Antiproliferative potential of essential oil from the leaves of Croton floribundus (Euphorbiaceae) against human metastatic melanoma cell lines.

Melanoma is a cancer type with high lethality, metastatic capacity, and limited therapeutic options. Different essential oils have been reported with antitumoral potential.  Thus, the essential oil (EO) of the leaves of C. floribundus was obtained by hydrodistillation and analyzed by GC-MS. The majority of substances annotated were ß-selinene, E-Caryophyllene, and Premnaspirodiene. The cytotoxic activity of EO was evaluated on three melanoma cell lines SKMEL-147, WM-1366, and CHL-1, which are representative of metastatic melanoma with different mutation profiles. The IC50 values found for EO were lower than temozolomide (reference drug) in all melanoma cell lines. In addition, the selectivity of EO was upward when compared to the reference drug. Interestingly, the WM-1366 cell line was the most responsive, and these findings are very promising considering that it has shown high resistance to the plethora of compounds. Thus,  the C. floribundus EO is a promising source to drive further studies for the development of new treatments for metastatic melanoma, which is urgently relevant given the resistance of this pathology to current treatments.

Integrative open workflow for confident annotation and molecular networking of metabolomics MSE/DIA data.

Liquid chromatography coupled with high-resolution mass spectrometry data-independent acquisition (LC-HRMS/DIA), including MSE, enable comprehensive metabolomics analyses though they pose challenges for data processing with automatic annotation and molecular networking (MN) implementation. This motivated the present proposal, in which we introduce DIA-IntOpenStream, a new integrated workflow combining open-source software to streamline MSE data handling. It provides 'in-house' custom database construction, allows the conversion of raw MSE data to a universal format (.mzML) and leverages open software (MZmine 3 and MS-DIAL) all advantages for confident annotation and effective MN data interpretation. This pipeline significantly enhances the accessibility, reliability and reproducibility of complex MSE/DIA studies, overcoming previous limitations of proprietary software and non-universal MS data formats that restricted integrative analysis. We demonstrate the utility of DIA-IntOpenStream with two independent datasets: dataset 1 consists of new data from 60 plant extracts from the Ocotea genus; dataset 2 is a publicly available actinobacterial extract spiked with authentic standard for detailed comparative analysis with existing methods. This user-friendly pipeline enables broader adoption of cutting-edge MS tools and provides value to the scientific community. Overall, it holds promise for speeding up metabolite discoveries toward a more collaborative and open environment for research.

Phytochemical investigation of Nigrospora zimmermanii isolated from Poincianella pluviosa (Sibipiruna): metabolites characterisation and screening for anti-inflammatory activity.

Endophytic fungi residing symbiotically in plant tissues are promising sources of bioactive natural products. This study explored the anti-inflammatory potential of an endophytic fungus isolated from the Brazilian medicinal plant Poincianella pluviosa (Sibipiruna). The extract from the endophyte FPD13 exhibited potential ex vivo anti-inflammatory effects by inhibiting prostaglandin E2 (PGE2) release by 75.22%. Phytochemical analysis using High-Performance Liquid Chromatography (HPLC), Nuclear Magnetic Resonance (NMR), and Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) enabled the isolation and identification of three compounds, including the macrolide Nigrosporolide, the phenyl-propanol Tyrosol, and the terpene Decarestrictine A. Morphological characteristics and Internal Transcribed Spacers region (ITS) sequencing classified fungus FPD13 as Nigrospora zimmermanii. The results reveal the anti-inflammatory potential and chemical diversity of P. pluviosa endophytes, warranting further investigation into the bioactivity and structure elucidation of their bioactive metabolites.

In Situ Preparation of Dehydrodieugenol-Loaded Silver Nanoparticles and their Antischistosomal Activity.

Schistosomiasis is a major neglected disease that imposes a substantial worldwide health burden, affecting approximately 250 million people globally. As praziquantel is the only available drug to treat schistosomiasis, there is a critical need to identify new anthelmintic compounds, particularly from natural sources. To enhance the activity of different natural products, one potential avenue involves its combination with silver nanoparticles (AgNP). Based on this approach, a one-step green method for the in situ preparation of dehydrodieugenol (DHDG) by oxidation coupling reaction using silver and natural eugenol is presented. AgNP formation was confirmed by UV-Vis spectroscopy due to the appearance of the surface plasmon resonance (SPR) band at 430 nm which is characteristic of silver nanoparticles. The nanoparticles were spherical with sizes in the range of 40 to 50 nm. Bioassays demonstrated that the silver nanoparticles loaded with DHDG exhibited significant anthelmintic activity against Schistosoma mansoni adult worms without toxicity to mammalian cells and an in vivo animal model (Caenorhabditis elegans), contributing to the development of new prototypes based on natural products for the treatment of schistosomiasis.

