Production Of Toxic Metabolites Research Articles

Additional data on the ongoing naturalization of the non-native woody plant Duranta erecta ( Verbenaceae) in Sicily, Italy

We recorded the occurrence of Duranta erecta L. in the Aeolian Islands (Sicily, Italy), where it currently behaves as a casual alien. At the global scale, however, this woody species has shown highly invasive behaviour in different island ecosystems. On the basis of this evidence, we have investigated which ecological and biological traits may have allowed its establishment and spread, and could trigger its further expansion in the Aeolian Islands in the near future. Several factors seem to have favoured its success on a global scale, such as the wide edaphic and climatic range, the tolerance to anthropogenic disturbance, and the production of toxic metabolites that protect it from herbivore browsing and from competition with other plants. The study of the organisms that perform pollination and seed dispersal is probably the key to understanding the local naturalization of this plant, introduced about three centuries ago in Europe and the Mediterranean, here discussed in detail for the first time.

Engineering a carbon source-responsive promoter for improved biosynthesis in the non-conventional yeast Kluyveromyces marxianus

Many desired biobased chemicals exhibit a range of toxicity to microbial cell factories, making industry-level biomanufacturing more challenging. Separating microbial growth and production phases is known to be beneficial for improving production of toxic products. Here, we developed a novel synthetic carbon-responsive promoter for use in the rapidly growing, stress-tolerant yeast Kluyveromyces marxianus, by fusing carbon-source responsive elements of the native ICL1 promoter to the strong S. cerevisiae TDH3 or native NC1 promoter cores. Two hybrids, PIT350 and PIN450, were validated via EGFP fluorescence and demonstrated exceptional strength, partial repression during growth, and late phase activation in glucose- and lactose-based medium, respectively. Expressing the Gerbera hybrida 2-pyrone synthase (2-PS) for synthesis of the polyketide triacetic acid lactone (TAL) under the control of PIN450 increased TAL more than 50% relative to the native NC1 promoter, and additional promoter engineering further increased TAL titer to 1.39 g/L in tube culture. Expression of the Penicillium griseofulvum 6-methylsalicylic acid synthase (6-MSAS) under the control of PIN450 resulted in a 6.6-fold increase in 6-MSA titer to 1.09 g/L and a simultaneous 1.5-fold increase in cell growth. Finally, we used PIN450 to express the Pseudomonas savastanoi IaaM and IaaH proteins and the Salvia pomifera sabinene synthase protein to improve production of the auxin hormone indole-3-acetic acid and the monoterpene sabinene, respectively, both extremely toxic to yeast. The development of carbon-responsive promoters adds to the synthetic biology toolbox and available metabolic engineering strategies for K. marxianus, allowing greater control over heterologous protein expression and improved production of toxic metabolites.

Safety and efficacy of a feed additive consisting of l-tryptophan (produced with Escherichia coliCGMCC 7.460) for all animal species (Kempex Holland B.V.).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the feed additive consisting of l-tryptophan produced by fermentation with Escherichia coli CGMCC 7.460 when used as a nutritional additive in feed and water for drinking for all animal species and categories. The production strain is not genetically modified. Viable cells of the production strain were not detected in the final additive. The additive does not give rise to any safety concern regarding the production strain. The use of l-tryptophan (≥ 98%) produced with E. coli CGMCC 7.460 to supplement feed is safe for non-ruminant species. There may be a risk for an increased production of toxic metabolites when unprotected tryptophan is used in ruminants. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) has concerns on the safety of the simultaneous oral administration of l-tryptophan via water for drinking and feed due to possible amino acid imbalances and hygienic reasons. The use of l-tryptophan produced with E. coli CGMCC 7.460 in animal nutrition raises no safety concerns to consumers of animal products and to the environment. In the absence of data, the FEEDAP Panel cannot conclude on the potential of the additive to be irritant to skin or eyes, or on its potential to be a dermal sensitiser. The endotoxin activity of the additive in combination with the high dusting potential may represent a risk of exposure by inhalation to endotoxins for users. The additive l-tryptophan is regarded as an effective source of the amino acid l-tryptophan for all non-ruminant species. To be as efficacious in ruminants as in non-ruminants, it should be protected from ruminal degradation.

