Human T Cell Lymphotropic Virus Type 1 Global Prevalence Associated with the Human Development Index: Systematic Review with Meta-Analysis.

In 2012, the number of people infected with human T cell lymphotropic virus type 1 (HTLV-1) was estimated to be 10 million worldwide. Prevalence varies according to geographic location, ethnic factors, sex, age, populations exposed to risk factors, income, and education, reaching countries with the worst socioeconomic scenarios. There is a need to determine the current global prevalence of HTLV-1 and examine its association with countries' human development index (HDI) to provide data for global health policy. Systematic review with meta-analysis is according to PRISMA 2020 recommendations. It was registered at PROSPERO, CRD42021223146. Prevalence or cross-sectional studies of HTLV-1 infection with at least 100 participants, screening, and confirmatory serologic testing were included. Studies with incomplete or unavailable results or with duplicate information were excluded. Data were selected by two independent investigators and analyzed using R software, a metapackage that generated the forest plots [95% confidence interval (CI)]. Heterogeneity was assessed using the I2 statistic, and funnel plot asymmetry was assessed using Egger's test. Countries were compared using an HDI cutoff ≥0.8. Methodological quality was assessed using Joanna Briggs Institute (JBI) criteria. The overall prevalence of HTLV-1 infection was 0.91% (95% CI: 0.80-1.02, p < .0001) and was higher in low HDI countries [1.18% (95% CI: 1.03-1.34)] than in high HDI countries [0.41% (95% CI: 0.27-0.57)]. Prevalence varied according to the populations studied: it was higher in the general population [1.65% (95% CI: 1.08-2.34)] compared to pregnant women [0.34% (95% CI: 0.17-0.57)] and blood donors [0.04% (95% CI: 0.01-0.08)]. Consistently, prevalence for each population group was higher in low HDI countries than in high HDI countries. The worldwide prevalence of HTLV-1 infection is highly heterogeneous, with a global prevalence of 0.91%. In high HDI countries, the observed prevalence is approximately three times lower than in low HDI countries. In the general population, the observed prevalence is about 5 times higher than in pregnant women and 41 times higher than in blood donors.

Elastase inhibitory activity of secondary metabolites from the fungus Virgaria nigra CF-231658.

Three known compounds were isolated from Virgaria nigra CF-231658; 2,7-dihydroxy naphthalene (1), virgaricin B (2) and virgaricin (3). The isolated compounds was obtained from liquid-state and agar-supported fermentation using Amberlite XAD-16 solid-phase extraction during the cultivation step. Their structures were elucidated on the basis of 1D and 2D NMR as well as HRMS spectroscopic analyses. The isolated compounds were examined for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 2 displayed the most potent activity with 76.7 ± 2.12% inhibition of the enzyme activity at 5 µM concentration.

Efeito do pré-condicionamento isquêmico remoto no consumo máximo de oxigênio e potência máxima em corredores e ciclistas: revisão sistemática e metanálise / Effect of remote ischemic pre-conditioning on maximum oxygen consumption and maximum power in runners and cyclists: systematic review and metanalysis

INTRODUÇÃO: O pré-condicionamento isquêmico remoto (PCIR) é uma intervenção cardioprotetora não invasiva que atenua a lesão celular sofrida por uma isquemia prolongada. Seus efeitos de proteção sobre o coração, quando aplicado ao esporte, pode melhorar o desempenho do exercício. OBJETIVO: Investigar o efeito do pré-condicionamento isquêmico remoto no consumo máximo de oxigênio (VO2máx) e potência máxima (Wmáx) em corredores e ciclistas. METODOLOGIA: Revisão sistemática e metanálise, com ensaios clínicos randomizados. Baseado no PRISMA e avaliado pelo repositório de projetos de revisões sistemática PROSPERO; entretanto, não obteve o registro por se tratar de um desfecho de performance esportiva. As buscas foram realizadas nas bases de dados Medline/PubMed, SciELO, Periódicos CAPES. A seleção dos estudos foi realizada em duas etapas: leitura do título e resumo, e leitura completa dos artigos. A extração dos dados foi realizada pela transcrição das informações. A qualidade metodológica foi avaliada pela escala risco de viés através da ferramenta Cochrane. Excluíram-se estudos que investigaram variáveis diferentes dos desfechos selecionados para esta revisão. RESULTADOS: Foram incluídos oito ensaios clínicos. Verificou-se que nos itens geração de sequência aleatória, ocultação de alocação e cegamento de avaliadores de desfecho em quase todos os estudos tiveram alto risco de viés. Os resultados da metanálise não mostraram diferenças significativas no VO2máx e Wmáx. CONCLUSÃO: O pré-condicionamento isquêmico remoto não se mostrou eficaz para aumentar o VO2máx e a Wmáx em corredores e ciclistas.

