUSIONS: This review summarizes discussions about the P. glomerata species, highlighting its ethnopharmacological, chemical, biotechnological, and nutraceutical importance. New scientific studies on this species are encouraged in the search for new therapeutic molecules with pharmaceutical potential and nutraceutical applications.

Evaluation of antitumoral and antioxidant activities of the hydroalcoholic extract and fractions obtained from the fruit pericarp of Sapindus saponaria L.

The fruits of Sapindus saponaria L., popularly known as 'saboeiro', have been used in medicine. This study evaluated the antioxidant and antitumor activities of the hydroethanolic extract (HAE) and fractions obtained from the fruit pericarp of S. saponaria. The HAE was obtained from the S. saponaria fruit pericarp by maceration; this was followed by fractionation using reversed-phase solid-phase extraction, resulting in fractions enriched with acyclic sesquiterpenic oligoglycosides (ASOG) and saponins (SAP1, and SAP2), confirmed by mass spectrometry with electrospray ionization (ESI-QTOF-MS). The greatest citotoxic activity was observed with the SAP1 fraction against the CaCo2 cell line with a GI50 of 8.1 µg mL-1, while the SAP2 fraction had a GI50 of 13.6 µg mL-1 against CaCo2. The HAE demonstrated the greatest antioxidant activity. S. saponaria has potential therapeutic use in the pharmaceutical industry as a natural anti-oxidant or antitumor product.

Production of exopolysaccharide from Klebsiella oxytoca: Rheological, emulsifying, biotechnological properties, and bioremediation applications.

Bacteria can synthesize a broad spectrum of multifunctional polysaccharides including extracellular polysaccharides (EPS). Bacterial EPS can be utilized in the food, pharmaceutical, and biomedical areas owing to their physical and rheological properties in addition to generally presenting low toxicity. From an ecological viewpoint, EPS are biodegradable and environment compatible, offering several advantages over synthetic compounds. This study investigated the EPS produced by Klebsiella oxytoca (KO-EPS) by chemically characterizing and evaluating its properties. The monosaccharide components of the KO-EPS were determined by HPLC coupled with a refractive index detector and GC-MS. The KO-EPS was then analyzed by methylation analysis, FT-IR and NMR spectroscopy to give a potential primary structure. KO-EPS demonstrated the ability to stabilize hydrophilic emulsions with various hydrophobic compounds, including hydrocarbons and vegetable and mineral oils. In terms of iron chelation capacity, the KO-EPS could sequester 41.9 % and 34.1 % of the most common iron states, Fe2+ and Fe3+, respectively. Moreover, KO-EPS exhibited an improvement in the viscosity of aqueous dispersion, being proportional to the increase in its concentration and presenting a non-Newtonian pseudoplastic flow behavior. KO-EPS also did not present a cytotoxic effect indicating that the KO-EPS could have potential applications as a natural thickener, bioemulsifier, and bioremediation agent.

Peptide PaDBS1R6 has potent antibacterial activity on clinical bacterial isolates and integrates an immunomodulatory peptide fragment within its sequence.

BACKGROUND: Resistant infectious diseases caused by gram-negative bacteria are among the most serious worldwide health problems. Antimicrobial peptides (AMPs) have been explored as promising antibacterial, antibiofilm, and anti-infective candidates to address these health challenges. MAJOR CONCLUSIONS: Here we report the potent antibacterial effect of the peptide PaDBS1R6 on clinical bacterial isolates and identify an immunomodulatory peptide fragment incorporated within it. PaDBS1R6 was evaluated against Acinetobacter baumannii and Escherichia coli clinical isolates and had minimal inhibitory concentration (MIC) values from 8 to 32 µmol L-1. It had a rapid bactericidal effect, with eradication showing within 3 min of incubation, depending on the bacterial strain tested. In addition, PaDBS1R6 inhibited biofilm formation for A. baumannii and E. coli and was non-toxic toward healthy mammalian cells. These findings are explained by the preference of PaDBS1R6 for anionic membranes over neutral membranes, as assessed by surface plasmon resonance assays and molecular dynamics simulations. Considering its potent antibacterial activity, PaDBS1R6 was used as a template for sliding-window fr agmentation studies (window size = 10 residues). Among the sliding-window fragments, PaDBS1R6F8, PaDBS1R6F9, and PaDBS1R6F10 were ineffective against any of the bacterial strains tested. Additional biological assays were conducted, including nitric oxide (NO) modulation and wound scratch assays, and the R6F8 peptide fragment was found to be active in modulating NO levels, as well as having strong wound healing properties. GENERAL SIGNIFICANCE: This study proposes a new concept whereby peptides with different biological properties can be derived by the screening of fragments from within potent AMPs.