Safety Assessment of Levilactobacillus brevis KU15006: A Comprehensive Analysis of its Phenotypic and Genotypic Properties.

Levilactobacillus brevis KU15006, isolated from kimchi, exhibits pathogen-antagonistic and anti-diabetic activities; however, the safety of this strain has not been assessed. In the present study, L. brevis KU15006 was evaluated to elucidate its safety as a probiotic strain using phenotypic and genotypic analyses. Its safety was assessed using a minimum inhibitory concentration test comprising nine antibiotics, 26 antibiotic resistance genes, a single conjugative element, virulence gene analysis, hemolysis, cell cytotoxicity, mucin degradation, and toxic metabolite production. L. brevis KU15006 exhibited equal or lower minimum inhibitory concentration for the nine antibiotics than the cut-off value established by the European Food Safety Authority. It did not harbor antibiotic resistance and virulence genes. L. brevis KU15006 lacked β-hemolysis, mucin degradation, cytotoxicity against Caco-2 cells, gelatin liquefaction, bile salt deconjugation, and toxic metabolite production abilities. Based on the results, L. brevis KU15006, which has antagonistic and anti-diabetic effects, could be marketed as a probiotic in the future.

Comparison of microbial communities and the profile of sulfate-reducing bacteria in patients with ulcerative colitis and their association with bowel diseases: a pilot study.

Considerable evidence has accumulated regarding the molecular relationship between gut microbiota (GM) composition and the onset (clinical presentation and prognosis of ulcerative colitis (UC)). In addition, it is well documented that short-chain fatty acid (SCFA)-producing bacteria may play a fundamental role in maintaining an anti-inflammatory intestinal homeostasis, but sulfate- and sulfite reducing bacteria may be responsible for the production of toxic metabolites, such as hydrogen sulfide and acetate. Hence, the present study aimed to assess the GM composition - focusing on sulfate-reducing bacteria (SRB) - in patients with severe, severe-active and moderate UC. Each one of the six enrolled patients provided two stool samples in the following way: one sample was cultivated in a modified SRB-medium before 16S rRNA sequencing and the other was not cultivated. Comparative phylogenetic analysis was conducted on each sample. Percentage of detected gut microbial genera showed considerable variation based on the patients' disease severity and cultivation in the SRB medium. In detail, samples without cultivation from patients with moderate UC showed a high abundance of the genera Bacteroides, Bifidobacterium and Ruminococcus, but after SRB cultivation, the dominant genera were Bacteroides, Klebsiella and Bilophila. On the other hand, before SRB cultivation, the main represented genera in patients with severe UC were Escherichia-Shigella, Proteus, Methanothermobacter and Methanobacterium. However, after incubation in the SRB medium Bacteroides, Proteus, Alistipes and Lachnoclostridium were predominant. Information regarding GM compositional changes in UC patients may aid the development of novel therapeutic strategies (e.g., probiotic preparations containing specific bacterial strains) to counteract the mechanisms of virulence of harmful bacteria and the subsequent inflammatory response that is closely related to the pathogenesis of inflammatory bowel diseases.

Long-term effects of oil contamination on soil quality and metabolic function.

Widespread soil contamination with oil and the toxicity of petroleum hydrocarbons to soil biota make it extremely important to study microbial responses to oil stress. Soil metabolites reflect the main metabolic pathways in the soil microbial community. The examination of changes in the soil metabolic profile and metabolic function is essential for a better understanding of the nature of the pollution and restoration of the disturbed soils. The present study aimed to assess the long-term effect of oil on the ecological state of the soil, evaluate quantitative and qualitative differences in metabolite composition between soil contaminated with oil and non-contaminated soil, and reveal biologically active metabolites that are related to oil contamination and can be used for contamination assessment. A long-term field experiment was conducted to examine the effects of various oil concentrations on the biochemical properties and metabolic profile of the soil. Podzolic soil contaminated with oil demonstrated the long-term inhibition of soil biological activity and vegetation. Oil affected the metabolic activity of soil fungi increasing the production of toxic metabolites. A metabolomic approach was employed to determine soil metabolites. The metabolite profile was found to vary greatly between oil-contaminated and non-contaminated soils. Carbohydrates had the largest number of metabolites negatively affected by oil, while the content of organic acids, phenolic compounds, and terpenoids was mainly increased in oil-contaminated soil. The evaluation of the long-term impact of oil on microbial metabolism can make a valuable contribution to the assessment of soil quality and the activity of soil microorganisms being under stress from oil pollution. The results contribute to a further understanding of the role of microorganisms in the ecological functions of contaminated soil, which can be useful in the development of rehabilitation strategies for disturbed sites.

