Solidagenone from Solidago chilensis Meyen Protects against Acute Peritonitis and Lipopolysaccharide-Induced Shock by Regulating NF-κB Signaling Pathway.

Anti-inflammatory agents are widely used for the treatment of inflammatory diseases. Nevertheless, the associated side effects of the available drugs make it necessary to search for new anti-inflammatory drugs. Here, we investigated the anti-inflammatory activity of solidagenone. Initially, we observed that a single dose of 30, 60, or 90 mg/kg of solidagenone did not result in mortality or elicit any discernible signs of toxicity in mice. At the same doses, solidagenone promoted a significant reduction in the migration of neutrophils in an acute peritonitis model and decreased mortality in a lipopolysaccharide-induced endotoxic shock model. Interestingly, treatment with solidagenone conferred a protective effect against leukopenia and thrombocytopenia, hematological disorders commonly observed in sepsis conditions. In addition, treatment with all the doses of solidagenone promoted a significant reduction in nitric oxide, TNF-α, and IL-1ß levels relative to the LPS-stimulated vehicle-treated cultures. Furthermore, gene expression and in silico analyses also supported the modulation of the NF-κB pathway by solidagenone. Finally, in silico pharmacokinetics predictions indicated a favorable drugability profile for solidagenone. Taken together, the findings of the present investigation show that solidagenone exhibits significant anti-inflammatory properties in acute experimental models, potentially through the modulation of the NF-κB signaling pathway.

Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-N-acyl Hydrazones as Immunomodulatory Agents.

Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141−156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p < 0.05) the production of nitrite, TNF-α, and IL-1ß. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.

Therapeutic Applications of Physalins: Powerful Natural Weapons.

Physalins, or 16,24-cyclo-13,14-seco steroids, are compounds belonging to the class of withanolides that can be found in plants of Solanaceae family, mainly in species belonging to the genus Physalis spp., which are annual herbaceous plants widely distributed in tropical and subtropical regions of the world. Physalins are versatile molecules that act in several cell signaling pathways and activate different mechanisms of cell death or immunomodulation. A number of studies have shown a variety of actions of these compounds, including anticancer, anti-inflammatory, antiparasitic, antimicrobial, antinociceptive, and antiviral activities. Here we reviewed the main findings related to the anticancer, immunomodulatory, and antiparasitic activities of physalins and its mechanisms of action, highlighting the \challenges and future directions in the pharmacological application of physalins.

The protective effect of solidagenone from Solidago chilensis Meyen in a mouse model of airway inflammation.

Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF and IL-1ß, as well as gene expression of pro-inflammatory mediators in macrophages cultures, were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed, and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether, solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity.

Structural Design, Synthesis and Antioxidant, Antileishmania, Anti-Inflammatory and Anticancer Activities of a Novel Quercetin Acetylated Derivative.

Quercetin (Q) is a bioflavonoid with biological potential; however, poor solubility in water, extensive enzymatic metabolism and a reduced bioavailability limit its biopharmacological use. The aim of this study was to perform structural modification in Q by acetylation, thus, obtaining the quercetin pentaacetate (Q5) analogue, in order to investigate the biological potentials (antioxidant, antileishmania, anti-inflammatory and cytotoxicity activities) in cell cultures. Q5 was characterized by FTIR, 1H and 13C NMR spectra. The antioxidant potential was evaluated against the radical ABTS•+. The anti-inflammatory potential was evaluated by measuring the pro-inflammatory cytokine tumor necrosis factor (TNF) and the production of nitric oxide (NO) in peritoneal macrophages from BALB/c mice. Cytotoxicity tests were performed using the AlamarBlue method in cancer cells HepG2 (human hepatocarcinoma), HL-60 (promyelocytic leukemia) and MCR-5 (healthy human lung fibroblasts) as well as the MTT method for C6 cell cultures (rat glioma). Q and Q5 showed antioxidant activity of 29% and 18%, respectively, which is justified by the replacement of hydroxyls by acetyl groups. Q and Q5 showed concentration-dependent reductions in NO and TNF production (p < 0.05); Q and Q5 showed higher activity at concentrations > 40µM when compared to dexamethasone (20 µM). For the HL-60 lineage, Q5 demonstrated selectivity, inducing death in cancer cells, when compared to the healthy cell line MRC-5 (IC50 > 80 µM). Finally, the cytotoxic superiority of Q5 was verified (IC50 = 11 µM), which, at 50 µM for 24 h, induced changes in the morphology of C6 glioma cells characterized by a round body shape (not yet reported in the literature). The analogue Q5 had potential biological effects and may be promising for further investigations against other cell cultures, particularly neural ones.

