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The decoction of Salvia lachnostachys Benth. leaves is used in Brazilian folk medicine for anti-spasmodic, antipyretic, and anxiolytic purposes. Some of the biological effects of an S. lachnostachys extract have been shown to be anti-inflammatory, anti-cancer, and antidepressant effects. In addition, this medicinal plant produces several compounds including icetexane diterpenoids, such as fruticuline A and fruticuline B. The aim of the present work was to evaluate the anti-hyperalgesic and anti-inflammatory properties of fruticuline B (FRUT B) and the ethanolic extract obtained from the leaves of S. lachnostachys (EESL) in experimental mouse models. EESL (30, 100, and 300 mg/kg) and FRUT B (1 mg/kg) were evaluated in articular inflammation-induced models in Swiss mice. In articular inflammation induced by Zymosan, EESL (300 mg/kg) and FRUT B (1 mg/kg) significantly reduced mechanical hyperalgesia (83.17% inhibition for EESL and 81.19% for FRUT B); edema (68.75% reduction for EESL and 33.66% for FRUT B); leukocyte migration (81.3% for EESSL and 92.2% for FRUT B), and nitric oxide production (88.3% for EESL and 74.4% for FRUT B). The exposure to fruticuline B significantly inhibited the edema (51.5%), mechanical (88.12%) and cold hyperalgesia (80.8%), and myeloperoxidase (MPO) (63.4%) activity 24 h after CFA injection. In the pleurisy model, FRUT B reduced 89.1% of leukocyte migration and 50.3% in nitric oxide production. Four hours after carrageenan injection, FRUT B (1 mg/kg) diminished 89.11% of mechanical hyperalgesia, 65.8% of paw edema, and 82.12% of the response to cold hyperalgesia. In the MTT test, EESL and fruticuline B caused no cytotoxicity. The present study revealed, for the first time, the anti-arthritic and anti-nociceptive effects of FRUT B, pointing out the therapeutic potential of the species to control inflammation and nociception. Future studies are needed to evaluate other biological properties of fruticuline B and to better understand its mechanism of action.

The present study investigated the effects of the ethanolic extract (ESa), fractions, and compounds isolated from Sinningia aggregata in male Swiss mice on carrageenan-induced paw edema, neutrophil migration, mechanical hyperalgesia, formalin-induced nociception, and lipopolysaccharide-induced fever. The ESa did not alter edema, neutrophil migration, or fever at any of the doses tested. However, the ESa reduced phase II of formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The petroleum ether (PE) and ethyl acetate (EA) fractions and aggregatin D (AgD; isolated from the EA fraction) reduced formalin-induced nociception. Anthraquinones from the PE fraction were ineffective. AgD also inhibited carrageenan-induced mechanical hyperalgesia. Neither the ESa nor AgD altered thermal nociception or motor performance. Local administration of AgD also reduced hyperalgesia induced by carrageenan, bradykinin, tumor necrosis factor-α, interleukin-1β, cytokine-induced neutrophil chemoattractant, prostaglandin E2, and dopamine but not hyperalgesia induced by forskolin or dibutyryl cyclic adenosine monophosphate. The positive control dipyrone reduced the response induced by all of the stimuli. Additionally, glibenclamide abolished the analgesic effect of dipyrone but not the one induced by AgD. AgD did not change lipopolysaccharide-induced nitric oxide production by macrophages or the nociception induced by capsaicin, cinnamaldehyde, acidified saline, or menthol. These results suggest that the ESa has important antinociceptive activity, and this activity results at least partially from the presence of AgD. AgD reduced mechanical hyperalgesia induced by several inflammatory mediators through mechanisms that are different from classic analgesic drugs.

