Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of... more Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development. Keywords Acetohydroxamate. Drug development. Cancer. Melanoma Abbreviations ATCC American Type Culture Collection CMC iPS Cardiomyocytes derived from induced pluripotent stem cells FDA Food and Drug Administration GI 50 Growth inhibition 50% HDAC Histone deacetylase MMP Mitochondrial membrane potential MTT 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide NHDF Non-tumoural human dermal fibroblasts NHLF Non-tumoural human lung fibroblasts SrB Sulphorhodamine B TCA Trichloroacetic acid TGI Total growth inhibition UPLC-MS/MS Ultra-performance liquid chromatography-tandem mass spectrometry
Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ... more Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and...
Baumgart et al., 2010). Another major type of inflammatory bowel disease known as ulcerative coli... more Baumgart et al., 2010). Another major type of inflammatory bowel disease known as ulcerative colitis was described as a pathological entity through studies conducted by Samuel Wilks, an English physician, in 1859 (Wilks, 1859). In 1862, Samuel Osborne Habershon, another Contents lists available at ScienceDirect
Pterodon emarginatus Vogel is a medicinal plant commonly used in Brazilian traditional medicine a... more Pterodon emarginatus Vogel is a medicinal plant commonly used in Brazilian traditional medicine as a folk therapy due to its immunosuppressive, anti-inflammatory, anti-rheumatic, healing, tonic and depurative activities. The essential oil (EO) of Pterodon emarginatus is composed of volatile aromatic terpenes and phenyl propanoids, mainly, β-elemene and β-caryophyllene sesquiterpenes. Here we reported the effects and some underlying mechanisms of action of EO during murine model of MS, the experimental autoimmune encephalomyelitis (EAE). EO (50 and 100 mg/kg) was orally administered during the entire period of development of EAE (preventive treatment, day 0-25). In vitro and in vivo immunological responses were evaluated by ELISA, immunohistochemistry, immunofluorescence and flow cytometry. We provide evidence that EO of Pterodon emarginatus (100 mg/kg, p.o.) significantly attenuates neurological signs and also the development of EAE. Furthermore, at the same dose EO consistently inhibited Th1 cell-mediated immune response and upregulated Treg response in vitro. Moreover, the EO inhibited both microglial activation and expression of iNOS, associated with inhibition of axonal demyelization and neuronal death during the development of the disease. This is the first experimental evidence showing that oral administration of EO consistently reduces and limits the severity and development of EAE, mainly, through the modulation of Th1/Treg immune balance, and might represent a helpful new tool for control immunoinflammatory conditions, such as MS.
Scope: We investigated the protective effect of the flavonoid myricitrin in dextran sulfate sodiu... more Scope: We investigated the protective effect of the flavonoid myricitrin in dextran sulfate sodium (DSS) induced colitis as promising candidate for the treatment of ulcerative colitis which is considered an important worldwide public health problem. Methods and results: Male CD1 mice were provided with a solution of filtered water containing 3% w/v DSS ad libitum over a 5-day period followed by 2 days with normal drinking water. Myricitrin was administered orally, once a day, at the doses 1, 3, and 10 mg/kg of body weight. At the end of day 7th, the animals were euthanized and the colonic tissue was collected to be analyzed by RT-PCR, immunohistochemistry and Western blot. Our results showed that oral treatment with myricitrin exerts consistent anti-inflammatory action in DSS-induced acute colitis in mice by the inhibition of the Akt/phosphatidylinositol-3 kinase-dependent phosphorylation. Consequently, the phosphorylation of mitogen-activated protein kinases (MAPK) p38, extracellular signal-regulated protein kinase (ERK1/2), and c-Jun N-terminal kinase and of the nuclear factor B (NF-B) was reduced and prevented an increase in the cytokines/chemokines levels. Conclusion: Together, these data reveal that the anti-inflammatory effect of myricitrin in DSSinduced colitis in mice is likely associated with its ability to prevent the activation of upstream kinases, such as phosphatidylinositol-3 kinase-dependent Akt, NF-B, and mitogen-activated protein kinase.