Evaluation of the anti-inflammatory activity of Acacia polyphylla and identification of a new apigenin-3-C- glycosylated type flavonoid.

Owing to the potentially harmful adverse effects of current anti-inflammatory drugs, there is a need to identify new alternative substances. Thus, this study aimed to perform a phytochemical analysis of A. polyphylla to identify compounds responsible for its anti-inflammatory activity. Several fractions of the A. polyphylla extract were obtained and evaluated in an ex vivo anti-inflammatory assay using fresh human blood. Among the evaluated fractions, the BH fraction displayed the highest percentage of PGE2 inhibition (74.8%) compared to the reference drugs dexamethasone and indomethacin, demonstrating its excellent potential for anti-inflammatory activity. Astragalin (P1), a known 3-O-glucoside of kaempferol, was isolated from the A. polyphylla extract for the first time. In addition, a new compound (P2) was isolated and identified as the apigenin-3-C-glycosylated flavonoid. Astragalin showed moderate PGE2 activity (48.3%), whereas P2 was not anti-inflammatory. This study contributes to the phytochemical studies of A. polyphylla and confirms its anti-inflammatory potential.

Bioprospecting-based untargeted metabolomics identifies alkaloids as potential anti-inflammatory bioactive markers of Ocotea species (Lauraceae).

BACKGROUND: Species within the Ocotea genus (Lauraceae), have demonstrated an interesting profile of bioactivities. Renowned for their diverse morphology and intricate specialized metabolite composition, Ocotea species have re-emerged as compelling candidates for bioprospecting in drug discovery research. However, it is a genus insufficiently studied, particularly regarding anti-inflammatory activity. PURPOSE: To investigate the anti-inflammatory activity of Ocotea spp. extracts and determine the major markers in this genus. METHODS: Extracts of 60 different Ocotea spp. were analysed by an ex vivo anti-inflammatory assay in human whole blood. The experiment estimates the prostaglandin E2 levels, which is one of the main mediators of the inflammatory cascade, responsible for the classical symptoms of fever, pain, and other common effects of the inflammatory process. Untargeted metabolomics analysis through liquid chromatography coupled with high-resolution mass spectrometry was performed, along with statistical analysis, to investigate which Ocotea metabolites are correlated with their anti-inflammatory activity. RESULTS: The anti-inflammatory screening indicated that 49 out of 60 Ocotea spp. extracts exhibited significant inhibition of PGE2 release compared to the vehicle (p < 0.05). Furthermore, 10 of these extracts showed statistical similarity to the reference drugs. The bioactive markers were accurately identified using multivariate statistics combined with a fold change (> 1.5) and adjusted false discovery rate analysis as unknown compounds and alkaloids, with a majority of aporphine and benzylisoquinolines. These alkaloids were annotated with an increased level of confidence since MSE spectra were compared with comprehensive databases. CONCLUSION: This study represents the first bioprospecting report revealing the anti-inflammatory potential of several Ocotea spp. The determination of their anti-inflammatory markers could contribute to drug discovery and the chemical knowledge of the Ocotea genus.

Insecticidal activity of extracts of handroanthus impetiginosus on Plutella xylostella (Lepidoptera: plutellidae) larvae.

Plutella xylostella is considered the main pest of cabbage in Brazil and the world, causing damage of up to 100%. Thus, this study evaluated the insecticidal activity of extracts obtained from the fruits, seeds, bark, leaves, and flowers of Handroanthus impetiginosus against the diamondback moth, P. xylostella larvae. The seed extract showed the highest mortality (97.0%) compared to the control treatment. The LC50 values indicated that the seed and flower extracts (0.01003 and 0.01288 mg/L respectively) assumed the highest toxicity to P. xylostella larvae after 24 h of exposure. The results of this study indicated that the seeds extract is the most promising toxic extract, with measured mortality of approximately 97.0% for P. xylostella larvae after 144 h of exposure in kale plants. Seed extract showed the best insecticidal activity. Thus, this extract can be applied to develop an insecticide based on H. impetiginosus seed.

Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design.

Gibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these compounds against T. cruzi trypomastigotes and explore structure-activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups - ester and amide - and variating the substituent at the p-position in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC50 < 20 µM) and no mammalian cytotoxicity to fibroblasts (CC50 > 200 µM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results suggested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.