Proficient sonophotocatalytic degradation of organic pollutants using Co3O4/TiO2 nanocomposite immobilized on zeolite: Optimization, and artificial neural network modeling

The health of all living organisms is greatly influenced by the quality of the water. Therefore, developing cost-effective, eco-friendly, and easily accessible methods is desperately needed to meet the high global demand for clean water. Recently, nanozyme-based dye degradation methods have been promising for the remediation of water pollution. In this work, peroxidase-mimic Co3O4/TiO2 nanocomposite was synthesized and characterized for its size, morphology, and crystalline structure. Colorimetric assay results showed that the peroxidase-like activity of the Co3O4/TiO2 nanocomposite was considerably enhanced compared to the pure Co3O4 NPs and TiO2 NPs. Besides excellent enzyme-mimic activity, the higher sonophotocatalytic dye degradation capability of the nanocomposite after immobilization on zeolite (Co3O4/TiO2@Ze) was also demonstrated. Under optimal conditions (pH = 5.0, 25 °C), 0.1 g/L of catalyst was able to degrade 100 % of methylene blue (MB) with 600 μM in the presence of 30 μM H2O2 within 12 min. GC/MS analysis and toxicity studies revealed less toxic metabolite production after treatment of MB with sonophotocatalytic Co3O4/TiO2@Ze. Modeling of MB degradation using artificial neural networks (ANN) with a 5:6:1 topology was successfully performed, and the results confirmed the fitness of theoretical and experimental outputs according to the calculated correlation coefficient values. The prepared nanocomposite could thus be used as a promising and highly effective catalyst for the removal of organic dyes from polluted water.

Evaluation of in vitro effects of ifosfamide drug on mitochondrial functions using isolated mitochondria obtained from vital organs.

Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as, brain, heart, kidney, and liver. Ifosfamide (IFO) as an anticancer drug, is associated with increased risk of neurotoxicity, cardiotoxicity nephrotoxicity, hepatotoxicity, and hemorrhagic cystitis. The aim of this study was to evaluate the direct effect of IFO on isolated mitochondria obtained from the rat brain, heart, kidney, and liver. Mitochondria were isolated with mechanical lysis and differential centrifugation from different organs and treated with various concentrations of IFO. Using biochemical and flowcytometry assays, we evaluated mitochondrial succinate dehydrogenase (SDH) activity, mitochondrial swelling, lipid peroxidation, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP). Our data showed that IFO did not cause deleterious alterations in mitochondrial functions, mitochondrial swelling, lipid peroxidation ROS formation, and MMP collapse in mitochondria isolated from brain, heart, kidney, and liver. Altogether, the data showed that IFO is not directly toxic in mitochondria isolated from brain, heart, kidney, and liver. This study proved that mitochondria alone does not play the main role in the toxicity of IFO, and suggests to reduce the toxicity of this drug, other pathways resulting in the production of toxic metabolites should be considered.

Benzophenone-3 does not Cause Oxidative Stress or B-esterase Inhibition During Embryo Development of Octopus maya (Voss and Solís Ramírez, 1966)

Benzophenone-3 (BP-3) is an active ingredient in sunscreen lotions and personal-care products that protects against the damaging effects of ultraviolet rays. Given its worldwide dissemination, it has been linked with harmful effects on aquatic biota; however, its impact is not fully understood calling for further studies. To understand the impacts on an important economically and ecologically species, we evaluated the toxicity of BP-3 during the embryonic development of Octopus maya. Embryos were exposed to increasing concentrations of up to 500 µg BP-3/L until hatching. Antioxidant enzyme activities, oxidative-stress indicators, and B-esterases activities were measured at different developmental phases (organogenesis, activation, and growth). There were no significant differences between treatments, suggesting the lack of production of toxic metabolites that may be related to a protective chorion, an underdeveloped detoxification system, and the experimental conditions that limited phototoxicity.

Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Development of a centrifugal bioreactor for rapid expansion of CD8 cytotoxic T cells for use in cancer immunotherapy.