INTRODUCTION: Remote ischemic preconditioning (PIRC) is a non-invasive cardioprotective intervention that attenuates cell damage suffered by prolonged ischemia. Its protective effects on the heart, when applied to sport, can improve exercise performance. OBJECTIVE: To investigate the effect of remote ischemic preconditioning on maximum oxygen consumption (VO2max) and maximum power (Wmax) in runners and cyclists. METHODOLOGY: Systematic review and metaanalysis, with randomized clinical trials. Based on PRISMA and evaluated by the PROSPERO systematic review project repository; however, it did not obtain registration because it is an outcome of sports performance. The searches were carried out in the Medline / PubMed, SciELO, Capes Periodicals databases. The selection of studies was carried out in two stages: reading the title and summary and reading the articles in full. Data extraction was performed by transcribing the information. Methodological quality was assessed by the risk of bias scale using the Cochrane tool. Studies that investigated variables other than the outcomes selected for this review were excluded. RESULTS: Eight clinical trials were included. In the generation of the item of random sequence, concealment of allocation and blinding of outcome evaluators in almost all studies had a high risk of bias. The analysis of the risk of bias was high risk. The results of the meta-analysis did not show significant differences in VO2max and Wmax. CONCLUSION: Remote ischemic preconditioning was not effective in increasing VO2max and Wmax in runners and cyclists.

Efeito do pré-condicionamento isquêmico remoto no consumo máximo de oxigênio e potência máxima em corredores e ciclistas: revisão sistemática e metanálise / Effect of remote ischemic pre-conditioning on maximum oxygen consumption and maximum power in runners and cyclists: systematic review and metanalysis

INTRODUÇÃO: O pré-condicionamento isquêmico remoto (PCIR) é uma intervenção cardioprotetora não invasiva que atenua a lesão celular sofrida por uma isquemia prolongada. Seus efeitos de proteção sobre o coração, quando aplicado ao esporte, pode melhorar o desempenho do exercício. OBJETIVO: Investigar o efeito do pré-condicionamento isquêmico remoto no consumo máximo de oxigênio (VO2máx) e potência máxima (Wmáx) em corredores e ciclistas. METODOLOGIA: Revisão sistemática e metanálise, com ensaios clínicos randomizados. Baseado no PRISMA e avaliado pelo repositório de projetos de revisões sistemática PROSPERO; entretanto, não obteve o registro por se tratar de um desfecho de performance esportiva. As buscas foram realizadas nas bases de dados Medline/PubMed, SciELO, Periódicos CAPES. A seleção dos estudos foi realizada em duas etapas: leitura do título e resumo, e leitura completa dos artigos. A extração dos dados foi realizada pela transcrição das informações. A qualidade metodológica foi avaliada pela escala risco de viés através da ferramenta Cochrane. Excluíram-se estudos que investigaram variáveis diferentes dos desfechos selecionados para esta revisão. RESULTADOS: Foram incluídos oito ensaios clínicos. Verificou-se que nos itens geração de sequência aleatória, ocultação de alocação e cegamento de avaliadores de desfecho em quase todos os estudos tiveram alto risco de viés. Os resultados da metanálise revelou VO2máx (p < 0,01), o PCIR mostrou ser eficaz; Wmáx não houve diferença significativa. CONCLUSÃO: O pré-condicionamento isquêmico remoto pode ser capaz de aumentar o VO2máx em corredores e ciclistas. A Wmáx demonstra não ser influenciada pelo PCIR.

