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Protocatechuate acid (PCA) is a phenolic acid naturally synthesized by various organisms. Protocatechuic acid is synthesized by plants for physiological, metabolic functions, and self-defense, but extraction from plants is less efficient compared to the microbial culture process. The microbial synthesis of protocatechuic acid is sustainable and, due to its high yield, can save energy consumption when producing the same amount. To enhance PCA production using Corynebacterium glutamicum, a statistical optimization of the production medium was performed using full factorial design, the steepest ascent method, and the response surface method. The optimized production medium enabled a PCA production of over 5 g/L in a 72 h batch culture. However, PCA cytotoxicity affected the strain growth and PCA production rate, with an inhibitory concentration of approximately 5 g/L in the fermentation broth. Finally, continuous fermentation was operated for 150 h in the steady-state mode, maintaining the concentration of PCA below 5 g/L. The optimization method established in this study successfully increased PCA production levels, and the findings presented herein are anticipated to contribute to the industrialization of PCA production using C. glutamicum.

Continuous cropping changes soil physiochemical parameters, enzymes and microorganism communities, causing “replant problem” in strawberry cultivation. We hypothesized that soil nematode community would reflect the changes in soil conditions caused by long-term continuous cropping, in ways that are consistent and predictable. To test this hypothesis, we studied the soil nematode communities and several soil parameters, including the concentration of soil phenolic acids, organic matter and nitrogen levels, in strawberry greenhouse under continuous-cropping for five different durations. Soil pH significantly decreased, and four phenolic acids, i.e., p-hydroxybenzoic acid, ferulic acid, cinnamic acid and p-coumaric acid, accumulated with time under continuous cropping. The four phenolic acids were highly toxic to Acrobeloides spp., the eudominant genus in non-continuous cropping, causing it to reduce to a resident genus after seven-years of continuous cropping. Decreased nematode diversity indicated loss of ecosystem stability and sustainability because of continuous-cropping practice. Moreover, the dominant decomposition pathway was altered from bacterial to fungal under continuous cropping. Our results suggest that along with the continuous-cropping time in strawberry habitat, the soil food web is disturbed, and the available plant nutrition as well as the general health of the soil deteriorates; these changes can be indicated by soil nematode community.

The marine dinoflagellate Gymnodinium catenatum has been associated with paralytic shellfish poisoning (PSP) outbreaks in Portuguese waters for many years. PSP syndrome is caused by consumption of seafood contaminated with paralytic shellfish toxins (PSTs), a suite of potent neurotoxins. Gymnodinium catenatum was frequently reported along the Portuguese coast throughout the late 1980s and early 1990s, but was absent between 1995 and 2005. Since this time, G. catenatum blooms have been recurrent, causing contamination of fishery resources along the Atlantic coast of Portugal. The aim of this study was to evaluate the toxin profile of G. catenatum isolated from the Portuguese coast before and after the 10-year hiatus to determine changes and potential impacts for the region. Hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) was utilized to determine the presence of any known and emerging PSTs in sample extracts. Several PST derivatives were identified, including the N-sulfocarbamoyl analogues (C1-4), gonyautoxin 5 (GTX5), gonyautoxin 6 (GTX6), and decarbamoyl derivatives, decarbamoyl saxitoxin (dcSTX), decarbamoyl neosaxitoxin (dcNeo) and decarbamoyl gonyautoxin 3 (dcGTX3). In addition, three known hydroxy benzoate derivatives, G. catenatum toxin 1 (GC1), GC2 and GC3, were confirmed in cultured and wild strains of G. catenatum. Moreover, two presumed N-hydroxylated analogues of GC2 and GC3, designated GC5 and GC6, are reported. This work contributes to our understanding of the toxigenicity of G. catenatum in the coastal waters of Portugal and provides valuable information on emerging PST classes that may be relevant for routine monitoring programs tasked with the prevention and control of marine toxins in fish and shellfish.