One of the current difficulties limiting the use of adoptive cell therapy (ACT) for cancer treatment is the lack of methods for rapidly expanding T cells. As described in the present report, we developed a centrifugal bioreactor (CBR) that may resolve this manufacturing bottleneck. The CBR operates in perfusion by balancing centrifugal forces with a continuous feed of fresh medium, preventing cells from leaving the expansion culture chamber while maintaining nutrients for growth. A bovine CD8 cytotoxic T lymphocyte (CTL) cell line specific for an autologous target cell infected with a protozoan parasite, Theileria parva, was used to determine the efficacy of the CBR for ACT purposes. Batch culture experiments were conducted to predict how CTLs respond to environmental changes associated with consumption of nutrients and production of toxic metabolites, such as ammonium and lactate. Data from these studies were used to develop a kinetic growth model, allowing us to predict CTL growth in the CBR and determine the optimal operating parameters. The model predicts the maximum cell density the CBR can sustain is 5.5 × 107 cells/mL in a single 11-mL conical chamber with oxygen being the limiting factor. Experimental results expanding CTLs in the CBR are in 95% agreement with the kinetic model. The prototype CBR described in this report can be used to develop a CBR for use in cancer immunotherapy.

Ayurvedic Management of Shwitra : The Case Study

Kushtha is one among the Ashtamahagad explained in Ayurveda as there is structural changes in appearance of skin[i]. In Ayurveda Vitiligo is known as "Shwitra”. It is one of the varieties of Kushta in Ayurvedic classics, caused due to vitiation of Tridosha and Dhatus like Rasa, Rakta, Mamsa and Medas. Unbalanced diet (Virrudhahara) is also an important cause. It signifies production of toxic metabolites as an important cause for the development of the disease. Vitiligo is a specific type of a acquired leukoderma and this is idiopathic, patterned, circumscribed hypomelanosis of the skin and hair in which other cause of leukoderma have been excluded. The disease is important principally because of the social stigma associated with vitiligo. Diet restriction and psychological counselling was also a necessary part of the treatment. Leech saliva is reported to have many therapeutic contents like hirudin, bdellins, Hyaluronidase, etc.; among them, eglins and bdellins have anti-inflammatory and antifungal property which gives relief in symptoms. The Shamanaushadhis are also had a crucial part in easing the symptoms by reducing the size of lesion, and restoring normal skin colour.
 
 Daga, H. , Toshikhane,H. , Thakur K. , Raole V.,(2020) “Ayurvedic Management of Vicharchika – Single Case Study, International Journal Of Pharmaceutical Research, Vol 12 | Issue 4. org/10.31838/ijpr/2021.13.02.075.

Debottlenecking and reformulating feed media for improved CHO cell growth and titer by data-driven and model-guided analyses.

Designing and selecting cell culture media along with their feeding are a key strategy to maximize culture performance in biopharmaceutical processes. However, the sensitivity of mammalian cells to their culture environment necessitates specific nutritional requirements for their growth and the production of high-quality proteins such as antibodies, depending on the cell lines and operational conditions employed. In this regard, previously we developed a data-driven and in-silico model-guided systematic framework to investigate the effect of growth media on Chinese hamster ovary (CHO) cell culture performance, allowing us to design and reformulate basal media. To expand our exploration for media development research, we evaluated two chemically defined feed media, A and B, using a monoclonal antibody-producing CHO K1 cell line in ambr15 bioreactor runs. We observed a significant impact of the feed media on various aspects of cell culture, including growth, longevity, viability, productivity, and the production of toxic metabolites. Specifically, the concentrated feed A was inadequate in sustaining prolonged cell culture and achieving high titers when compared to feed B. Within our framework, we systematically investigated the major metabolic bottlenecks in the tricarboxylic acid cycle and relevant amino acid transferase reactions. This analysis identified target components that play a crucial role in alleviating bottlenecks and designing highly productive cell cultures, specifically the addition of glutamate to feed A and asparagine to feed B. Based on our findings, we reformulated the feeds by adjusting the amounts of the targeted amino acids and successfully validated the effectiveness of the strategy in promoting cell growth, life span, and/or titer. This article is protected by copyright. All rights reserved.