Background: The tetracyclic triterpene euphol is the main constituent found in the sap of Euphorb... more Background: The tetracyclic triterpene euphol is the main constituent found in the sap of Euphorbia tirucalli. This plant is widely known in Brazilian traditional medicine for its use in the treatment of several kinds of cancer, including leukaemia, prostate and breast cancers. Here, we investigated the effect of euphol on experimental models of colitis and the underlying mechanisms involved in its action. Methodology/Principal Findings: Colitis was induced in mice either with dextran sulfate sodium (DSS) or with 2,4,6trinitrobenzene sulfonic acid (TNBS), and the effect of euphol (3, 10 and 30 mg/kg) on colonic injury was assessed. Proinflammatory mediators and cytokines were measured by immunohistochemistry, enzyme-Linked immunoabsorbent assay (ELISA), real time-polymerase chain reaction (RT-PCR) and flow cytometry. Preventive and therapeutic oral administration of euphol attenuated both DSS-and TNBS-induced acute colitis as observed by a significant reduction of the disease activity index (DAI), histological/microscopic damage score and myeloperoxidase (MPO) activity in colonic tissue. Likewise, euphol treatment also inhibited colon tissue levels and expression of IL-1b, CXCL1/KC, MCP-1, MIP-2, TNF-a and IL-6, while reducing NOS2, VEGF and Ki67 expression in colonic tissue. This action seems to be likely associated with inhibition of activation of nuclear factor-kB (NF-kB). In addition, euphol decreased LPS-induced MCP-1, TNF-a, IL-6 and IFN-c, but increased IL-10 secretion from bone marrow-derived macrophages in vitro. Of note, euphol, at the same schedule of treatment, markedly inhibited both selectin (P-and E-selectin) and integrin (ICAM-1, VCAM-1 and LFA-1) expression in colonic tissue. Conclusions/Significance: Together, these results clearly demonstrated that orally-administered euphol, both preventive or therapeutic treatment were effective in reducing the severity of colitis in two models of chemically-induced mouse colitis and suggest this plant-derived compound might be a potential molecule in the management of inflammatory bowel diseases.
Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia o... more Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia obscurata provided a highly branched glucomannan fraction (GM), whose chemical structure was determined. This was based on monosaccharide composition, methylation, partial acid hydrolysis, and NMR spectroscopic analysis. It consisted of a main chain of (1 ? 6)-linked aD -mannopyranosyl units, almost all being substituted at O-2 with aD -glucopyranosyl, aD -mannopyranosyl, and 4-O-substituted aD -mannopyranosyl groups. Intra-peritoneal administration of this GM induced a marked and dose-dependent inhibition of acetic acid-induced visceral pain with an ID 50 of 0.6 (0.2-2.0) mg/kg and inhibition of 88 ± 4%. It also reduced leukocyte migration by 58 ± 4%, but did not alter plasmatic extravasation to the peritoneal cavity. The results suggest that the glucomannan from the H. obscurata might have potential for antinociceptive and anti-inflammatory utilization.
Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitati... more Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. Here, we assessed the effects and the underlying mechanisms of action of euphol in preventing inflammatory and neuropathic pain. Oral treatment with euphol (30 and 100 mg/kg) reduced carrageenan-induced mechanical hyperalgesia. Likewise, euphol given through the spinal and intracerebroventricular routes prevented mechanical hyperalgesia induced by carrageenan. Euphol consistently blocked the mechanical hyperalgesia induced by complete Freund's adjuvant, keratinocytederived chemokine, interleukin-1b, interleukin-6 and tumor necrosis factor-alpha associated with the suppression of myeloperoxidase activity in the mouse paw. Oral treatment with euphol was also effective in preventing the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels and mRNA of cytokines/chemokines in both paw and spinal cord tissues following i.pl. injection of complete Freund's adjuvant. In addition, the pre-treatment with either CB 1 R or CB 2 R antagonists, as well as the knockdown gene of the CB 1 R and CB 2 R, significantly reversed the antinociceptive effect of euphol. Interestingly, even in higher doses, euphol did not cause any relevant action in the central nervous system. Considering that few drugs are currently available for the treatment of chronic pain states, the present results provided evidence that euphol constitutes a promising molecule for the management of inflammatory and neuropathic pain states.