New bicyclic [3.2.1] octane neolignan derivative from Aniba firmula.

bicyclic [3.2.1] octane neolignans have garnered increasing interest, because of their unique structural features and biological activities. This study describes the isolation and identification of a new bicyclic octane neolignan 1 obtained through fractionation of the crude extract of the stem of Aniba firmula (Lauraceae family). The structure of bicyclic octane neolignan 1 was determined through NMR analysis and mass spectrometry data.

Dereplication of Cytochalasans and Octaketides in Cytotoxic Extracts of Endophytic Fungi from Casearia arborea (Salicaceae).

Endophytes have been shown to be a source of novel drug prototypes. The Casearia genus is known for presenting cytotoxic clerodane diterpenes; however, there are few reports on secondary metabolites produced by its fungal microbiota. Thus, in the present study endophytic fungi obtained from the fresh leaves of C. arborea were grown in potato dextrose broth and rice to perform a secondary metabolite prospection study. The cytotoxic profile of the crude extracts at 10 µg/mL was determined by a colorimetric assay on tumor cell lines. The endophytes producing cytotoxic extracts were identified through phylogenetic analysis and belong to Diaporthe and Colletotrichum species. Metabolites present in these extracts were organized in molecular networking format based on HRMS-MS, and a dereplication process was performed to target compounds for chromatographic purification. Metabolic classes, such as lipids, peptides, alkaloids, and polyketides were annotated, and octaketide and cytochalasin derivatives were investigated. Cytochalasin H was purified from the cytotoxic Diaporthe sp. CarGL8 extract and its cytotoxic activity was determined on human cancer cell lines A549, MCF-7, and HepG2. The data collected in the present study showed that molecular networking is useful to understand the chemical profile of complex matrices to target compounds, minimizing the cost and time spent in purification processes.

Ex vivo inhibition of PGE2 formation in human blood by four bicyclico [3.2.1] octane neolignans isolated from Aniba firmula bark, two with unusual structural pattern.

The phytochemical investigation of the stem bark crude extract of Aniba firmula (Lauraceae) led to the isolation of undescribed bicyclic [3.2.1] octane neolignans, 1 and 2, characterized by unusual bicyclic patterns and two other known bicyclic neolignans 3 and 4. Anti-inflammatory bicyclic [3.2.1] octane neolignans metabolites were previously reported in the literature, and the A. firmula stands out in the Lauraceae family as a source of potentially bioactive compounds. Thus, herein the anti-inflammatory potential of four isolated compounds from A. firmula was accessed via an ex vivo anti-inflammatory model that included plasmatic quantification of the prostaglandin E2 (PGE2) inflammatory mediator. Compounds 2 and 3 exhibited significant anti-inflammatory activity by inhibiting the production of PGE2 in plasma samples, thus by interference with the cyclooxygenase (COX) inflammatory pathway. Therefore, these findings demonstrate that the bicyclic octane neolignan classes [3.2.1] can present anti-inflammatory potential.

Absolute Configuration and Antileishmanial Activity of (-)-Cyclocolorenone Isolated from Duguetia lanceolata (Annonaceae).

BACKGROUND: The fractionation of the n-hexane phase of the EtOH extract from the leaves of Duguetia lanceolata (Annonaceae) led to the identification of the sesquiterpene (-)-cyclocolorenone. OBJECTIVES: Chemical characterization, including determination of the absolute stereochemistry, and in vitro evaluation of antileishmanial activity of the sesquiterpene (-)-cyclocolorenone, isolated from D. lanceolata, were carried out. METHODS: (-)-Cyclocolorenone was isolated from D. lanceolata leaves using different chromatographic steps and its structure was defined by analysis of NMR and ESI-HRMS data. Additionally, the absolute configuration of (-)-cyclocolorenone was ambiguously assigned by means of vibrational circular dichroism (VCD). Antileishmanial activity of (-)-cyclocolorenone was evaluated on promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. The integrity of the cell membrane of L. (L.) amazonensis was analyzed using the SYTOX green probe. RESULTS: (-)-(1R,6S,7R,10R)-Cyclocolorenone displayed activity against promastigotes and amastigotes forms of L. (L.) amazonensis with IC50 of 4.54 and 28.44 µM, respectively. Furthermore, this compound was non-toxic in J774 macrophage cells (CC50 > 458.71 µM) with a selectivity index > 100 (promastigotes) and > 32.2 (amastigotes). Additionally, (-)-cyclocolorenone was observed to target the parasite cell membrane. CONCLUSION: Obtained data suggested that (-)-cyclocolorenone, in which absolute configuration was determined, can be considered as a scaffold for the development of new drugs for the treatment of leishmaniasis.