INTRODUCTION: Remote ischemic preconditioning (PIRC) is a non-invasive cardioprotective intervention that attenuates cell damage suffered by prolonged ischemia. Its protective effects on the heart, when applied to sport, can improve exercise performance. OBJECTIVE: To investigate the effect of remote ischemic preconditioning on maximum oxygen consumption (VO2max) and maximum power (Wmax) in runners and cyclists. METHODOLOGY: Systematic review and metaanalysis, with randomized clinical trials. Based on PRISMA and evaluated by the PROSPERO systematic review project repository; however, it did not obtain registration because it is an outcome of sports performance. The searches were carried out in the Medline / PubMed, SciELO, Capes Periodicals databases. The selection of studies was carried out in two stages: reading the title and summary and reading the articles in full. Data extraction was performed by transcribing the information. Methodological quality was assessed by the risk of bias scale using the Cochrane tool. Studies that investigated variables other than the outcomes selected for this review were excluded. RESULTS: Eight clinical trials were included. In the generation of the item of random sequence, concealment of allocation and blinding of outcome evaluators in almost all studies had a high risk of bias. The analysis of the risk of bias was high risk. The meta-analysis results revealed VO2max (p <0.01), the PCIR proved to be effective; Wmax there was no significant difference. CONCLUSION: Remote ischemic preconditioning may be able to increase VO2max in runners and cyclists. Wmax demonstrates that the PCIR does not influence it.

A potential third-order role of the host endoplasmic reticulum as a contact site in interkingdom microbial endosymbiosis and viral infection.

The normal functioning of eukaryotic cells depends on the compartmentalization of metabolic processes within specific organelles. Interactions among organelles, such as those between the endoplasmic reticulum (ER) - considered the largest single structure in eukaryotic cells - and other organelles at membrane contact sites (MCSs) have also been suggested to trigger synergisms, including intracellular immune responses against pathogens. In addition to the ER-endogenous functions and ER-organelle MCSs, we present the perspective of a third-order role of the ER as a host contact site for endosymbiotic microbial non-pathogens and pathogens, from endosymbiont bacteria to parasitic protists and viruses. Although understudied, ER-endosymbiont interactions have been observed in a range of eukaryotic hosts, including protists, plants, algae, and metazoans. Host ER interactions with endosymbionts could be an ER function built from ancient, conserved mechanisms selected for communicating with mutualistic endosymbionts in specific life cycle stages, and they may be exploited by pathogens and parasites. The host ER-'guest' interactome and traits in endosymbiotic biology are briefly discussed. The acknowledgment and understanding of these possible mechanisms might reveal novel evolutionary perspectives, uncover the causes of unexplained cellular disorders and suggest new pharmacological targets.

Correlação da ventilação voluntária máxima com a força e resistência dos músculos respiratórios em jovens / Correlation of maximum voluntary ventilation to the strength and resistance of young respiratory muscles

A ventilação voluntária máxima é um dos testes difundidos para avaliação da resistência da musculatura respiratória, mesmo sem ser validado para este fim. Na literatura ainda são encontradas controvérsias quanto a interpretação e aplicabilidade do uso da VVM na prática clínica. OBJETIVO: Verificar a correlação entre a ventilação voluntária máxima e a força e resistência dos músculos respiratórios em jovens hígidos. MATERIAIS E MÉTODOS: Estudo observacional de corte transversal realizado na Clínica. Foram incluídos indivíduos > 18 anos, de ambos os sexos e hígidos. Os participantes tiveram sua avaliação da força muscular respiratória através do manovacuômetro, no qual se obteve a Pimáx e Pemáx. A resistência foi avaliada através do teste de carga constante pelo Power Breathe, utilizando 60% da Pimáx. A ventilação voluntária máxima foi realizada pelo espirômetro. Para a correlação das variáveis Pimáx, Pemáx e VVM foi aplicado o teste de correlação de Pearson. O estudo foi aprovado pelo comitê de ética, CAAE 10849519.9.0000.5544. RESULTADOS: Foram avaliados 27 participantes, em que 59,3% eram do sexo masculino e 55,6% ativos. A ventilação voluntária máxima com a Pimáx e Pemáx, apresentaram respectivamente p = 0,04 e 0,02 e r = 0,53 e 0,57. CONCLUSÃO: O teste de ventilação voluntária máxima possui uma correlação moderada com a força muscular respiratória, e não obtém correlação com o teste de carga constante.