Bradykinin B 1 and B 2 receptors Multiple sclerosis (MS) is a progressive, demyelinating inflamma... more Bradykinin B 1 and B 2 receptors Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B 1 (B 1 R) and B 2 (B 2 R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B 1 R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B 1 R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B 1 R mRNA and protein level in the mouse spinal cord 14 days after EAE immunization. Blockade of B 1 R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B 1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B 1 R and B 2 R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B 1 R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B 1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B 1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.
The pentacyclic triterpene ␣,-amyrin has been previously reported as an effective compound in th... more The pentacyclic triterpene ␣,-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that ␣,-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the ␣,-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with ␣,-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, ␣,-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-␣, interleukin (IL)-1 and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the ␣,-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1),  2-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB 1), but not CB 2 , pharmacological blockade significantly reversed the beneficial effects of ␣,-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of ␣,-amyrintreated mice. Altogether, these results suggest that the ␣,-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.
It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fat... more It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid–derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)– and 2,4,6-trinitrobenzenesulfonic acid–induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid–induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. MaR1 treatment also induced a significant decrease in levels of inflammatory mediators, such as IL-1β, TNF-α, IL-6, and IFN-γ, in the acute protocol, as well as IL-1β and IL-6, but not TNF-α and INF-γ, in the chronic DSS colitis protocol. Additionally, MaR1 decreased ICAM-1 mRNA expression in both the acute and chronic protocols of DSS-induced col...
International Journal of Biological Macromolecules, 2012
-d-Glucan, a polysaccharide isolated from an edible mushroom Pleurotus pulmonarius (Fr.) Quel., ... more -d-Glucan, a polysaccharide isolated from an edible mushroom Pleurotus pulmonarius (Fr.) Quel., presented antinociceptive activity in mice. This study evaluated the involvement of transient receptor potential (TRP) channels and protein kinase C (PKC) on antinociceptive effect of a (1→3),(1→6)-linked -d-glucan (GL) in mice. Intraperitoneal administration of GL potently inhibited nociceptive responses induced by intraplantar injections of capsaicin, cinnamaldehyde, menthol, acidified saline and phorbol myristate acetate (PMA). Moreover, Western blot analysis revealed that GL treatment also prevented PMA-induced PKC activation. Collectively, present results demonstrate that GL could constitute an attractive molecule of interest for the development of new analgesic drugs.
Inflammation underlies the development and progression of a number of skin disorders including ps... more Inflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100 mg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPAinduced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol's ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCa and PKCd isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component.
A glucan was extracted with hot water from the basidiomycete Pleurotus pulmonarius and shown to h... more A glucan was extracted with hot water from the basidiomycete Pleurotus pulmonarius and shown to have a (1→3)linked β-D-glucopyranosyl main-chain substituted at O-6 of every third unit by single β-D-glucopyranosyl nonreducing end units. This was shown by mono-and bidimensional nuclear magnetic resonance (NMR) spectroscopy, methylation analysis, and a controlled Smith degradation. The glucan was tested for its effects on the acetic acid-induced writhing reaction in mice, a typical model for quantifying inflammatory pain. It caused a marked and dose-dependent anti-inflammatory response, demonstrated by the inhibition of leukocyte migration to injured tissues (82 ± 6%) with an ID 50 of 1.19 (0.74-1.92) mg/kg. Furthermore, animals previously treated with the glucan (3 mg/kg i.p.), showed a reduction of 85± 5% of writhes, after receiving the acetic acid injection. Furthermore, in the formalin test, the glucan (3-30 mg/kg, i.p.) also caused significant inhibition of both the early (neurogenic pain) and the late phases (inflammatory pain) of formalin-induced licking. However, it was more potent and effective in relation to the late phase of the formalin test, with mean ID 50 values for the neurogenic and the inflammatory phases of N 30 and 12.9 (6.7-24.6) mg/kg and the inhibitions observed were 43± 5% and 96± 4%, respectively. These data showed that the glucan had potent anti-inflammatory and analgesic (antinociceptive) activities, possibly by the inhibition of pro-inflammatory cytokines.