Identification of flavonoid-3-O-glycosides from leaves of Casearia arborea (Salicaceae) by UHPLC-DAD-ESI-HRMS/MS combined with molecular networking and NMR.

INTRODUCTION: Casearia is an essential source of cytotoxic highly oxidised clerodane diterpenes, in addition to phenolics, flavonoids, and glycoside derivatives. Here we identify flavonoid-3-O-glycoside derivatives in the ethyl acetate (EtOAc) fraction of the methanolic extract from leaves C. arborea leaves. OBJECTIVE: To characterise the EtOAc phase from the methanolic extract of C. arborea leaves using ultra-high-performance liquid chromatography diode array detector high-resolution tandem mass spectrometry (UHPLC-DAD-HRMS/MS) and molecular networking-based dereplication. Methodology We identified compounds not annotated in the GNPS platform by co-injection of standards in HPLC-DAD or by isolation and characterisation of the metabolites using nuclear magnetic resonance (NMR) spectroscopy. A workflow on the GNPS platform aided the organisation of spectral data and dereplication by annotations. We subjected the EtOAc phase to HPLC-DAD analysis using standard compound co-injection to corroborate the GNPS annotations. We isolated unidentified compounds with semi-preparative HPLC-DAD for structural identification using NMR. RESULTS: We annotated a molecular family of flavonoid-3-O-glycosides in the molecular networking created using the GNPS platform. These included avicularin, cacticin, isoquercitrin, quercitrin, rutin, and a quercetin-3-O-pentoside cluster. We confirmed the annotations with standard compounds using HPLC-DAD co-injection analysis, besides identifying quercetin-3-O-robinobioside and kaempferol. We isolated three flavonoid-3-O-pentosides and characterised them using one- and two-dimensional NMR; we identified them as reynoutrin, guaijaverin, and avicularin. CONCLUSION: This work describes the isolation of kaempferol and nine known flavonoid-3-O-glycosides from the polar fraction of the methanolic extract (EtOAc) from C. arborea leaves using molecular networking to guide the chromatographic procedures. We identified eight compounds for the first time in Casearia that amplify and reinforce the genus' chemotaxonomy with the presence of glycosylated flavonoids.

Aporphine Alkaloids from Ocotea puberula with Anti-Trypanosoma Cruzi Potential - Activity of Dicentrine-ß-N-Oxide in the Plasma Membrane Electric Potentials.

One new aporphine, dicentrine-ß-N-oxide (1), together with five related known alkaloids dehydrodicentrine (2), predicentrine (3), N-methyllaurotetanine (4), cassythicine (5), and dicentrine (6) were isolated from the leaves of Ocotea puberula (Lauraceae). Antiprotozoal activity of the isolated compounds was evaluated in vitro against trypomastigote forms of Trypanosoma cruzi. Among the tested compounds, alkaloid 1 exhibited higher potential with EC50 value of 18.2 µM and reduced toxicity against NCTC cells (CC50 >200 µM - SI>11.0), similar to positive control benznidazole (EC50 of 17.7 µM and SI=10.7). Considering the promising results of dicentrine-ß-N-oxide (1) against trypomastigotes, the mechanism of parasite death caused by this alkaloid was investigated. As observed, this compound reached the plasma membrane electric potential directly after 2 h of incubation and triggered mitochondrial depolarization, which probably leads to trypomastigote death. Therefore, dicentrine-ß-N-oxide (1), reported for the first time in this work, can contribute to future works for the development of new trypanocidal agents.

Neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: applicability to Parkinson's disease.