Lentinus crinitus: Traditional use, phytochemical and pharmacological activities, and industrial and biotechnological applications.

The saprophytic basidiomycete Lentinus crinitus (L.) Fr is a Brazilian native fungus with pantropical occurrence. L. crinitus produces edible fruiting bodies with medicinal, nutritional, and biotechnological applications. The compounds from fungal fruiting bodies can be applied to the preparation of products in the food, cosmetic, biomedical, and pharmaceutical industries. Our aim was to review the literature on L. crinitus concerning its botanical description, geographical distribution, phytochemistry, pharmacological properties, nutritional value, and biotechnology potential (in vitro cultivation and enzyme production). Scientific search engines, including ScienceDirect, CAPES Journals Portal, Google Scholar, PubMed, SciELO, MEDLINE, LILACS, and SciFinder, were consulted to gather data on L. crinitus. The present review is an up-to-date and comprehensive analysis of the phytochemical compounds, phytopharmacological activities, and biotechnological value of L. crinitus. Extracts from L. crinitus have been reported to exhibit numerous in vitro pharmacological activities such as antioxidant, antifungal, antibacterial, antiviral, and anticancer. The substances in these extracts belong to different classes of chemical compounds such as polysaccharides, fatty acids, terpenes, phenolic acids, and flavonoids. Reviews on Brazilian native fungi are of great importance for scientific knowledge, with great applicability as a mirror for species of the same family. The ethnobotanical, phytochemical, pharmacological, ethnomedicinal, and biotechnological properties of L. crinitus highlighted in this review provide information for future studies and commercial exploitation, and reveal that this fungus has enormous potential for pharmaceutical, nutraceutical, biotechnological, and ecological applications.

Inulin extraction from Stevia rebaudiana roots in an autoclave.

Inulin is a polymer of d-fructose, characterized by the presence of a terminal glucose, and are a major component of Stevia rebaudiana roots. This type of polymer has nutritional properties and technological applications, such as fat substitutes in low-calorie foods and as the coating of pharmaceuticals. The aim of this study was to evaluate an alternative method for inulin extraction, in terms of extraction time and yield, since the traditional method of extraction under reflux is both time and energy consuming. Using the response surface methodology (RSM) with Box-Behnken design it was observed that the alternative extraction method using autoclave presented similar yields to the reflux-based method, but with a shorter extraction time, 121 °C by 17.41 min 1H Nuclear Magnetic Resonance and Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-ToF-MS) analysis showed that inulin crude extract from S. rebaudiana roots obtained by autoclave extraction had a higher degree of polymerization when compared to those obtained by the traditional method. Thus, it is concluded that the proposed method using an autoclave is a faster alternative for the extraction of inulin.

Biosynthesis of indole-3-acetic acid by new Klebsiella oxytoca free and immobilized cells on inorganic matrices.

While many natural and synthetic compounds exhibit auxin-like activity in bioassays, indole-3-acetic acid (IAA) is recognized as the key auxin in most plants. IAA has been implicated in almost all aspects of plant growth and development and a large array of bacteria have been reported to enhance plant growth. Cells of Klebsiella oxytoca isolated from the rhizosphere of Aspidosperma polyneuron and immobilized by adsorption on different inorganic matrices were used for IAA production. The matrices were prepared by the sol-gel method and the silica-titanium was the most suitable matrix for effective immobilization. In operational stability assays, IAA production was maintained after four cycles of production, obtaining 42.80 ± 2.03 µg mL(-1) of IAA in the third cycle, which corresponds to a 54% increase in production in relation to the first cycle, whereas free cells began losing activity after the first cycle. After 90 days of storage at 4°C the immobilized cells showed the slight reduction of IAA production without significant loss of activity.

Thalidomide-induced acute cholestatic hepatitis: case report and review of the literature.

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Cereus peruvianus Mill. (Cactaceae) as a source of natural antioxidants: Phenolic compounds and antioxidant activity of cladode extracts in two collection periods.

The economic potential of the cactus species Cereus peruvianus Mill. (syn. C. hildmannianus K. Schum.) has already been demonstrated through the generation of products and patents. However, the phenolic compounds and antioxidant activity have not yet been evaluated. The aim of our study was to determine the total phenolic compounds, evaluate the antioxidant activity and characterize the phenolic compounds of cladode extracts from C. peruvianus grown in the southern region of Brazil, in two collection periods. Higher total content of phenolic compounds and antioxidant activity were detected in the cladode extract collected in 2016 than in the cladode extract collected in 2015. The profile of phenolic compounds identified five flavonoids that had not previously been reported in species of the genus Cereus. The phenolic compounds linked to antioxidant activities identified in the cladode extract from C. peruvianus support the use of this species in human food as a source of natural antioxidants.