Canadian Journal of Physiology and Pharmacology, 2010
This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stim... more This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stimulation of the lower abdomen and hind paw associated with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The frequency of withdrawal responses to 10 consecutive applications of von Frey probes to the lower abdomen (0.07 g) or hind paw (0.4 g) was assessed in male BALB/c mice before and after intracolonic TNBS injection (0.5 mg in 100 µL of 35% ethanol). TNBS (0.5 mg) induced referred mechanical hyperalgesia in the abdomen (response frequencies at 24 h: saline 11.0% ± 3.1%, TNBS 48.0% ± 6.9%) and hind paw (frequencies at 24 h: saline 12.5% ± 4.7%, TNBS 47.1% ± 7.1%) lasting up to 72 and 48 h, respectively. Mice receiving 1.0 or 1.5 mg TNBS assumed hunch-backed postures and became immobile during abdominal mechanical stimulation, suggestive of excessive ongoing pain. Atrasentan (ETA receptor antagonist; 10 and 30 mg/kg, i.v.) given 24 h after TNBS abolished hind paw and abdomi...
Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory di... more Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by downregulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B 1 R mRNA expression occurred selectively in the hippocampus, whereas protein level was upregulated in both brain areas. Genetic deletion of kinin B 1 R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-c in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B 1 R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.
Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a ... more Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a synthetic compound derivative from natural precursor α, β-amyrin, against nociceptive response induced by acetic acid and formalin. Here, we investigated some of the mechanisms of action underlying the antinociceptive effects of amyrin octanoate. Amyrin octanoate given intraperitoneally (0.001-1 mg /kg) or intrathecally (10-1000 ng /site) caused dose-dependent and long-lasting inhibition of acetic acid-induced visceral nociception, with mean ID 50 values of 0.003 (0.001-0.005) mg/kg and 122.4 (60.8-246.6) ng/site, respectively. In the capsaicin-and glutamate-induced paw licking, amyrin octanoate caused significant and dose-dependent inhibition of both nociceptive responses, with ID 50 values of 1.36 and 0.04 mg/kg, respectively. Furthermore, amyrin octanoate also reduced significantly the nociception caused by intrathecal injection of glutamate, substance P and capsaicin, with inhibitions of 36 ± 11%, 67 ± 10% and 78 ± 5%, respectively. The antinociception caused by amyrin octanoate in the acetic acid test was significantly attenuated by neonatal pretreatment of mice with capsaicin, but seems to involve mechanisms independent of G i/o protein, opioidergic, serotonergic, noradrenergic and cholinergic system, since it was not affected by pertussis toxin, naloxone, yohimbine, mecamylamine or atropine. In addition, amyrin octanoate reduced thermal and mechanical hyperalgesia induced by bradykinin and phorbol myristate acetate in rats, without affecting similar responses caused by prostaglandin E 2. Taken together, the present results shown that octanoate amyrin produces antinociceptive and antihyperalgesic effects, through an interaction with capsaicin-sensitive fibers and the inhibition of the PKC signaling pathway.
Fucogalactans from Agaricus brasiliensis (EPF-Ab) and A. bisporus var. hortensis (EPF-Ah) were pr... more Fucogalactans from Agaricus brasiliensis (EPF-Ab) and A. bisporus var. hortensis (EPF-Ah) were prepared via by aqueous extraction and a purification procedure. EPF-Ab had M(w) 19.4 x 10(3)g/mol and EPF-Ah M(w) 31.1 x 10(3)g/mol. EPF-Ab had a (1-->6)-linked alpha-D-Galp main-chain partially substituted in O-2 by non-reducing end-units of alpha-L-Fucp. EPF-Ah had a similar main-chain with O-2 substitution, but was partially methylated at HO-3, as well as having 2.5% non-reducing end-units of beta-D-Gal. In mice, EPF-Ab gave 39% antinociceptive inhibition (ID(50)>100mg/kg) and no anti-inflammatory activity. EPF-Ah also gave an inhibition of 39% at ID(50) 0.33 mg/kg and also inhibited by 61% (ID(50) 5.0mg/kg) total cell migration and by 32% peritoneal capillary permeability, which is related to the anti-inflammatory effect. The small differences in chemical structure in these polysaccharides thus modified their biological activities.
Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of... more Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development. Keywords Acetohydroxamate. Drug development. Cancer. Melanoma Abbreviations ATCC American Type Culture Collection CMC iPS Cardiomyocytes derived from induced pluripotent stem cells FDA Food and Drug Administration GI 50 Growth inhibition 50% HDAC Histone deacetylase MMP Mitochondrial membrane potential MTT 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide NHDF Non-tumoural human dermal fibroblasts NHLF Non-tumoural human lung fibroblasts SrB Sulphorhodamine B TCA Trichloroacetic acid TGI Total growth inhibition UPLC-MS/MS Ultra-performance liquid chromatography-tandem mass spectrometry
Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ... more Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and...
Baumgart et al., 2010). Another major type of inflammatory bowel disease known as ulcerative coli... more Baumgart et al., 2010). Another major type of inflammatory bowel disease known as ulcerative colitis was described as a pathological entity through studies conducted by Samuel Wilks, an English physician, in 1859 (Wilks, 1859). In 1862, Samuel Osborne Habershon, another Contents lists available at ScienceDirect
Pterodon emarginatus Vogel is a medicinal plant commonly used in Brazilian traditional medicine a... more Pterodon emarginatus Vogel is a medicinal plant commonly used in Brazilian traditional medicine as a folk therapy due to its immunosuppressive, anti-inflammatory, anti-rheumatic, healing, tonic and depurative activities. The essential oil (EO) of Pterodon emarginatus is composed of volatile aromatic terpenes and phenyl propanoids, mainly, β-elemene and β-caryophyllene sesquiterpenes. Here we reported the effects and some underlying mechanisms of action of EO during murine model of MS, the experimental autoimmune encephalomyelitis (EAE). EO (50 and 100 mg/kg) was orally administered during the entire period of development of EAE (preventive treatment, day 0-25). In vitro and in vivo immunological responses were evaluated by ELISA, immunohistochemistry, immunofluorescence and flow cytometry. We provide evidence that EO of Pterodon emarginatus (100 mg/kg, p.o.) significantly attenuates neurological signs and also the development of EAE. Furthermore, at the same dose EO consistently inhibited Th1 cell-mediated immune response and upregulated Treg response in vitro. Moreover, the EO inhibited both microglial activation and expression of iNOS, associated with inhibition of axonal demyelization and neuronal death during the development of the disease. This is the first experimental evidence showing that oral administration of EO consistently reduces and limits the severity and development of EAE, mainly, through the modulation of Th1/Treg immune balance, and might represent a helpful new tool for control immunoinflammatory conditions, such as MS.
Scope: We investigated the protective effect of the flavonoid myricitrin in dextran sulfate sodiu... more Scope: We investigated the protective effect of the flavonoid myricitrin in dextran sulfate sodium (DSS) induced colitis as promising candidate for the treatment of ulcerative colitis which is considered an important worldwide public health problem. Methods and results: Male CD1 mice were provided with a solution of filtered water containing 3% w/v DSS ad libitum over a 5-day period followed by 2 days with normal drinking water. Myricitrin was administered orally, once a day, at the doses 1, 3, and 10 mg/kg of body weight. At the end of day 7th, the animals were euthanized and the colonic tissue was collected to be analyzed by RT-PCR, immunohistochemistry and Western blot. Our results showed that oral treatment with myricitrin exerts consistent anti-inflammatory action in DSS-induced acute colitis in mice by the inhibition of the Akt/phosphatidylinositol-3 kinase-dependent phosphorylation. Consequently, the phosphorylation of mitogen-activated protein kinases (MAPK) p38, extracellular signal-regulated protein kinase (ERK1/2), and c-Jun N-terminal kinase and of the nuclear factor B (NF-B) was reduced and prevented an increase in the cytokines/chemokines levels. Conclusion: Together, these data reveal that the anti-inflammatory effect of myricitrin in DSSinduced colitis in mice is likely associated with its ability to prevent the activation of upstream kinases, such as phosphatidylinositol-3 kinase-dependent Akt, NF-B, and mitogen-activated protein kinase.