ETHNOPHARMACOLOGY RELEVANCE: Ayahuasca is a tea produced through decoction of Amazonian plants. It has been used for centuries by indigenous people of South America. The beverage is considered to be an ethnomedicine, and it is traditionally used for the treatment of a wide range of diseases, including neurological illness. Besides, some scientific evidence suggests it may be applicable to Parkinson's disease (PD) treatment. Thus, Ayahuasca deserves in depth studies to clarify its potential role in this disease. AIM OF THE STUDY: This study aimed to use an untargeted metabolomics approach to evaluate the neuroprotective potential of the Ayahuasca beverage, the extracts from its matrix plants (Banisteriopsis caapi and Psychotria viridis), its fractions and its main alkaloids on the viability of SH-SY5Y neuroblastoma cells in an in vitro PD model. MATERIAL AND METHODS: The cytotoxicity of Ayahuasca, crude extracts, and fractions of B. caapi and P. viridis, as well as neuroprotection promoted by these samples in a 6-hydroxydopamine (6-OHDA)-induced neurodegeneration model, were evaluated by the MTT assay at two time-points: 48 h (T1) and 72 h (T2). The main alkaloids from Ayahuasca matrix plants, harmine (HRE) and N,N-dimethyltryptamine (DMT), were also isolated and evaluated. An untargeted metabolomics approach was developed to explore the chemical composition of samples with neuroprotective activity. Ultra-Performance Liquid Chromatography coupled to Electrospray Ionisation and Time-of-Flight (UPLC-ESI-TOF) metabolome data was treated and further analysed using multivariate statistical analyses (MSA): principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The metabolites were dereplicated using the Dictionary of Natural Products and an in house database. The main alkaloids were also quantified by UPLC-MS/MS. RESULTS: The samples did not cause cytotoxicity in vitro and three of samples intensely increased cell viability at T1. The crude extracts, alkaloid fractions and HRE demonstrated remarkable neuroprotective effect at T2 while the hydroalcoholic fractions demonstrated this neuroprotective effect at T1 and T2. Several compounds from different classes, such as ß-carbolines and monoterpene indole alkaloids (MIAs) were revealed correlated with this property by MSA. Additionally, a total of 2419 compounds were detected in both ionisation modes. HRE showed potent neuroprotective action at 72 h, but it was not among the metabolites positively correlated with the most efficacious neuroprotective profile at either time (T1 and T2). Furthermore, DMT was statistically important to differentiate the dataset (VIP value > 1), although it did not exhibit sufficient neuroprotective activity by in vitro assay, neither a positive correlation with T1 and T2 neuroprotective profile, which corroborated the MSA results. CONCLUSION: The lower doses of the active samples stimulated neuronal cell proliferation and/or displayed the most efficacious neuroprotection profile, namely by preventing neuronal damage and improving cell viability against 6-OHDA-induced toxicity. Intriguingly, the hydroalcoholic fractions exhibited enhanced neuroprotective effects when compared to other samples and isolated alkaloids. This finding corroborates the significance of a holistic approach. The results demonstrate that Ayahuasca and its base plants have potential applicability for PD treatment and to prevent its progression differently from current drugs to treat PD.

Anti-urolithiatic and anti-inflammatory activities through a different mechanism of actions of Cissus gongylodes corroborated its ethnopharmacological historic.

ETHNOPHARMACOLOGICAL RELEVANCE: Species Cissus gongylodes has been used in the traditional medicine in South America and India for the treatment of urolithiasis, biliary and inflammatory problems without any scientific evidence. AIM OF THE STUDY: This work was developed to investigate for the first time the anti-inflammatory and anti-urolithiatic activities of leaf decoction of C. gongylodes. MATERIALS AND METHODS: Decoction was subjected to anti-inflammatory evaluation by the in vivo assay of ear oedema and quantification of the main mediators of inflammation PGE2 and LTB4, and the cytokine TNF-α. The decoction's anti-urolithiatic activity was determined by different in vitro assays to evaluate the inhibition and dissolution of the most prevalent types of kidney stones: calcium oxalate (CaOx) and struvite. Diffusion in gel technique and fresh urine of a patient with renal stone were used to investigate the inhibition and dissolution of CaOx, respectively, and the single diffusion gel growth technique was used to evaluate the inhibition and dissolution of struvite crystals. The decoction was chemically characterized by UHPLC-ESI-HRMS analysis. RESULTS: Decoction showed in vivo anti-inflammatory activity by potent decreasing the level of both the main mediators of inflammation and dose-dependent in vitro anti-urolithiatic action by inhibition and dissolution of both type of crystals, CaOx and struvite. CONCLUSIONS: Results obtained corroborate the reports of the traditional use of the decoction of Cissus gongylodes. Besides, it showed multi-target mechanisms actions, inhibition of the main inflammatory pathways, and inhibition/dissolution of the most prevalent types of crystals on urolithiasis. These actions make the decoction a promissory source to the development of new and more efficient drugs.

Anti-Inflammatory Derivatives with Dual Mechanism of Action from the Metabolomic Screening of Poincianella pluviosa.