Maximum voluntary ventilation is one of the widespread tests for assessing respiratory muscle strength, even without being validated for this purpose. Controversies are still found in the literature regarding the interpretation and applicability of the use of MVV in clinical practice. OBJECTIVE: To verify the correlation between maximum voluntary ventilation and respiratory muscle strength and endurance in healthy youngsters. MATERIALS AND METHODS: Observational cross-sectional study conducted at the Clinic. Individuals> 18 years of age, of both sexes and healthy were included. Participants had their respiratory muscle strength assessment using a manovacuometer, in which Pimax and Pmax were obtained. The resistance was evaluated through the constant load test by Power Breathe, using 60% of the Pimáx. Maximum voluntary ventilation was performed by a spirometer. Pearson's correlation test was applied to correlate the variables Pimax, Pmax and VVM. The study was approved by the ethics committee, CAAE 10849519.9.0000.5544. RESULTS: 27 participants were evaluated, of which 59.3% were male and 55.6% were active. The maximum voluntary ventilation with Pimax and Pmax, presented respectively p = 0.04 and 0.02 and r = 0.53 and 0.57. CONCLUSION: The maximum voluntary ventilation test has a moderate correlation with respiratory muscle strength and has no correlation with the constant load test.

A central role of the endoplasmic reticulum in the cell emerges from its functional contact sites with multiple organelles.

Early eukaryotic cells emerged from the compartmentalization of metabolic processes into specific organelles through the development of an endomembrane system (ES), a precursor of the endoplasmic reticulum (ER), which was essential for their survival. Recently, substantial evidence emerged on how organelles communicate among themselves and with the plasma membrane (PM) through contact sites (CSs). From these studies, the ER-the largest single structure in eukaryotic cells-emerges as a central player communicating with all organelles to coordinate cell functions and respond to external stimuli to maintain cellular homeostasis. Herein we review the functional insights into the ER-CSs with other organelles in a physiological perspective. We hypothesize that, in addition to the primitive role by the ES in the appearance of proto-eukaryotes, its successor-the ER-emerges as the key coordinator of inter-organelle/PM communication. The ER thus appears to be the 'maestro' driving eukaryotic cell evolution by incorporating new functions/organelles, while remaining the real coordinator overarching cellular functions and orchestrating them with the external milieu.

Modulação da variabilidade da frequência cardíaca em praticantes de CrossFit® / Modulation of heart rate variability in CrossFit® practitioners

INTRODUÇÃO: O CrossFit® é um tipo de exercício físico que afeta a homeostase do corpo exigindo ajustes pela via autonômica. Devido sua intensidade de treino ocorre uma modificação no tônus vagal e adaptações fisiológicas cardiovasculares. OBJETIVO: Verificar a variabilidade da frequência cardíaca em praticantes de CrossFit®. MATERIAIS E MÉTODOS: Corte transversal em praticantes de CrossFit® no período de março a junho de 2017, com idade ≥18 anos, tempo de prática ≥3 meses e uma frequência ≥2 vezes na semana. Excluídos: fumantes, gestantes, comorbidades auto referidas (Diabetes Mellitus, hipertensão, doenças cardiorrespiratórias e disfunção na tireoide), mulheres no período menstrual, menopausa, ou aqueles que tiveram dificuldade na compreensão do teste proposto. Para a mensuração da variabilidade da frequência cardíaca (VFC) foi utilizado o cardiofrequencimetro da marca Polar® modelo V800 heart rate monitor, para a sua análise foi utilizado KUBIOS HRV versão 2.0. Aprovação do CEP-BAHIANA (CAAE 46685415.0.0000.5544). RESULTADOS: Foram pesquisados 16 participantes, com idade média de 32,11 ± 6,44 anos, 10 (62, 5%) homens. O IMC encontrado foi de 26,39±3,80 kg/m², classificando 9 (56,3%) indivíduos como sobrepeso e 6 (37,5%)com peso normal. Os valores obtidos da VFC no domínio do tempo:VLFms2: 1544(859-3640); LFms2:827(550-2115); HFms2:661(335-1577);LF/ HF:1,18(0,86-1,8). CONCLUSÃO: Na amostra estudada, observou-se que praticantes de CrossFit® possuem leve predomínio da atividade simpática, especialmente o sexo masculino e naqueles que praticam atividade física cinco ou mais vezes por semana.