Background: The tetracyclic triterpene euphol is the main constituent found in the sap of Euphorb... more Background: The tetracyclic triterpene euphol is the main constituent found in the sap of Euphorbia tirucalli. This plant is widely known in Brazilian traditional medicine for its use in the treatment of several kinds of cancer, including leukaemia, prostate and breast cancers. Here, we investigated the effect of euphol on experimental models of colitis and the underlying mechanisms involved in its action. Methodology/Principal Findings: Colitis was induced in mice either with dextran sulfate sodium (DSS) or with 2,4,6trinitrobenzene sulfonic acid (TNBS), and the effect of euphol (3, 10 and 30 mg/kg) on colonic injury was assessed. Proinflammatory mediators and cytokines were measured by immunohistochemistry, enzyme-Linked immunoabsorbent assay (ELISA), real time-polymerase chain reaction (RT-PCR) and flow cytometry. Preventive and therapeutic oral administration of euphol attenuated both DSS-and TNBS-induced acute colitis as observed by a significant reduction of the disease activity index (DAI), histological/microscopic damage score and myeloperoxidase (MPO) activity in colonic tissue. Likewise, euphol treatment also inhibited colon tissue levels and expression of IL-1b, CXCL1/KC, MCP-1, MIP-2, TNF-a and IL-6, while reducing NOS2, VEGF and Ki67 expression in colonic tissue. This action seems to be likely associated with inhibition of activation of nuclear factor-kB (NF-kB). In addition, euphol decreased LPS-induced MCP-1, TNF-a, IL-6 and IFN-c, but increased IL-10 secretion from bone marrow-derived macrophages in vitro. Of note, euphol, at the same schedule of treatment, markedly inhibited both selectin (P-and E-selectin) and integrin (ICAM-1, VCAM-1 and LFA-1) expression in colonic tissue. Conclusions/Significance: Together, these results clearly demonstrated that orally-administered euphol, both preventive or therapeutic treatment were effective in reducing the severity of colitis in two models of chemically-induced mouse colitis and suggest this plant-derived compound might be a potential molecule in the management of inflammatory bowel diseases.
Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia o... more Successive aqueous and alkaline extraction of the thallus of the lichenized fungus Heterodermia obscurata provided a highly branched glucomannan fraction (GM), whose chemical structure was determined. This was based on monosaccharide composition, methylation, partial acid hydrolysis, and NMR spectroscopic analysis. It consisted of a main chain of (1 ? 6)-linked aD -mannopyranosyl units, almost all being substituted at O-2 with aD -glucopyranosyl, aD -mannopyranosyl, and 4-O-substituted aD -mannopyranosyl groups. Intra-peritoneal administration of this GM induced a marked and dose-dependent inhibition of acetic acid-induced visceral pain with an ID 50 of 0.6 (0.2-2.0) mg/kg and inhibition of 88 ± 4%. It also reduced leukocyte migration by 58 ± 4%, but did not alter plasmatic extravasation to the peritoneal cavity. The results suggest that the glucomannan from the H. obscurata might have potential for antinociceptive and anti-inflammatory utilization.
Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitati... more Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. Here, we assessed the effects and the underlying mechanisms of action of euphol in preventing inflammatory and neuropathic pain. Oral treatment with euphol (30 and 100 mg/kg) reduced carrageenan-induced mechanical hyperalgesia. Likewise, euphol given through the spinal and intracerebroventricular routes prevented mechanical hyperalgesia induced by carrageenan. Euphol consistently blocked the mechanical hyperalgesia induced by complete Freund's adjuvant, keratinocytederived chemokine, interleukin-1b, interleukin-6 and tumor necrosis factor-alpha associated with the suppression of myeloperoxidase activity in the mouse paw. Oral treatment with euphol was also effective in preventing the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels and mRNA of cytokines/chemokines in both paw and spinal cord tissues following i.pl. injection of complete Freund's adjuvant. In addition, the pre-treatment with either CB 1 R or CB 2 R antagonists, as well as the knockdown gene of the CB 1 R and CB 2 R, significantly reversed the antinociceptive effect of euphol. Interestingly, even in higher doses, euphol did not cause any relevant action in the central nervous system. Considering that few drugs are currently available for the treatment of chronic pain states, the present results provided evidence that euphol constitutes a promising molecule for the management of inflammatory and neuropathic pain states.