Primary coenzyme Q 10 (CoQ 10 ) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype–phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene ( Coq9 Q95X and Coq9 R239X ), and their responses to 2,4‐dihydroxybenzoic acid (2,4‐diHB). Coq9 R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4‐diHB increasing CoQ levels. In contrast, Coq9 Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late‐onset mild mitochondrial myopathy, which does not respond to 2,4‐diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9 R239X mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype–phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder. Synopsis Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences. The first mouse model of mild mitochondrial myopathy due to CoQ deficiency was generated and characterized ( Coq9 Q95X ). The clinical phenotypes of CoQ deficiency observed in two mouse models ( Coq9 Q95X and Coq9 R239X ) are caused by genotypic difference in the Coq9 gene and were influenced by the efficiency of nonsense‐mediated mRNA decay. CoQ multiprotein complex for CoQ biosynthesis was destabilized by the presence of a truncated protein in Coq9 R239X mice, leading to a severe CoQ deficiency and clinical phenotype. Whether a bypass therapy aimed at increasing CoQ biosynthesis is successful depends on CoQ biosynthetic proteins levels. Graphical Abstract Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences.

Formation of advanced glycation end products (AGEs), which are associated with diabetes mellitus, contributes to prominent features of osteoarthritis, i.e., inflammation-mediated destruction of articular cartilage. Among the phytochemicals which play a role in anti-inflammatory effects, anthocyanins have also been demonstrated to have anti-diabetic properties. Purple corn is a source of three major anthocyanins: cyanidin-3-O-glucoside, pelargonidin-3-O-glucoside and peonidin-3-O-glucoside. Purple corn anthocyanins have been demonstrated to be involved in the reduction of diabetes-associated inflammation, suggesting that they may have a beneficial effect on diabetes-mediated inflammation of cartilage. This investigation of the chondroprotective effects of purple corn extract on cartilage degradation found a reduction in glycosaminoglycans released from AGEs induced cartilage explants, corresponding with diminishing of uronic acid loss of the cartilage matrix. Investigation of the molecular mechanisms in human articular chondrocytes showed the anti-inflammatory effect of purple corn anthocyanins and the metabolite, protocatechuic acid (PCA) on AGEs induced human articular chondrocytes via inactivation of the NFκb and MAPK signaling pathways. This finding suggests that purple corn anthocyanins and PCA may help ameliorate AGEs mediated inflammation and diabetes-mediated cartilage degradation.

Topoisomerase inhibitors are effective for antibacterial and anticancer therapy because they can lead to the accumulation of the intermediate DNA cleavage complex formed by the topoisomerase enzymes, which trigger cell death. Here we report the application of a novel enzyme-based high-throughput screening assay to identify natural product extracts that can lead to increased accumulation of the DNA cleavage complex formed by recombinant Yersinia pestis topoisomerase I as part of a larger effort to identify new antibacterial compounds. Further characterization and fractionation of the screening positives from the primary assay led to the discovery of a depside, anziaic acid, from the lichen Hypotrachyna sp. as an inhibitor for both Y. pestis and Escherichia coli topoisomerase I. In in vitro assays, anziaic acid exhibits antibacterial activity against Bacillus subtilis and a membrane permeable strain of E. coli. Anziaic acid was also found to act as an inhibitor of human topoisomerase II but had little effect on human topoisomerase I. This is the first report of a depside with activity as a topoisomerase poison inhibitor and demonstrates the potential of this class of natural products as a source for new antibacterial and anticancer compounds.

We characterize a novel nanocomposite that acts as an efficient anticancer agent. This nanocomposite consists of zinc layered hydroxide intercalated with protocatechuate (an anionic form of protocatechuic acid), that has been synthesized using a direct method with zinc oxide and protocatechuic acid as precursors. The resulting protocatechuic acid nanocomposite (PAN) showed a basal spacing of 12.7 Å, indicating that protocatechuate was intercalated in a monolayer arrangement, with an angle of 54° from the Z-axis between the interlayers of the zinc layered hydroxide, and an estimated drug loading of about 35.7%. PAN exhibited the properties of a mesoporous type material, with greatly enhanced thermal stability of protocatechuate as compared to its free counterpart. The presence of protocatechuate in the interlayers of the zinc layered hydroxide was further supported by Fourier transform infrared spectroscopy. Protocatechuate was released from PAN in a slow and sustained manner. This mechanism of release was well represented by a pseudo-second order kinetics model. PAN has shown increased cytotoxicity compared to the free form of protocatechuic acid in all cancer cell lines tested. Tumor growth suppression was extensive, particularly in HepG2 and HT29 cell lines. PAN is suitable for use as a controlled release formulation, and our in vitro evidence indicates that PAN is an effective anticancer agent. PAN may have potential as a chemotherapeutic drug for human cancer.