INTRODUCTION: CrossFit® is a type of physical exercise that affects the homeostasis of the body requiring adjustments through the autonomic pathway. Due to its intensity of training there is a modification in vagal tone and cardiovascular physiological adaptations. OBJECTIVE: To verify heart rate variability in CrossFit® practitioners. MATERIALS AND METHODS: Cross-section in CrossFit® practitioners from March to June 2017, aged ≥18 years, practice time ≥3 months and a frequency ≥2 times in the week. Excluded: smokers, pregnant women, self-referenced comorbidities (Diabetes Mellitus, hypertension, cardiorespiratory diseases and thyroid dysfunction), women in the menstrual period, menopause, or those who had difficulty understanding the proposed test. For the measurement of heart rate variability (HRV), the heart rate monitor model V800 heart rate monitor was used for its analysis was KUBIOS HRV version 2.0. Approval of CEP-BAHIANA (CAAE 46685415.0.0000.5544). 5544. RESULTS: 16 participants were studied, with a mean age of 32.11 ± 6.44 years, 10 men (62.5%). The mean BMI found was 26.39 ± 3.80 kg/ m², classifying 9 (56.3%) individuals as overweight and 6 (37.5%) with normal weight. The values obtained from HRV in the time domain: VLF:1544 (859-3640), LF: 827 (550-2115), HF: 661 (335-1577), LF / HF: 1.18 (0.86-1,8). CONCLUSION: In the studied sample, it was observed that CrossFit® practitioners have a slight predominance of sympathetic activity, especially males and those who practice physical activity five or more times per week.

Osmanicin, a Polyketide Alkaloid Isolated from Streptomyces osmaniensis CA-244599 Inhibits Elastase in Human Fibroblasts.

The strain Streptomyces osmaniensis CA-244599 isolated from the Comoros islands was submitted to liquid-state fermentation coupled to in situ solid-phase extraction with amberlite XAD-16 resin. Elution of the trapped compounds on the resin beads by ethyl acetate afforded seven metabolites, osmanicin (1), streptazolin (2), streptazone C (3), streptazone B1 (4), streptenol C (5), nocardamine (6) and desmethylenylnocardamine (7). Osmanicin (1) is a newly reported unusual scaffold combining streptazolin (2) and streptazone C (3) through a Diels-Alder type reaction. Experimental evidence excluded the spontaneous formation of 1 from 2 and 3. The isolated compounds were evaluated for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 1 exhibited the most potent activity with an IC50 of 3.7 µM.

Cercospora sp. as a source of anti-aging polyketides targeting 26S proteasome and scale-up production in submerged bioreactor.

From a large screening of microbial extracts for the discovery of proteasome modulating natural products, the fungal strain Cercospora sp. (CF-223709) was selected as the most promising for further investigation. Different liquid cultures of the strain were initially screened for their anti-oxidant activity (DPPH, ABTS) and for their cytotoxicity against the A2058, HepG2 and CCD25sk cell lines. A detailed chemical analysis and evaluation of the capacity to activate 26S-proteasome was followed for the most active extract. Three main polyketides were isolated and characterized by extensive analysis of NMR and HRMS spectra data as penialidine F (1), fulvic acid (2), and SB238569 (3). Fulvic acid showed the most significant anti-oxidant activity. Its IC50 value (8.16 µM) against the ABTS radical resulted 3-fold lower than the standard trolox. Fulvic acid also demonstrated a significant effect on proteasome by enhancing the chymotrypsin- and caspase-like activities of the 26S proteasome of human fibroblasts by 71.43% and 37.5% at 1 µM, respectively. Furthermore by scaling up the culture in a 30 L submerged bioreactor, Cercospora sp. produced up to 162.6 ±â€¯1.3 mg of fulvic acid/L. Our findings suggest that CF-223709 can be a promising source of proteasome activating natural compounds.