FILAMENTOUS MICROMYCETES RESPONSIBLE FOR THE SPOILAGE OF SELECTED VEGETABLES IN THE FOOD RETAIL CHAIN

Vegetables represent a very important part of the diet. However, one of the problems of the vegetable market is its shelf life and related safety. A significant reason for vegetable losses in the retail network is the development of microorganisms, mainly micromycetes. They can significantly affect the quality of products, and due to the production of toxic metabolites, they also carry a toxicological risk. The aim of our study was to detect fungi that cause damage to selected types of vegetables in the food retail chains in Slovakia and are therefore directly responsible for product losses. Totally 44 samples of root, cabbage, and fruiting vegetables were mycologically analysed. Micromycetes, causing visible damage to the analysed vegetable samples, were inoculated to M137, M096, or M696 media from HiMedia and cultivated for 7 days at 25±1 °C. Important isolates were subjected to toxicological analysis by the thin-layer chromatography. The results show that the most common cause of carrot spoilage is the genus Berkeleyomyces. In the case of parsley, it was yeast Geotrichum candidum. Alternaria spp. occurred most often in the case of broccoli and cauliflower. Tomatoes were the most frequently spoiled by representatives of the genus Penicillium, or Botrytis cinerea and Cladosporium, cucumbers by Cladosporium and Alternaria species, similar to peppers, and the main spoiler of eggplants was Botrytis cinerea. Alternaria spp. showed a relatively high ability to produce altenuene, alternariol, and alternariol monomethyl ether. Penicillium expansum from carrots produced roquefortine C, patulin, and citrinin, and Penicillium paneum from tomatoes synthesized roquefortine C.

The effects of traditional Chinese medicine and dietary compounds on digestive cancer immunotherapy and gut microbiota modulation: A review.

Digestive tract-related cancers account for four of the top ten high-risk cancers worldwide. In recent years, cancer immunotherapy, which exploits the innate immune system to attack tumors, has led to a paradigm shifts in cancer treatment. Gut microbiota modification has been widely used to regulate cancer immunotherapy. Dietary compounds and traditional Chinese medicine (TCM) can alter the gut microbiota and its influence on toxic metabolite production, such as the effect of iprindole on lipopolysaccharide (LPS), and involvement in various metabolic pathways that are closely associated with immune reactions. Therefore, it is an effective strategy to explore new immunotherapies for gastrointestinal cancer to clarify the immunoregulatory effects of different dietary compounds/TCMs on intestinal microbiota. In this review, we have summarized recent progress regarding the effects of dietary compounds/TCMs on gut microbiota and their metabolites, as well as the relationship between digestive cancer immunotherapy and gut microbiota. We hope that this review will act as reference, providing a theoretical basis for the clinical immunotherapy of digestive cancer via gut microbiota modulation.

Deuterated colchicine liposomes based on oligomeric hyaluronic acid modification enhance anti-tumor effect and reduce systemic toxicity

Deuterated drugs are produced by substituting hydrogen atoms with deuterium atoms at specific sites in a drug molecule to prolong its metabolic cycle and reduce the production of toxic metabolites. Deuterated drugs have recently attracted increasing attention from the pharmaceutical industry. Colchicine exhibits a strong anti-tumor activity but has a short half-life, rapid attenuated drug concentration, narrow treatment window, and lack of tumor-specific targeting in vivo, resulting in toxicity and side effects. In this study, we explored whether deuteration could reduce the toxicity of colchicine. We prepared deuterated colchicine liposomes coated with oligo-hyaluronic acid, which can bind to the tumor-specific CD44 receptor and reduce the clearance of immune cells from the blood, resulting in a long blood circulation time and active targeting. We observed that deuteration of the colchicine B ring reduced drug toxicity and improved the anti-tumor response in 4 T1 breast cancer. Liposomes modified with oligo-hyaluronic acid exhibited increased tumor accumulation, further improving the anti-tumor effect of the drugs. Our results provide a basis for the development and application of deuterated drugs in the field of nano-preparations.

Effect of CYP3A inducer/inhibitor and licorice on hepatotoxicity and in vivo metabolism of main alkaloids of Euodiae Fructus based on UPLC-Q-Exactive-MS

Ethnopharmacological relevanceAs a traditional Chinese medicine, Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism, but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing. Aim of the studyThe poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP). Materials and methodsRats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and Orthogonal Partial Least Squares Discriminant Analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups. ResultsEF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group. ConclusionLicorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity.