Widespread emergence of antibiotic-resistant pathogens in recent years has restricted the treatment options for various infectious diseases. Investigation of alternative antimicrobial agents and therapies is thus of utmost importance. Electrospinning of 50 mg/ml 2,3-dihydroxybenzoic acid (DHBA) into 24 % (w/v) poly( d , l -lactide) (PDLLA) and poly(ethylene oxide) (PEO) (1:1) produced nanofibers with an average diameter of 401 ± 122 nm. DHBA released from the nanofibers (315 ± 0.04 µg/ml within 2 h) inhibited the growth of Pseudomonas aeruginosa Xen 5, Klebsiella pneumoniae Xen 39, Escherichia coli Xen 14, Salmonella typhimurium Xen 26, and Staphylococcus aureus strains Xen 30, Xen 31, and Xen 36. The reason for the rapid diffusion of DHBA from PEO:PDLLA may be due to formation of hydrogen bonds between the hydroxyl groups of DHBA and the C=O groups of the PDLLA. DHBA formed a strong interaction with PDLLA and increased the thermal stability of the nanofiber mesh. The DHBA-containing nanofibers were non-hemolytic, suggesting that they may be incorporated in the development of a wound dressing.

Leaves of Chrysanthemum morifolium cv. Ramat were extracted sequentially with hexane, ethyl acetate, and methanol. The methanol fraction, when incorporated into artificial diet was found to reduce the growth of cabbage looper (Trichoplusia ni Hubner) larvae at concentrations between 500 and 5000 ppm of diet. Fractionation of the methanol extract on a Sephadex column yielded five fractions, three of which reduced the weight of larvae relative to the control. One fraction was analyzed using high performance liquid chromatography (HPLC) and found to contain three main constituents. These compounds were purified using a combination of gel permeation chromatography on Sephadex LH20 and HPLC, and analyzed by 1H and 13C NMR as well as undergoing chemical and physical analyses. The compounds were identified as: 1, chlorogenic acid (5-O-caffeoylquinic acid); 2, 3,5-O-dicaffeoylquinic acid; and 3, 3', 4', 5-trihydroxyflavanone 7-O-glucuronide (eriodictyol 7-O-glucuronide). At concentrations between 100 to 1000 ppm these compounds reduced both growth and photosynthesis of Lemna gibba L. with the order of efficacy being: flavanone > chlorogenic acid > 3,5-O-dicaffeoylquinic acid. Furthermore, when incorporated separately into artificial diet these compounds, at 10 to 1000 ppm, enhanced or reduced growth of the cabbage looper (Trichoplusia ni) and gypsy moth (Lymantria dispar L.).

Background Foodstuffs of both plant and animal origin contain a wide range of bioactive compounds. Although human intervention studies are mandatory to assess the health effects of bioactives, the in vitro approach is often used to select the most promising molecules to be studied in vivo. To avoid misleading results, concentration and chemical form, exposure time, and potential cytotoxicity of the tested bioactives should be carefully set prior to any other experiments. Methods In this study the possible cytotoxicity of different bioactives (docosahexaenoic acid, propionate, cyanidin-3-O-glucoside, protocatechuic acid), was investigated in HepG2 cells using different methods. Bioactives were supplemented to cells at different concentrations within the physiological range in human blood, alone or in combination, considering two different exposure times. Results Reported data clearly evidence that in vitro cytotoxicity is tightly related to the exposure time, and it varies among bioactives, which could exert a cytotoxic effect even at a concentration within the in vivo physiological blood concentration range. Furthermore, co-supplementation of different bioactives can increase the cytotoxic effect. Conclusions Our results underline the importance of in vitro cytotoxicity screening that should be considered mandatory before performing studies aimed to evaluate the effect of bioactives on other cellular parameters. Although this study is far from the demonstration of a toxic effect of the tested bioactives when administered to humans, it represents a starting point for future research aimed at verifying the existence of a potential hazard due to the wide use of high doses of multiple bioactives.