Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase.

AIMS: Azoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA. MATERIALS AND METHODS: Through various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles. KEY FINDINGS: It was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans. SIGNIFICANCE: This research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.

Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region.

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Identification, validation and quantification of thymoquinone in conjunction with assessment of bioactive possessions and GC-MS profiling of pharmaceutically valuable crop Nigella (Nigella sativa L.) varieties.

Background: Plants have been pivotal in traditional and modern medicine globally, with historical evidence supporting their therapeutic applications. Nigella (Nigella sativa L.) is an annual herbaceous plant of the Ranunculaceae family and is cultivated in the Middle East, Eastern Europe, and Western and Central Asia. The medicinal use of plants dates back thousands of years, documented in ancient writings from various civilizations. Alkaloids, phenolics, saponins, flavonoids, terpenoids, anthraquinones, and tannins found in plants exhibit antioxidant, immunomodulatory, anti-inflammatory, anticancer, antibacterial, and antidiabetic activities. Methodology: This study specifically examines the pharmacological potential of Nigella sativa L., emphasizing thymoquinone-a compound with diverse nutraceutical benefits. The extraction, characterization, and quantification of thymoquinone, alongside other physicochemical parameters, were carried out using ethanol through Soxhlet extraction procedures on five nigella varieties. HPLC analysis was performed to determine the maximum accumulation of thymoquinone in the released variety of the plant and the chemical composition of the seed oil isolated from Nigella sativa L., varieties utilized in the study was determined through GC-MS analysis. Results: The research revealed that the Ajmer nigella-20 variety stands out, exhibiting elevated levels of thymoquinone (0.20 ± 0.07%), antioxidants (76.18 ± 1.78%), and substantial quantities of total phenols (31.85 ± 0.97 mg GAEg-1 seed) and flavonoids (8.150 ± 0.360 mg QE 100 g-1 seed) compared to other varieties. The GC-MS profiling showed the presence of 11 major compounds in the studied varieties, with p-cymene, longifolene, and myristic acid identified as the major chemical compounds present in the oil. Conclusion: The observed variations among Nigella varieties indicate the Ajmer nigella-20 variety as particularly promising for thymoquinone and bioactive compound extraction. This study underscores Nigella's potential as a source of pharmacologically active compounds, highlighting the need for further exploration in therapeutic applications.

Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.

Respiratory complex I is a redox-driven proton pump. Several high-resolution structures of complex I have been determined providing important information about the putative proton transfer paths and conformational transitions that may occur during catalysis. However, how redox energy is coupled to the pumping of protons remains unclear. In this article, we review biochemical, structural and molecular simulation data on complex I and discuss several coupling models, including the key unresolved mechanistic questions. Focusing both on the quinone-reductase domain as well as the proton-pumping membrane-bound domain of complex I, we discuss a molecular mechanism of proton pumping that satisfies most experimental and theoretical constraints. We suggest that protonation reactions play an important role not only in catalysis, but also in the physiologically-relevant active/deactive transition of complex I.

Self-micellizing solid dispersion of thymoquinone with enhanced biopharmaceutical and nephroprotective effects.

The present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5-15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

N-methyl-D-aspartate receptors and thymoquinone induce apoptosis and alteration in mitochondria in colorectal cancer cells.

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.

Effects of 5-fluorouracil, thymoquinone, and mammary stem cells' exosomes on in vitro cultured breast cancer cells.

