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The two-component system GacS/A and the posttranscriptional control system Rsm constitute a genetic regulation pathway in Gammaproteobacteria; in some species of Pseudomonas, this pathway is part of a multikinase network (MKN) that regulates the activity of the Rsm system. In this network, the activity of GacS is controlled by other kinases. One of the most studied MKNs is the MKN-GacS of Pseudomonas aeruginosa, where GacS is controlled by the kinases RetS and LadS; RetS decreases the kinase activity of GacS, whereas LadS stimulates the activity of the central kinase GacS. Outside of the Pseudomonas genus, the network has been studied only in Azotobacter vinelandii. In this work, we report the study of the RetS kinase of A. vinelandii; as expected, the phenotypes affected in gacS mutants, such as production of alginates, polyhydroxybutyrate, and alkylresorcinols and swimming motility, were also affected in retS mutants. Interestingly, our data indicated that RetS in A. vinelandii acts as a positive regulator of GacA activity. Consistent with this finding, mutation in retS also negatively affected the expression of small regulatory RNAs belonging to the Rsm family. We also confirmed the interaction of RetS with GacS, as well as with the phosphotransfer protein HptB.

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Since its introduction in 1952, topical glucocorticosteroids remain the initial and long-term treatment option for various forms of inflammatory dermatitis. A number of non-steroidal topicals for treating inflammatory dermatoses have been developed in the recent decades (such as topical calcineurin inhibitors, vitamin D analogues, and phophodiesterase-4 inhibitors), but none had the combination of broad therapeutic range, relatively rapid onset of action, high tolerability, and wide-spread clinical success; this allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically, with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was approved by the FDA in September 2021 for atopic dermatitis, and was the subject of the first report in this review series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA in May 2022 for treating plaque psoriasis, and is the focus of this present report. Finally and the most recently, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, received FDA approval in July 2022 for treating plaque psoriasis, and is reviewed in the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In short, in this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview which would allow dermatologists to confidently and appropriately integrate them into treatment paradigms.

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The interaction between sodium salicylate (NaSal) and the two macrocycles 5,11,17,23-tetrakissulfonatomethylene-2,8,14,20-tetra(ethyl)resorcinarene (Na4EtRA) and ß-cyclodextrin (ß-CD) has been studied by the determination of ternary mutual diffusion coefficients, and spectroscopic and computational techniques. The results obtained by the Job method suggest that the complex formation is given in a 1:1 ratio for all systems. The mutual diffusion coefficients and the computational experiments have shown that the ß-CD-NaSal system presents an inclusion process, whereas the Na4EtRA-NaSal system forms an outer-side complex. This fact is also in line with the results obtained from the computational experiments, where the calculated solvation free energy has been found to be more negative for the Na4EtRA-NaSal complex because of the partial entry of the drug inside the Na4EtRA cavity.

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We report a computational study of the anion states of the resveratrol (RV) and resorcinol (RS) molecules, also investigating dissociative electron attachment (DEA) pathways. RV has well-known beneficial effects in human health, and its antioxidant activity was previously associated with DEA reactions producing H2. Our calculations indicate a valence bound state (π1*) and four resonances (π2* to π5*) for that system. While the computed thermodynamic thresholds are compatible with DEA reactions producing H2 at 0 eV, the well-known mechanism involving vibrational Feshbach resonances built on a dipole bound state should not be present in RV. Our results suggest that the shallow π1* valence bound state is expected to account for H2 elimination, probably involving π1*/σOH* couplings along the vibration dynamics. The RS molecule is also an oxidant and a subunit of RV. Because two close-lying hydroxyl groups are found in the RS moiety, the H2-elimination reaction in RV should take place at the RS site. Our calculations point out a correspondence between the anion states of RV and RS and even between the thresholds. Nevertheless, the absence of bound anion states in RS, indicated by our calculations, is expected to suppress the H2-formation channel at 0 eV. One is led to conclude that the ethene and phenol subunits in RV stabilize the π1* state, thus switching on the DEA mechanism producing H2.