Bradykinin B 1 and B 2 receptors Multiple sclerosis (MS) is a progressive, demyelinating inflamma... more Bradykinin B 1 and B 2 receptors Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B 1 (B 1 R) and B 2 (B 2 R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B 1 R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B 1 R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B 1 R mRNA and protein level in the mouse spinal cord 14 days after EAE immunization. Blockade of B 1 R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B 1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B 1 R and B 2 R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B 1 R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B 1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B 1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.
The pentacyclic triterpene ␣,-amyrin has been previously reported as an effective compound in th... more The pentacyclic triterpene ␣,-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that ␣,-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the ␣,-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with ␣,-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, ␣,-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-␣, interleukin (IL)-1 and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the ␣,-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1),  2-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB 1), but not CB 2 , pharmacological blockade significantly reversed the beneficial effects of ␣,-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of ␣,-amyrintreated mice. Altogether, these results suggest that the ␣,-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.
It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fat... more It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid–derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)– and 2,4,6-trinitrobenzenesulfonic acid–induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid–induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. MaR1 treatment also induced a significant decrease in levels of inflammatory mediators, such as IL-1β, TNF-α, IL-6, and IFN-γ, in the acute protocol, as well as IL-1β and IL-6, but not TNF-α and INF-γ, in the chronic DSS colitis protocol. Additionally, MaR1 decreased ICAM-1 mRNA expression in both the acute and chronic protocols of DSS-induced col...
International Journal of Biological Macromolecules, 2012
-d-Glucan, a polysaccharide isolated from an edible mushroom Pleurotus pulmonarius (Fr.) Quel., ... more -d-Glucan, a polysaccharide isolated from an edible mushroom Pleurotus pulmonarius (Fr.) Quel., presented antinociceptive activity in mice. This study evaluated the involvement of transient receptor potential (TRP) channels and protein kinase C (PKC) on antinociceptive effect of a (1→3),(1→6)-linked -d-glucan (GL) in mice. Intraperitoneal administration of GL potently inhibited nociceptive responses induced by intraplantar injections of capsaicin, cinnamaldehyde, menthol, acidified saline and phorbol myristate acetate (PMA). Moreover, Western blot analysis revealed that GL treatment also prevented PMA-induced PKC activation. Collectively, present results demonstrate that GL could constitute an attractive molecule of interest for the development of new analgesic drugs.
Inflammation underlies the development and progression of a number of skin disorders including ps... more Inflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100 mg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPAinduced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol's ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCa and PKCd isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component.
A glucan was extracted with hot water from the basidiomycete Pleurotus pulmonarius and shown to h... more A glucan was extracted with hot water from the basidiomycete Pleurotus pulmonarius and shown to have a (1→3)linked β-D-glucopyranosyl main-chain substituted at O-6 of every third unit by single β-D-glucopyranosyl nonreducing end units. This was shown by mono-and bidimensional nuclear magnetic resonance (NMR) spectroscopy, methylation analysis, and a controlled Smith degradation. The glucan was tested for its effects on the acetic acid-induced writhing reaction in mice, a typical model for quantifying inflammatory pain. It caused a marked and dose-dependent anti-inflammatory response, demonstrated by the inhibition of leukocyte migration to injured tissues (82 ± 6%) with an ID 50 of 1.19 (0.74-1.92) mg/kg. Furthermore, animals previously treated with the glucan (3 mg/kg i.p.), showed a reduction of 85± 5% of writhes, after receiving the acetic acid injection. Furthermore, in the formalin test, the glucan (3-30 mg/kg, i.p.) also caused significant inhibition of both the early (neurogenic pain) and the late phases (inflammatory pain) of formalin-induced licking. However, it was more potent and effective in relation to the late phase of the formalin test, with mean ID 50 values for the neurogenic and the inflammatory phases of N 30 and 12.9 (6.7-24.6) mg/kg and the inhibitions observed were 43± 5% and 96± 4%, respectively. These data showed that the glucan had potent anti-inflammatory and analgesic (antinociceptive) activities, possibly by the inhibition of pro-inflammatory cytokines.