Background: 5-fluorouracil (5-FU) is an antimetabolic agent used for treating slowly growing solid tumors like breast and ovarian carcinoma. Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa, it has been found to demonstrate anticancerous effects in several preclinical studies, and this is because TQ possesses multitarget nature. Stem cells-derived exosomes are in the spotlight of research and are promising tissue regenerative and anticancer cell-derived nanovesicles. Aim: Herein, we studied the antineoplastic effects of Exosomes derived from mammary stem cells (MaSCs-Exo) on breast cancer cells, alone or combined with TQ when compared to a breast cancer chemotherapeutic agent; 5-FU. Methods: Our approach included performing viability test and measuring the expression of pro-apoptotic gene (Bax), anti-apoptotic gene (BCL-2) and angiogenic gene (VEGF) on Human MCF-7 cells (breast adenocarcinoma cells), the MCF-7 cells were cultured and incubated with medium containing 5-FU (25 µg/ml), TQ (200 µg/ml), MaSCs-Exo (100 µg protein equivalent), a combination of TQ (200 µg/ml) and MaSCs-Exo (100 µg). Results: Our obtained results show that TQ and MaSCs-Exo each can effectively inhibit breast cancer cell line (MCF-7) proliferation and growth. Also, the results show that the combination of TQ and MaSCs-Exo had higher cytotoxic effects on MCF-7 breast cancer cells than TQ or 5-FU, alone. Conclusion: The present study shows a promising anticancer potential of exosomes isolated from mammary stem cells; this effect was potentiated by adding TQ with MaSCs-derived exosomes.

Thymoquinone is a natural antibiofilm and pathogenicity attenuating agent in Pseudomonas aeruginosa.

Pseudomonas aeruginosa belongs to the critical pathogens that represent a global public health problem due to their high rate of resistance as listed by WHO. P. aeruginosa can result in many nosocomial infections especially in individuals with compromised immune systems. Attenuating virulence factors by interference with quorum sensing (QS) systems is a promising approach to treat P. aeruginosa-resistant infections. Thymoquinone is a natural compound isolated from Nigella sativa (black seed) essential oil. In this study, the minimum inhibitory concentration of thymoquinone was detected followed by investigating the antibiofilm and antivirulence activities of the subinhibitory concentration of thymoquinone against P. aeruginosa PAO1. The effect of thymoquinone on the expression of QS genes was assessed by quantitative real-time PCR, and the protective effect of thymoquinone against the pathogenesis of PAO1 in mice was detected by the mouse survival test. Thymoquinone significantly inhibited biofilm, pyocyanin, protease activity, and swarming motility. At the molecular level, thymoquinone markedly downregulated QS genes lasI, lasR, rhlI, and rhlR. Moreover, thymoquinone could protect mice from the pathologic effects of P. aeruginosa increasing mouse survival from 20% to 100%. In conclusion, thymoquinone is a promising natural agent that can be used as an adjunct therapeutic agent with antibiotics to attenuate the pathogenicity of P. aeruginosa.

Taxonomy of Candida parapsilosis complex isolated from neonates and the role of Hsp90 inhibitors to enhanced the antifungal activity of micafungin.

Species from Candida parapsilosis complex are frequently found in neonatal candidemia. The antifungal agents to treat this infection are limited and the occurrence of low in vitro susceptibility to echinocandins such as micafungin has been observed. In this context, the chaperone Hsp90 could be a target to reduce resistance. Thus, the objective of this research was to identify isolates from the C. parapsilosis complex and verify the action of Hsp90 inhibitors associated with micafungin. The fungal identification was based on genetic sequencing and mass spectrometry. Minimal inhibitory concentrations were determined by broth microdilution method according to Clinical Laboratory and Standards Institute. The evaluation of the interaction between micafungin with Hsp90 inhibitors was realized using the checkerboard methodology. According to the polyphasic taxonomy, C. parapsilosis sensu stricto was the most frequently identified, followed by C. orthopsilosis and C. metapsilosis, and one isolate of Lodderomyces elongisporus was identified by genetic sequencing. The Hsp90 inhibitor geladanamycin associated with micafungin showed a synergic effect in 31.25% of the isolates, a better result was observed with radicicol, which shows synergic effect in 56.25% tested yeasts. The results obtained demonstrate that blocking Hsp90 could be effective to reduce antifungal resistance to echinocandins.