In vitro and In Vivo Immunomodulatory Activity of Physalis angulata Concentrated Ethanolic Extract.

The need for new immunomodulatory drugs is due to the side effects associated with the prolonged use of the currently used immunomodulatory drugs. In this context, the present work aimed to investigate the immunomodulatory effect of an ethanolic concentrated extract from Physalis angulata. The cytotoxicity of samples was determined using peritoneal macrophages though the Alamar Blue assay. The immunomodulatory activity of the ethanolic extract from P. angulata on activated macrophages was determined by measurement of nitrite and cytokine production. The immunosuppressive effects of the ethanolic extract from P. angulata was evaluated on lymphocyte proliferation and cytokine production. The effects of the extract on cell cycle progression and cell death on lymphocytes were evaluated by flow cytometry. Lastly, the ethanolic extract from P. angulata was tested in vivo in toxicological tests and in models of peritonitis and delayed-type hypersensitivity response. The ethanolic extract from P. angulata decreased nitrite, interleukin-6, interleukin-12, and TNF-α production by activated macrophages without affecting the cell viability. In addition, the ethanolic extract from P. angulata inhibited lymphoproliferation and the secretion of interleukin-2, interleukin-6, and IFN-γ, and increased interleukin-4 secretion by activated splenocytes. Flow cytometry analysis in lymphocyte cultures showed that treatment with the ethanolic extract from P. angulata induces cell cycle arrest in the G1 phase followed by cell death by apoptosis. Moreover, mice treated with the extract from P. angulata at 100 or 200 mg/kg did not show signs of toxicity or alterations in serum components. Finally, the ethanolic extract from P. angulata significantly reduced neutrophil migration and reduced paw edema in bovine serum albumin-induced the delayed-type hypersensitivity response model. Our results demonstrate the potential of the ethanolic extract of P. angulata as an alternative for the treatment of immune-inflammatory diseases.

Mesenchymal Stem Cells and Atopic Dermatitis: A Review.

Mesenchymal stem/stromal cells (MSCs) are stromal-derived non-hematopoietic progenitor cells that reside in and can be expanded from various tissues sources of adult and neonatal origin, such as the bone marrow, umbilical cord, umbilical cord blood, adipose tissue, amniotic fluid, placenta, dental pulp and skin. The discovery of the immunosuppressing action of MSCs on T cells has opened new perspectives for their use as a therapeutic agent for immune-mediated disorders, including allergies. Atopic dermatitis (AD), a chronic and relapsing skin disorder that affects up to 20% of children and up to 3% of adults worldwide, is characterized by pruritic eczematous lesions, impaired cutaneous barrier function, Th2 type immune hyperactivation and, frequently, elevation of serum immunoglobulin E levels. Although, in the dermatology field, the application of MSCs as a therapeutic agent was initiated using the concept of cell replacement for skin defects and wound healing, accumulating evidence have shown that MSC-mediated immunomodulation can be applicable to the treatment of inflammatory/allergic skin disorders. Here we reviewed the pre-clinical and clinical studies and possible biological mechanisms of MSCs as a therapeutic tool for the treatment of atopic dermatitis.

Phenylpropanoids from Croton velutinus with cytotoxic, trypanocidal and anti-inflammatory activities.

This current study presents the phytochemical analysis of Croton velutinus, describing phenylpropanoids obtained from this species. The fractionation of the roots hexane extract led to the isolation of four new phenylpropanoids derivatives, velutines A-D (1-4) and three known (5-7). Their structures were established based on spectroscopic (1D-2D NMR; HRMS and IR) analysis. Cytotoxic, trypanocidal and anti-inflammatory activities of compounds 1-7 were evaluated. Only compounds 2 and 5 showed cytotoxic activity against cancer cell lines (B16F10, HL-60, HCT116, MCF-7 and HepG2), with IC50 values ranging from 6.8 to 18.3 µM and 11.1 to 18.3 µM, respectively. Compounds 2 and 5 also showed trypanocidal activity against bloodstream trypomastigotes with EC50 values of 9.0 and 9.58 µM, respectively. Finally, the anti-inflammatory potential of these compounds was evaluated on cultures of activated macrophages. All compounds exhibited concentration-dependent suppressive activity on the production of nitrite and IL-1ß by macrophages stimulated with LPS and IFN-γ. These results indicate phenylpropanoids esters (2 and 5) from C. velutinus as promising cytotoxic, trypanocidal and anti-inflammatory candidates that warrants further studies.