Low-cost alternative for the bioproduction of bioactive phenolic compounds of callus cultures from Cereus hildmannianus (K.) Schum.

The aim of this study was to establish a sustainable alternative callus culture of Cereus hildmannianus for the production and bioactive determination of phenolic compounds from this species. The conventional callus was cultivated using agar and Murashige and Skoog (MS) medium, while for the alternative culture the agar was replaced with a cotton support covered with filter paper and MS medium (incubated at 32 °C with photoperiod of 16 h), and the morphological characteristics and growth index were assessed (8 weeks). Extracts were obtained by maceration followed by partition, characterized by nuclear magnetic resonance - NMR and ultra-high performance liquid chromatography - UHPLC, quantified (phenolic compounds) by UV-Vis methods, and their antioxidant, antitumor activities, as well as cytotoxicity, were evaluated. The establishment of an alternative callus culture was carried out successfully. Characteristic signals of phenolic compounds were determined by NMR, and 46 compounds with fragment ions were identified using UHPLC analysis. The highest concentrations of phenolic compounds, and greatest antioxidant and antitumor activities, were obtained with the dichloromethane fractions of both callus tissue cultures, which were not cytotoxic. The callus culture from C. hildmannianus has shown promise as a source for the sustainable production of phenolic compounds with antioxidant and antiproliferative activities and thus, has potential use as a natural antitumor product.

Antimicrobial and antioxidant activities of secondary metabolites from endophytic fungus Botryosphaeria fabicerciana (MGN23-3) associated to Morus nigra L.

This study was to evaluate the biological activity of the extract of Botryosphaeria fabicerciana isolated from leaves of Morus nigra. The volatile compounds from the crude extract were analysed by GC-MS which demonstrate that mellein and ß-orcinaldehyde were are the major compounds. The best minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extract was observed against Gram-positive bacteria, with a MIC of 15.6 µg/mL towards B. cereus and MIC of 62.5 µg/mL towards S. aureus and B. subtilis. MBC values of 31.25 µg/mL, 62.5 µg/mL, and 250 µg/mL were observed towards B. cereus, B. subtilis, and S. aureus, respectively. The cytotoxicity analyses showed CC50 of 115 µg/mL. The crude extract showed antioxidant activity by the DPPH, ABTS, and FRAP assays. Therefore, the extract of the endophytic fungus presented biotechnological potential as an antibacterial and antioxidant agent.

Cereus hildmannianus (K.) Schum. (Cactaceae): Ethnomedical uses, phytochemistry and biological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Cereus hildmannianus (K.) Schum. (syn. C. peruvianus) is a native medicinal plant in the Neotropical region. C. hildmannianus cladodes extracts are used in folk medicine for weight loss, reducing cholesterol, low-density lipoprotein (LDL) levels, as diuretic and cardiotonic, and to treat various diseases, including pulmonary disorders, rheumatism, and in topical treatment for wounds and lithiasis. Fruits and flowers of C. hildmmanianus have high nutritional value. AIM OF THE REVIEW: In this review, previous reports on C. hildmannianus (syn. C. peruvianus) concerning its botanical description, geographical distribution, ethnomedicinal use, phytochemistry, in vitro and in vivo pharmacological properties, food benefits and plant biotechnology were summarized. MATERIALS AND METHODS: Scientific search engines, including ScienceDirect, Capes Journals Portal, Google Scholar, PubMed, Scielo, and Scifinder, were consulted to gather data on C. hildmannianus. The present review is an up-to-date and comprehensive analysis of phytochemical compounds, ethnomedicinal uses, phytopharmacological activities, and food value of cladodes, flowers, fruits, seeds, and tissue culture from C. hildmannianus. RESULTS: In traditional medicine, C.hildmannianus is used to treat various diseases, including pulmonary disorders, rheumatism, and in topical treatment for wounds and lithiasis. The extracts from the cladodes of C. hildmannianus exhibited numerous in vitro and in vivo pharmacological activities such as gastroprotective, antioxidant, antifungal, ovicidal, hemagglutinating and slimming, and anticancer activity. These extracts' substances belong to different classes of chemical compounds such as fatty acids, polysaccharides, terpenes, alkaloids, phenolic acids, and flavonoids CONCLUSIONS: Ethnomedicinal surveys have indicated the use of C. hildmannianus, an important medicinal plant in South America, for the treatment of various diseases. The ethnobotanical, phytochemical, pharmacological, and ethnomedicinal properties from various morphological parts of the plant of C. hildmannianus were highlighted in this review, which provides information for future studies, commercial exploration and reveals that this plant has a huge potential for pharmaceutical and nutraceutical applications.