Canadian Journal of Physiology and Pharmacology, 2010
This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stim... more This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stimulation of the lower abdomen and hind paw associated with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The frequency of withdrawal responses to 10 consecutive applications of von Frey probes to the lower abdomen (0.07 g) or hind paw (0.4 g) was assessed in male BALB/c mice before and after intracolonic TNBS injection (0.5 mg in 100 µL of 35% ethanol). TNBS (0.5 mg) induced referred mechanical hyperalgesia in the abdomen (response frequencies at 24 h: saline 11.0% ± 3.1%, TNBS 48.0% ± 6.9%) and hind paw (frequencies at 24 h: saline 12.5% ± 4.7%, TNBS 47.1% ± 7.1%) lasting up to 72 and 48 h, respectively. Mice receiving 1.0 or 1.5 mg TNBS assumed hunch-backed postures and became immobile during abdominal mechanical stimulation, suggestive of excessive ongoing pain. Atrasentan (ETA receptor antagonist; 10 and 30 mg/kg, i.v.) given 24 h after TNBS abolished hind paw and abdomi...
Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory di... more Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by downregulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B 1 R mRNA expression occurred selectively in the hippocampus, whereas protein level was upregulated in both brain areas. Genetic deletion of kinin B 1 R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-c in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B 1 R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.
Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a ... more Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a synthetic compound derivative from natural precursor α, β-amyrin, against nociceptive response induced by acetic acid and formalin. Here, we investigated some of the mechanisms of action underlying the antinociceptive effects of amyrin octanoate. Amyrin octanoate given intraperitoneally (0.001-1 mg /kg) or intrathecally (10-1000 ng /site) caused dose-dependent and long-lasting inhibition of acetic acid-induced visceral nociception, with mean ID 50 values of 0.003 (0.001-0.005) mg/kg and 122.4 (60.8-246.6) ng/site, respectively. In the capsaicin-and glutamate-induced paw licking, amyrin octanoate caused significant and dose-dependent inhibition of both nociceptive responses, with ID 50 values of 1.36 and 0.04 mg/kg, respectively. Furthermore, amyrin octanoate also reduced significantly the nociception caused by intrathecal injection of glutamate, substance P and capsaicin, with inhibitions of 36 ± 11%, 67 ± 10% and 78 ± 5%, respectively. The antinociception caused by amyrin octanoate in the acetic acid test was significantly attenuated by neonatal pretreatment of mice with capsaicin, but seems to involve mechanisms independent of G i/o protein, opioidergic, serotonergic, noradrenergic and cholinergic system, since it was not affected by pertussis toxin, naloxone, yohimbine, mecamylamine or atropine. In addition, amyrin octanoate reduced thermal and mechanical hyperalgesia induced by bradykinin and phorbol myristate acetate in rats, without affecting similar responses caused by prostaglandin E 2. Taken together, the present results shown that octanoate amyrin produces antinociceptive and antihyperalgesic effects, through an interaction with capsaicin-sensitive fibers and the inhibition of the PKC signaling pathway.
Fucogalactans from Agaricus brasiliensis (EPF-Ab) and A. bisporus var. hortensis (EPF-Ah) were pr... more Fucogalactans from Agaricus brasiliensis (EPF-Ab) and A. bisporus var. hortensis (EPF-Ah) were prepared via by aqueous extraction and a purification procedure. EPF-Ab had M(w) 19.4 x 10(3)g/mol and EPF-Ah M(w) 31.1 x 10(3)g/mol. EPF-Ab had a (1-->6)-linked alpha-D-Galp main-chain partially substituted in O-2 by non-reducing end-units of alpha-L-Fucp. EPF-Ah had a similar main-chain with O-2 substitution, but was partially methylated at HO-3, as well as having 2.5% non-reducing end-units of beta-D-Gal. In mice, EPF-Ab gave 39% antinociceptive inhibition (ID(50)>100mg/kg) and no anti-inflammatory activity. EPF-Ah also gave an inhibition of 39% at ID(50) 0.33 mg/kg and also inhibited by 61% (ID(50) 5.0mg/kg) total cell migration and by 32% peritoneal capillary permeability, which is related to the anti-inflammatory effect. The small differences in chemical structure in these polysaccharides thus modified their biological activities.
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Papers by Rodrigo Marcon