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The search for effective and less toxic drugs for the treatment of Cutaneous Leishmaniasis (CL) is desirable due to the emergence of resistant parasites. The present study shows the preparation, characterization and in vitro antileishmanial activity of green-based silver nanoparticles (AgNPs) with Cashew Nutshell Liquid (CNSL, main constituents: anacardic acid (AA) and cardol (CD). The synthesis of silver nanoparticles was achieved by reduction with sodium borohydride in the presence of anacardic acid or cardol under microwave irradiation (400 W, 60 °C, 5 min) resulting in AgAA and AgCD. In vitro assay showed opposite effects for AgAA and AgCD. While AgAA is highly toxic to macrophages (CC50 = 6.910 µg mL-1) and almost non-toxic for L.braziliensis (IC50 = 86.61 µg mL-1), AgCD results very selective toward killing the parasite (CC50 = 195.0 µg mL-1, IC50 = 11.54 µg mL-1). AA's higher polarity and conical shape easily promote cell lysis by increasing cell permeability, while CD has a protective effect: for that reason, AA and AgAA were not further used for tests. CD (EC50 = 2.906 µg mL-1) had higher ability to kill intracellular amastigotes than AgCD (EC50 = 16.00 µg mL-1), however, less intact cells were seen on isolated CD tests. In addition, considering that NO is one of the critical molecular species for the intracellular control of Leishmania, we used Griess colorimetric test to analyze the effect of treatment with AgCD and CD. Overall, the in vitro antileishmanial tests indicate that AgCD should be further explored as a promising non-toxic treatment for CL.

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Since the classic studies of Alexander Flemming, Penicillium strains have been known as a rich source of antimicrobial substances. Recent studies have identified novel metabolites produced by Penicillium sclerotiorum that have antibacterial, antifouling and pharmaceutical activities. Here, we report the isolation of a P. sclerotiorum (LM 5679) from Amazonian soil and carry out a culture-based study to determine whether it can produce any novel secondary metabolite(s) that are not thus-far reported for this genus. Using a submerged culture system, secondary metabolites were recovered by solvent extract followed by thin-layer chromatography, nuclear magnetic resonance, and mass spectroscopy. One novel secondary metabolite was isolated from P. sclerotiorum (LM 5679); the phenolic compound 5-pentadecyl resorcinol widely known as an antifungal, that is produced by diverse plant species. This metabolite was not reported previously in any Penicillium species and was only found once before in fungi (that time, in a Fusarium). Here, we discuss the known activities of 5-pentadecyl resorcinol in the context of its mode-of-action as a hydrophobic (chaotropicity-mediated) stressor.

Desde os estudos clássicos de Alexander Flemming, as cepas de Penicillium são conhecidas como uma fonte rica em substâncias antimicrobianas. Estudos recentes identificaram novos metabólitos produzidos pela espécie Penicillium sclerotiorum com atividades antibacteriana, anti-incrustante e farmacêutica. Aqui, relatamos o isolamento de uma colônia de P. sclerotiorum (LM 5679) do solo amazônico e relatamos também o estudo baseado em cultura para determinar se ele pode produzir qualquer novo metabólito (s) secundário (s) que não foram relatados até agora para este gênero. Usando um sistema de cultura submerso, os metabólitos secundários foram recuperados por extrato de solvente seguido por cromatografia em camada delgada, ressonância magnética nuclear e espectroscopia de massa. Um novo metabólito secundário foi isolado de P. sclerotiorum (LM 5679); o composto fenólico 5-pentadecil resorcinol que é amplamente conhecido como um antifúngico que é produzido por diversas espécies de plantas. Este metabólito não foi relatado anteriormente em nenhuma espécie de Penicillium, e foi encontrado apenas uma vez em fungos (Fusarium). Aqui, discutimos as atividades conhecidas do 5-pentadecil resorcinol no contexto de seu modo de ação como um estressor hidrofóbico (mediado pela caotropicidade).

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The present work reports the synthesis and a structural study of two novel dithiocarbazate, the 4,6-diacetylresorcinol-S-benzyldithiocarbazate (H3L1) and the 4,6-diacetylresorcinol-bis(S-benzyldithiocarbazate) (H4L2), and their Ni(II) complexes, [Ni(HL1)(Py)] (1) and [Ni2(L2)(PPh3)2] (2). Single crystal X-ray analyzes reveal mono and binuclear complexes and the metal centers with distorted square planar geometry. The analyses of the Hirshfeld surface and fingerprints plots revealed intermolecular contacts attributed to the H···H and C···H/H···C bonds. The Density Functional Theory (DFT), with the B3LYP functional and 6-311-G(d,p)/LanL2DZ basis sets, was employed to optimize the geometries of synthesized compounds. From the resulting geometries, the highest occupied and lowest unoccupied molecular orbital maps (HOMO-LUMO), orbital energy gap, electron localization function (ELF), electron density, natural bond orbital (NBO) analysis, and complexation of the ligands with Ni(II) were calculated supporting the experimental data. The ESI (+)-MS/MS data indicated the presence in solution of the characteristic fragmentation with the [H3L1]+ and [H4L2]+ molecular ions for the ligands. The pharmacological potential of the dithiocarbazate ligands and their Ni(II) complexes were evaluated in vitro against MDA-MB-231 human breast cancer cells. A remarkable cytotoxic activity was observed, more evident for free ligands than complexes at low concentrations; however, this latter showed a better dose-response pattern, being more attractive in terms of pharmacokinetics and therapeutic window.