Unveiling Concealed Functions of Endosymbiotic Bacteria Harbored in the Ascomycete Stachylidium bicolor.

Among the plethora of unusual secondary metabolites isolated from Stachylidium bicolor are the tetrapeptidic endolides A and B. Both tetrapeptides contain 3-(3-furyl)-alanine residues, previously proposed to originate from bacterial metabolism. Inspired by this observation, we aimed to identify the presence of endosymbiotic bacteria in S. bicolor and to discover the true producer of the endolides. The endobacterium Burkholderia contaminans was initially detected by 16S rRNA gene amplicon sequencing from the fungal metagenome and was subsequently isolated. It was confirmed that the tetrapeptides were produced by the axenic B. contaminans only when in latency. Fungal colonies unable to produce conidia and the tetrapeptides were isolated and confirmed to be free of B. contaminans A second endosymbiont identified as related to Sphingomonas leidyi was also isolated. In situ imaging of the mycelium supported an endosymbiotic relationship between S. bicolor and the two endobacteria. Besides the technical novelty, our in situ analyses revealed that the two endobacteria are compartmentalized in defined fungal cells, prevailing mostly in latency when in symbiosis. Within the emerging field of intracellular bacterial symbioses, fungi are the least studied eukaryotic hosts. Our study further supports the Fungi as a valuable model for understanding endobacterial symbioses in eukaryotes.IMPORTANCE The discovery of two bacterial endosymbionts harbored in Stachylidium bicolor mycelium, Burkholderia contaminans and Sphingomonas leidyi, is described here. Production of tetrapeptides inside the mycelium is ensured by B. contaminans, and fungal sporulation is influenced by the endosymbionts. Here, we illustrate the bacterial endosymbiotic origin of secondary metabolites in an Ascomycota host.

Non-geminal Aliphatic Dihalogenation Pattern in Dichlorinated Diaporthins from Hamigera fusca NRRL 35721.

Two new epimeric dihalogenated diaporthins, (9 R *)-8-methyl-9,11-dichlorodiaporthin (2) and (9 S *)-8-methyl-9,11-dichlorodiaporthin (3), have been isolated from the soil fungus Hamigera fusca NRRL 35721 alongside the known regioisomeric isocoumarin 8-methyl-11,11-dichlorodiaporthin (1). Their structures were elucidated by high-resolution mass spectrometry and NMR spectroscopy combined with molecular modeling. Compounds 1-3 are the first isocoumarins and the first halogenated metabolites ever reported from the Hamigera genus. The new compounds 2 and 3 display a non-geminal aliphatic dichlorination pattern unprecedented among known fungal dihalogenated aromatic polyketides. A bifunctional methyltransferase/aliphatic halogenase flavoenzyme is proposed to be involved in the biosynthesis of dichlorinated diaporthins 1-3. These metabolites are weakly cytotoxic.

Draft Genome Sequence of Burkholderia contaminans 293K04B, an Endosymbiont of the Sponge-Derived Fungus Stachylidium bicolor.

Here, we present the draft genome of the endofungal symbiotic bacterium Burkholderia contaminans 293K04B, isolated from Stachylidium bicolor 293K04 (Ascomycota). The fungus was originally isolated from the sponge Callyspongia cf. C. flammeaS. bicolor 293K04 produces the endolides A-B, bioactive cyclic peptides possibly biosynthesized by its endobacterium B. contaminans 293K04B.

Insights into the Biosynthetic Origin of 3-(3-Furyl)alanine in Stachylidium sp. 293 K04 Tetrapeptides.

The marine-sponge-derived fungus Stachylidium sp. 293 K04 produces the N-methylated peptides endolide A (1) and endolide B (2), showing affinity for the vasopressin receptor 1A and serotonin receptor 5HT2B, respectively. Both peptides feature the rare amino acid 3-(3-furyl)alanine. Isotope labeling experiments, employing several 13C-enriched precursors, revealed that this unprecedented heterocyclic amino acid moiety in endolide A (1) is synthesized from a cyclic intermediate of the shikimate pathway, but not from phenylalanine. Two new tetrapeptide analogues, endolides C and D (3 and 4), were characterized, as well as the previously described hirsutide (5).