Thymoquinone ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p.

microRNAs (miRNAs) play a significant role in the pathophysiology of Parkinson's disease. In this study, we evaluated the neuroprotective effect of thymoquinone on the expression profiles of miRNA and cognitive functions in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's model. Male adult Wistar albino rats (200-230 g, n  = 36) were randomly assigned to six groups: Sham, thymoquinone (10 mg/kg, p.o.), 6-OHDA, 6-OHDA + thymoquinone (10 mg/kg), 6-OHDA + thymoquinone (20 mg/kg), and 6-OHDA + thymoquinone (50 mg/kg). Behavioral changes were detected using the open field and the elevated plus maze tests. The mature 728 miRNA expressions were evaluated by miRNA microarray (GeneChip miRNA 4.0). Ten miRNAs were selected (rno-miR-212-5p, rno-miR-146b-5p, rno-miR-150-5p, rno-miR-29b-2-5p, rno-miR-126a-3p, rno-miR-187-3p, rno-miR-34a-5p, rno-miR-181d-5p, rno-miR-204-3p, and rno-miR-30c-2-3p) and confirmed by real-time PCR. Striatum samples were stained with hematoxylin-eosin to determine the effect of dopaminergic lesions. One-way ANOVA test and independent sample t -test were used for statistical analyses. rno-miR-204-3p was upregulated at 6-OHDA and downregulated at the 50 mg/kg dose of thymoquinone. In conclusion, thymoquinone at a dose of 50 mg/kg ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p. Also, the results showed that thymoquinone can improve locomotor activity and willing exploration and decreased anxiety. Therefore, thymoquinone can be used as a therapeutic agent.

UHRF1 poly-auto-ubiquitination induced by the anti-cancer drug, thymoquinone, is involved in the DNA repair machinery recruitment.

DNA methylation is one of the most important epigenetic mark involved in many physiologic cellular processes and pathologies. During mitosis, the transmission of DNA methylation patterns from a mother to the daughter cells is ensured through the action of the Ubiquitin-like, containing PHD and RING domains, 1/DNA methyltransferase 1 (UHRF1/DNMT1) tandem. UHRF1 is involved in the silencing of many tumor suppressor genes (TSGs) via mechanisms that remain largely to be deciphered. The present study investigated the role and the regulation of UHRF1 poly-ubiquitination induced by thymoquinone, a natural anti-cancer drug, known to enhance or re-activate the expression of TSGs. We found that the auto-ubiquitination of UHRF1, induced by TQ, is mediated by reactive oxygen species, and occurs following DNA damage. We demonstrated that the poly-ubiquitinated form of UHRF1 is K63-linked and can still silence the tumor suppressor gene p16INK4A/CDKN2A. We further showed that TQ-induced auto-ubiquitination is mediated via the activity of Tip60. Since this latter is known as a nuclear receptor co-factor, we investigated if the glucocorticoid receptor (GR) might be involved in the regulation of UHRF1 ubiquitination. Activation of the GR, with dexamethasone, did not influence auto-ubiquitination of UHRF1. However, we could observe that TQ induced a K48-linked poly-ubiquitination of GR, probably involved in the proteosomal degradation pathway. Mass-spectrometry analysis of FLAG-HA-tagged UHRF1 identified UHRF1 partners involved in DNA repair and showed that TQ increased their association with UHRF1, suggesting that poly-ubiquitination of UHRF1 is involved in the DNA repair process. We propose that poly-ubiquitination of UHRF1 serves as a scaffold to recruit the DNA repair machinery at DNA damage sites.

Relationship of Cytotoxic and Antimicrobial Effects of Triphenylphosphonium Conjugates with Various Quinone Derivatives.