Metabolomics approaches have become fundamental strategies for the analysis of complex mixtures, guiding the isolation of target compounds by focusing on unpublished or promising pharmacological properties. The discovery of novel anti-inflammatory agents is important due to several limitations regarding their potency, efficacy, and adverse effects. Thus, novel anti-inflammatory candidates are essential, aiming to find agents with better mechanisms of action. In this context, extracts from Poincianella pluviosa var. peltophoroides demonstrated significant in vivo anti-inflammatory potential. Thus, metabolomics analysis based on UHPLC-UV-HRFTMS data was performed for the identification of biomarkers with anti-inflammatory properties. Metabolomics-guided chromatographic process led to the isolation of novel compounds 4‴-methoxycaesalpinioflavone and 7-methoxycaesalpinioflavone, as well as known derivatives rhuschalcone VI and caesalpinioflavone. Isolated compounds caused edema inhibition and neutrophil recruitment. Two of them showed better efficacy than reference drugs (indomethacin and dexamethasone). Results of in vivo experiments corroborated those obtained through metabolomics and statistical analyses guiding the isolation of substances of interest.

A selective genome-guided method for environmental Burkholderia isolation.

The genus Burkholderia is an emerging source of novel natural products chemistry, yet to date few methods exist for the selective isolation of strains of this genus from the environment. More broadly, tools to efficiently design selection media for any given genus would be of significant value to the natural products and microbiology communities. Using a modification of the recently published SMART protocol, we have developed a two-stage isolation protocol for strains from the genus Burkholderia. This method uses a combination of selective agar isolation media and multiplexed PCR profiling to derive Burkholderia strains from environmental samples with 95% efficiency. Creation of this new method paves the way for the systematic exploration of natural products chemistry from this important genus and offers new insight into potential methods for selective isolation method development for other priority genera.

Design and Synthesis of New Benzophenone Derivatives with In Vivo Anti-Inflammatory Activity through Dual Inhibition of Edema and Neutrophil Recruitment.

A series of novel benzophenone derivatives containing a thiazole heterocyclic nucleus were designed by molecular hybridization. Molecular docking studies have demonstrated the inhibitory potential of the designed compounds against cyclooxygenase (COX) isoenzymes. These compounds were synthesized, characterized, and evaluated for their anti-inflammatory properties by the croton oil-induced ear edema assay to examine their effect on both prostaglandin (PG) production and neutrophils recruitment. The thiazole derivatives displayed a potent effect in terms of reducing ear edema. The analysis suggested that the presence of 4-phenyl-2-hydrazinothiazole and the absence of C4'-OCH3 on the benzophenone derivative structure are strongly related to the inhibition of PG production. In addition, the derivatives 2e, 3a and 3c concomitantly inhibit PG production and neutrophil recruitment, which may be a mechanism of action better than of common NSAIDs due to their inability to inhibit the neutrophil recruitment. Thus, these compounds can be considered as potential lead compounds toward the development of new anti-inflammatory drugs with an innovating mechanism of action.

Predictive metabolomic signatures of end-stage renal disease: A multivariate analysis of population-based data.

The variability of molecular signatures and predictive low molecular weight markers of chronic kidney disease (CKD) in different populations are poorly understood. Thus, in a large sample with 4763 people we compare the molecular signatures and metabolites with diagnostic relevance in plasma and urine of CKD patients of different geographical origins. From an integrated model based on dynamic networks and multivariate statistics, metabolites with predictive value obtained from targeted and untargeted molecular analysis, interactions between metabolic pathways affected by CKD, and the methodological quality of metabolomic studies were analyzed. The metabolites 3-methylhistidine, citrulline, kynurenine, p-cresol sulfate, urea, and citrate presented consistent expression in all population groups. Only increased kynurenine and p-cresol sulfate in plasma samples obtained acceptable scores as CKD biomarkers, independent of geographic origin. Metabolites such as leucine, alanine, isoleucine, serine, histidine, and citrate were nodal points, indicating that protein metabolism pathways are similarly impaired in Asian, European and North American patients. Based on our integrated model, we show that the metabolome of CKD patients exhibits a strong geographic influence, leading to unique metabolic signatures. Contrary to the likelihood of molecular similarities between geographically distinct populations, metabolic convergences in protein metabolism pathways and the molecules kynurenine and p-cresol sulfate were relevant as general predictors of CKD. In general, the quality assessment indicated that the current evidence is based on research models with variable methodological quality, whose limitations described in this study should be considered in the refinement of molecular approaches.