Characterization and Mycotoxin Screening of Fungal Isolates from Palm Sugar

The global demand for alternative sugars is rising due to their lower glycemic index and other health benefits. However, improper manufacture, processing, transport, export, and/or marketing of regional sugar products increases the risk of microbial infection upon consumption. Fungal exposure and contamination of alternative sugars may occur as a result of enhanced hygroscopicity of certain sugar forms such as coconut and palm sugars, which strongly attract water molecules to their surface and thereby fungal spores, a property affected by adulteration practices, e.g. incorporation of cane sugar. The present study highlights risks of unregulated processing of palm sugar in the form of fungal contaminants and their toxigenic potential. Palm sugar was sampled for fungal isolates which were identified as Aspergillus flavus, A. niger, A. carbonarius, A. terreus, and A. fumigatus, followed by colony enumeration. Subsequent extraction of fungal extracts by thin layer chromatography resulted in detection of mycotoxins, including aflatoxins B1 and G1, citrinin, and ochratoxin. The findings confirmed that humid conditions may be optimal for the presence of toxigenic fungi in the palm sugar and production of toxic metabolites, indicating that more stringent regulation is required for palm sugar processing, as the toxins can lead to detrimental health consequences, including acute poisoning, nephropathy, and liver cancer.

The Potential Role of Polyamines in Epilepsy and Epilepsy-Related Pathophysiological Changes.

Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic amines that are present at a relatively high level and help regulate the maintenance of cell membrane excitability and neuronal physiological functions in the central nervous system. Studies have shown abnormalities in the synthesis and catabolism of polyamines in patients with epilepsy and in animal models of epilepsy. The polyamine system seems to involve in the pathophysiological processes of epilepsy via several mechanisms such as the regulation of ion permeability via interaction with ion channels, involvement in antioxidation as hydroperoxide scavengers, and the induction of cell damage via the production of toxic metabolites. In this review, we try to describe the possible associations between polyamines and epilepsy and speculate that the polyamine system is a potential target for the development of novel strategies for epilepsy treatment.

Diabetes causes NLRP3-dependent barrier dysfunction in mice with detrusor overactivity but not underactivity.

Approximately half of the patients with diabetes develop diabetic bladder dysfunction (DBD). The initiation and progression of DBD is largely attributed to inflammation due to dysregulated glucose and the production of toxic metabolites that activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. NLRP3 activation leads to the production and release of proinflammatory cytokines and causes urothelial pyroptosis, a form of programmed cell necrosis, which we hypothesize compromises urothelial barrier integrity. Here, we investigated how NLRP3-dependent inflammation impacts barrier function during the progression of diabetes using a type 1 diabetic female Akita mouse model that progresses from an early overactive to a late underactive detrusor phenotype at 15 and 30 wk, respectively. To determine the specific role of NLRP3, Akita mice were crossbred with mice lacking the NLRP3 gene. To determine barrier function, permeability to small molecules was assessed, ex vivo using Evans blue dye and in vivo using sulfo-NHS-biotin. Both ex vivo and in vivo permeabilities were increased in diabetic mice at 15 wk. Expression of uroplakin and tight junction components was also significantly downregulated at 15 wk. Interestingly, diabetic mice lacking the NLRP3 gene showed no evidence of barrier damage or downregulation of barrier genes and proteins. At the 30-wk time point, ex vivo and in vivo barrier damage as well as barrier component downregulation was no longer evident in diabetic mice, suggesting urothelial repair or remodeling occurs between the overactive and underactive stages of DBD. Collectively, these findings demonstrate the role of NLRP3-mediated inflammation in urothelial barrier damage associated with detrusor overactivity but not underactivity.NEW & NOTEWORTHY This is the first study to demonstrate that NLRP3-mediated inflammation is responsible for urothelial barrier damage in type 1 diabetic female Akita mice with an overactive bladder. Eliminating the NLRP3 gene in these diabetic mice prevented barrier damage as a result of diabetes. By the time female Akita mice develop an underactive phenotype, the urothelial barrier has been restored, suggesting that inflammation is a critical causative factor early in the development of diabetic bladder dysfunction.