Quinone derivatives of triphenylphosphonium have proven themselves to be effective geroprotectors and antioxidants that prevent oxidation of cell components with participation of active free radicals - peroxide (RO2·), alkoxy (RO·), and alkyl (R·) radicals, as well as reactive oxygen species (superoxide anion, singlet oxygen). Their most studied representatives are derivatives of plastoquinone (SkQ1) and ubiquinone (MitoQ), which in addition to antioxidant properties also have a strong antibacterial effect. In this study, we investigated antibacterial properties of other quinone derivatives based on decyltriphenylphosphonium (SkQ3, SkQT, and SkQThy). We have shown that they, just like SkQ1, inhibit growth of various Gram-positive bacteria at micromolar concentrations, while being less effective against Gram-negative bacteria, which is associated with recognition of the triphenylphosphonium derivatives by the main multidrug resistance (MDR) pump of Gram-negative bacteria, AcrAB-TolC. Antibacterial action of SkQ1 itself was found to be dependent on the number of bacterial cells. It is important to note that the cytotoxic effect of SkQ1 on mammalian cells was observed at higher concentrations than the antibacterial action, which can be explained by (i) the presence of a large number of membrane organelles, (ii) lower membrane potential, (iii) spatial separation of the processes of energy generation and transport, and (iv) differences in the composition of MDR pumps. Differences in the cytotoxic effects on different types of eukaryotic cells may be associated with the degree of membrane organelle development, energy status of the cell, and level of the MDR pump expression.

Fragmentation Pattern-Based Screening Strategy Combining Diagnostic Ion and Neutral Loss Uncovered Novel para-Phenylenediamine Quinone Contaminants in the Environment.

Identifying transformed emerging contaminants in complex environmental compartments is a challenging but meaningful task. Substituted para-phenylenediamine quinones (PPD-quinones) are emerging contaminants originating from rubber antioxidants and have been proven to be toxic to the aquatic species, especially salmonids. The emergence of multiple PPD-quinones in various environmental matrices and evidence of their specific hazards underscore the need to understand their environmental occurrences. Here, we introduce a fragmentation pattern-based nontargeted screening strategy combining full MS/All ion fragmentation/neutral loss-ddMS2 scans to identify potential unknown PPD-quinones in different environmental matrices. Using diagnostic fragments of m/z 170.0600, 139.0502, and characteristic neutral losses of 199.0633, 138.0429 Da, six known and three novel PPD-quinones were recognized in air particulates, surface soil, and tire tissue. Their specific structures were confirmed, and their environmental concentration and composition profiles were clarified with self-synthesized standards. N-(1-methylheptyl)-N'-phenyl-1,4-benzenediamine quinone (8PPD-Q) and N,N'-di(1,3-dimethylbutyl)-p-phenylenediamine quinone (66PD-Q) were identified and quantified for the first time, with their median concentrations found to be 0.02-0.21 µg·g-1 in tire tissue, 0.40-2.76 pg·m-3 in air particles, and 0.23-1.02 ng·g-1 in surface soil. This work provides new evidence for the presence of unknown PPD-quinones in the environment, showcasing a potential strategy for screening emerging transformed contaminants in the environment.

Variation in the Composition and Quality of Nigella sativa L. Seed Oils-The Underestimated Impact on Possible Health-Promoting Properties.

Nigella sativa L. (black cumin) is one of the most investigated medicinal plants in recent years. Volatile compounds like thymoquinone and unsaponifiable lipid compounds are crucial functional components of this oil. Unfortunately, the composition of oils and their quality indicators are ambiguous both in terms of identified compounds and value ranges. Thirteen oils were extracted with hexane from black cumin seeds grown in India, Syria, Egypt, and Poland and analyzed for their fatty acid composition, unsaponifiable compound content and volatile compounds. Oils were also subjected to quality tests according to standard methods. The fatty acid composition and sterol content/composition were relatively stable among the tested oils. Tocol content varied in the range of 140-631 mg/kg, and among them, ß-tocotrienol and γ-tocopherol prevailed. Oils' volatile compounds were dominated by seven terpenes (p-cymene, α-thujene, α-pinene, ß-pinene, thymoquinone, γ-terpinene, and sabinene). The highest contents of these volatiles were determined in samples from Poland and in two of six samples from India. High acid and peroxide values were typical features of N. sativa L. oils. To sum up, future research on the medicinal properties of black cumin oil should always be combined with the analysis of its chemical composition.

Multifunctional embelin- poly (3-hydroxybutyric acid) and sodium alginate-based core-shell electrospun nanofibrous mat for wound healing applications.