Endolides A and B, Vasopressin and Serotonin-Receptor Interacting N-Methylated Peptides from the Sponge-Derived Fungus Stachylidium sp.

The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia sp. cf. C. flammea. Culture on a biomalt medium supplemented with sea salt led to the isolation of two new, most unusual N-methylated peptides, i.e., the tetrapeptides endolide A and B (1 and 2). Both of these contain the very rare amino acid 3-(3-furyl)-alanine. In radioligand binding assays endolide A (1) showed affinity to the vasopressin receptor 1A with a Ki of 7.04 µM, whereas endolide B (2) exhibited no affinity to the latter receptor, but was selective toward the serotonin receptor 5HT2b with a Ki of 0.77 µM.

Biosynthesis of phenylnannolone A, a multidrug resistance reversal agent from the halotolerant myxobacterium Nannocystis pusilla B150.

The myxobacterial strain Nannocystis pusilla B150 synthesizes the structurally new polyketides phenylnannolone A­C. Apart from some common volatiles and siderophores, these are the first natural products from the genus Nannocystis. Phenylnannolone A shows inhibitory activity towards the ABCB1 gene product P-glycoprotein and reverses daunorubicin resistance in cancer cells. To decipher the biochemical reactions leading to the formation of phenylnannolone A, the putative biosynthetic genes were identified (phn1, phn2). Phn2 is a polyketide synthase (PKS) with an NRPS-like loading module, and its domain order is consistent with the phenylnannolone A structure. The functionality and substrate selectivity of the loading module were determined by means of a γ-18O4-ATP pyrophosphate exchange and a phosphopantetheine ejection assay. A specific activation of cinnamic acid by the AMP-ligase was detected. Phn1 is a putative butyryl-CoA carboxylase (BCC), providing ethylmalonyl-CoA for the formation of the ethyl-substituted part of phenylnannolone A. Phn1 is the first BCC found in biosynthetic genes for an ethyl-substituted natural compound. Biosynthesis of phenylnannolone A, putatively encoded by phn1 and phn2, thus utilizes the first biosynthetic machinery in which both a BCC and a PKS are involved.

Corallorazines from the myxobacterium Corallococcus coralloides.

The myxobacterium Corallococcus coralloides is the producer of the antibiotic compound corallopyronin A, which is currently in preclinical evaluation. To obtain suitable amounts of this antibiotic, the production strain C. coralloides B035 was cultured in large volumes, which in the addition to the isolation of the target molecule facilitates the detection of additional metabolites of this myxobacterial strain (corallorazines A-C). Corallorazine A is a new structural type of dipeptide composed of a dehydroalanine and a glycine moiety that are linked via a semiaminal bond, thus forming a piperazine ring. The latter is further connected via an amide bond to an unusual aliphatic acyl chain.

Unprecedented polyketides from a marine sponge-associated Stachylidium sp.

From the marine sponge-derived fungus Stachylidium sp. six novel phthalide-related compounds, cyclomarinone (1), maristachones A-E (2-5), and marilactone (6), were isolated. The structure of compound 1 comprises a hydroxycyclopentenone ring instead of the furanone ring characteristic for phthalides and represents a new carbon arrangement within polyketides. In the epimeric compounds 5a and 5b the phthalide (=isobenzofuranone) nucleus is modified to an isobenzofuran ring with ketal and acetal functionalities. Biosynthetically the structural skeletons of cyclomarinone (1) and maristachones A (2), C (4), D (5a), and E (5b) are most unusual due to the presence of an additional carbon atom when compared to the basic polyketide skeleton. This special biosynthetic feature also holds true for the likewise isolated polyketide marilactone (6).

Marilines A-C: novel phthalimidines from the sponge-derived fungus Stachylidium sp.

A marine-derived fungus of the genus Stachylidium was isolated from the sponge Callyspongia cf. C. flammea. Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A(1) (1a), A(2) (1b), B (2), and C (3). The absolute configurations of the enantiomeric compounds 1a and 1b were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A(1) (1a) and A(2) (1b), inhibited human leukocyte elastase (HLE) with an IC(50) value of 0.86 µM.