Coupling the use of artificial chromosomes with metabolomics enables the high-throughput linkage of fungal natural products with their biosynthetic gene clusters. This method was used here to identify a novel polyketide–nonribosomal peptide scaffold. The genomes of filamentous fungi contain up to 90 biosynthetic gene clusters (BGCs) encoding diverse secondary metabolites—an enormous reservoir of untapped chemical potential. However, the recalcitrant genetics, cryptic expression, and unculturability of these fungi prevent scientists from systematically exploiting these gene clusters and harvesting their products. As heterologous expression of fungal BGCs is largely limited to the expression of single or partial clusters, we established a scalable process for the expression of large numbers of full-length gene clusters, called FAC-MS. Using fungal artificial chromosomes (FACs) and metabolomic scoring (MS), we screened 56 secondary metabolite BGCs from diverse fungal species for expression in Aspergillus nidulans . We discovered 15 new metabolites and assigned them with confidence to their BGCs. Using the FAC-MS platform, we extensively characterized a new macrolactone, valactamide A, and its hybrid nonribosomal peptide synthetase–polyketide synthase (NRPS–PKS). The ability to regularize access to fungal secondary metabolites at an unprecedented scale stands to revitalize drug discovery platforms with renewable sources of natural products.

We previously showed that plants from the genus Sinningia are a source of antiinflammatory and analgesic compounds with different mechanisms of action. The present study evaluated the antiinflammatory, antinociceptive, and antipyretic effects of a crude extract (CE) from Sinningia canescens , its fractions, and 6-methoxy-7-hydroxy-α-dunnione (MHD) in mice. These effects were evaluated using carrageenan (Cg)-induced paw edema, acetic acid- and formalin-induced nociception, mechanical hyperalgesia, lipopolysaccharide (LPS)-induced fever, and plasma cytokine levels. The CE and dichloromethane and hexane fractions reduced Cg-induced paw edema and hyperalgesia, LPS-induced fever, and plasma tumor necrosis factor-α (TNF-α) levels. The CE also reduced acetic acid-induced writhing and the second phase of formalin-induced nociception but did not alter thermal nociception or motor performance. Partition with solvents showed that the antiinflammatory, antihyperalgesic, and antipyretic activities were present in dichoromethane and hexane fractions, and the major compound isolated from these fractions was MHD. Oral and intraplantar MHD administration reduced paw edema. Oral MHD administration also reduced prostaglandin E 2 -induced hyperalgesia but did not alter hyperalgesia that was induced by dopamine and dibutyryl cyclic adenosine monophosphate. Treatment with glibenclamide, a K ATP channel blocker, did not alter the analgesic effect of MHD. Lipopolysaccharide-induced fever and TNF-α, interleukin-1β, and interleukin-6 levels were inhibited by MHD. Altogether, these data suggest that the CE has antiinflammatory, analgesic, and antipyretic activity, and these actions are at least partially related to MHD. These results also suggest that MHD acts by blocking cytokine synthesis and/or blocking prostaglandin activity.

The present study investigated the effects of the ethanolic extract (ESa), fractions, and compounds isolated from Sinningia aggregata in male Swiss mice on carrageenan-induced paw edema, neutrophil migration, mechanical hyperalgesia, formalin-induced nociception, and lipopolysaccharide-induced fever. The ESa did not alter edema, neutrophil migration, or fever at any of the doses tested. However, the ESa reduced phase II of formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The petroleum ether (PE) and ethyl acetate (EA) fractions and aggregatin D (AgD; isolated from the EA fraction) reduced formalin-induced nociception. Anthraquinones from the PE fraction were ineffective. AgD also inhibited carrageenan-induced mechanical hyperalgesia. Neither the ESa nor AgD altered thermal nociception or motor performance. Local administration of AgD also reduced hyperalgesia induced by carrageenan, bradykinin, tumor necrosis factor- alpha , interleukin-1 beta , cytokine-induced neutrophil chemoattractant, prostaglandin E2, and dopamine but not hyperalgesia induced by forskolin or dibutyryl cyclic adenosine monophosphate. The positive control dipyrone reduced the response induced by all of the stimuli. Additionally, glibenclamide abolished the analgesic effect of dipyrone but not the one induced by AgD. AgD did not change lipopolysaccharide-induced nitric oxide production by macrophages or the nociception induced by capsaicin, cinnamaldehyde, acidified saline, or menthol. These results suggest that the ESa has important antinociceptive activity, and this activity results at least partially from the presence of AgD. AgD reduced mechanical hyperalgesia induced by several inflammatory mediators through mechanisms that are different from classic analgesic drugs.