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Since the classic studies of Alexander Flemming, Penicillium strains have been known as a rich source of antimicrobial substances. Recent studies have identified novel metabolites produced by Penicillium sclerotiorum that have antibacterial, antifouling and pharmaceutical activities. Here, we report the isolation of a P. sclerotiorum (LM 5679) from Amazonian soil and carry out a culture-based study to determine whether it can produce any novel secondary metabolite(s) that are not thus-far reported for this genus. Using a submerged culture system, secondary metabolites were recovered by solvent extract followed by thin-layer chromatography, nuclear magnetic resonance, and mass spectroscopy. One novel secondary metabolite was isolated from P. sclerotiorum (LM 5679); the phenolic compound 5-pentadecyl resorcinol widely known as an antifungal, that is produced by diverse plant species. This metabolite was not reported previously in any Penicillium species and was only found once before in fungi (that time, in a Fusarium). Here, we discuss the known activities of 5-pentadecyl resorcinol in the context of its mode-of-action as a hydrophobic (chaotropicity-mediated) stressor.

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BACKGROUND: Melasma can be refractory to treatment, and relapses are frequent. Thiamidol is a new potent tyrosinase inhibitor that has been found effective as a cosmeceutical for the depigmenting of melasma. OBJECTIVE: This study compared the efficacy and tolerability of topical 0.2% Thiamidol vs. 4% hydroquinone for facial melasma. METHODS: Fifty women with facial melasma participated in a randomized, evaluator-blinded, controlled study from September through November 2020. Patients were randomly assigned to apply a double layer of 0.2% Thiamidol twice a day or 4% hydroquinone cream at bedtime, for 90 days. Both groups received tinted sunscreen (sun protection factor 60, PPD 20). The primary outcome was the change from the baseline Modified Melasma Area Seve:rity Index (mMASI) score. Secondary outcomes were improvements in the patients' quality of life [Melasma Quality of Life Index (MELASQoL)], colourimetry, and Global Aesthetic Improvement Scale (GAIS) evaluation. RESULTS: One participant, from the hydroquinone group, did not complete the study (unrelated to adverse effects). The mean (SD) age of the participants was 43 (6) years, and 86% were phototypes III-IV. Both groups exhibited a reduction in mMASI, MELASQoL, and colour contrast scores (P < 0.01). The mean [95% confidence interval (CI 95%)] reductions of the mMASI scores were 43% (35-50%) for Thiamidol and 33% (23-42%) for hydroquinone. There was no difference between the groups in the reductions in mMASI, MELASQoL, colourimetric contrast and GAIS scores (P ≥ 0.09). The GAIS analysis resulted in an improvement of 84% (CI: 95% 67-97%) for participants in the Thiamidol group and 74% (CI: 95% 61-93%) for those in the hydroquinone group. There were only mild adverse effects in the Thiamidol group, but allergic contact dermatitis was evidenced in two (8%) participants. CONCLUSION: The melasma improvement achieved using 0.2% Thiamidol did not differ from that of 4% hydroquinone cream. Thiamidol can be considered a suitable option for melasma patients with poor tolerability or treatment failure with hydroquinone.

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There is a need for new and effective topical treatment options for psoriasis. Recent phase I and II clinical trials have demonstrated efficacy of the novel nonsteroidal drug tapinarof to treat mild to moderate plaque psoriasis. Tapinarof is an aryl hydrocarbon receptor (AHR) agonist that induces antioxidant, immunomodulatory and epidermal differentiation regulation pathways. In this review, we examine the current preclinical and clinical studies with a focus on the mechanism of action, pharmacokinetics, safety and efficacy of tapinarof to treat psoriasis.

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