In this study, coaxial electrospinning is employed to make core-shell fibers, which represents a major advance in biomaterial innovation. Fibers that combine a protective shell and a therapeutic agent-loaded core, herald a revolutionary era in tissue engineering and wound care. Besides supporting cell growth, these fibers also preserve sterility, which makes them ideal for advanced wound dressings. We used embelin as the basis for this study because of its natural antibacterial properties. Its effectiveness in inhibiting the growth of bacteria made it the ideal candidate for our research. We have synthesized core-shell nanofibers that contain Sodium Alginate (SAL) in a Poly (ethylene oxide) (PEO) shell and Embelin in a Poly (3-hydroxybutyric acid) (PHB) core, which exhibit the homogeneity and flawless structure required for biomedical applications. When using SAL-PEO and EMB-PHB solutions dissolved in 1,1,1,3,3,3 hexafluoro-2-propanol (HFIP), high consistency in results can be achieved. A biocompatibility study was conducted using NIH-3T3 fibroblasts, which demonstrated remarkable adhesion and proliferation, with over 95 % growth supporting both PHB + SAL-PEO and EMB-PHB + SAL-PEO fibers. In addition, the scaffold loaded with Embelin shows strong antibacterial activity and cytocompatibility. The combined activity demonstrates the potential of EMB-PHB + SAL-PEO fibers in wound healing, where tissue regeneration and preservation of sterility are crucial. The optimized concentration of Embelin within these scaffolds demonstrates robust antibacterial efficacy while exhibiting minimal toxicity, thus positioning them as highly promising candidates for a wide range of biological applications, including wound healing.

Development and Characterization of Transdermal Patches Using Novel Thymoquinone-L-Arginine-Based Polyamide Nanocapsules for Potential Use in the Management of Psoriasis.

Thymoquinone (TQ) is a phytochemical compound present in Nigella sativa and has potential benefits for treating dermatological conditions such as psoriasis. However, its clinical use is limited due to its restricted bioavailability, caused mainly by its low solubility and permeability. To overcome this, a new transdermal drug delivery system is required. Nanoparticles are known to enhance material solubility and permeability, and hence, this study aimed to synthesize TQ-loaded L-arginine-based polyamide (TQ/Arg PA) nanocapsules incorporated into transdermal patches for prolonged delivery of TQ. To achieve this, Eudragit E polymer, plasticizers, and aloe vera as penetration enhancer were used to develop the transdermal patch. Furthermore, novel TQ/Arg-PA was synthesized via interfacial polymerization, and the resultant nanocapsules (NCs) were incorporated into the matrix transdermal patch. The Arg-PA NCs' structure was confirmed via NMR and FTIR, and optimal TQ/Arg-PA NCs containing formulation showed high entrapment efficiency of TQ (99.60%). Molecular and thermal profiling of TQ/Arg-PA and the transdermal patch revealed the effective development of spherical NCs with an average particle size of 129.23 ± 18.22 nm. Using Franz diffusion cells and synthetic membrane (STRAT M®), the in vitro permeation profile of the prepared patches demonstrated an extended release of TQ over 24 h, with enhanced permeation by 42.64% when aloe vera was employed. In conclusion, the produced formulation has a potential substitute for corticosteroids and other drugs commonly used to treat psoriasis due to its effectiveness, safety, and lack of the side effects typically associated with other drugs.

Mixture toxicity of 6PPD-quinone and polystyrene nanoplastics in zebrafish.

Plastic pollution, including micro- and nanoplastics, is a growing concern. Tyre-wear particles (TWPs) are the second largest source of microplastics in the ocean following abrasion of synthetic fibres. In addition to the particles themselves, TWPs contain many harmful chemicals, including 6PPD. This chemical reacts with atmospheric ozone and forms the toxic compound 6PPD-quinone (6PPDq), which poses a danger to aquatic life. There is a knowledge gap in understanding risks associated with the combined toxicity of nanoplastics (NPs) and 6PPDq. The present study aimed to investigate the toxicity of NPs and 6PPDq on adult zebrafish using phenotypic (behaviour, histology) and transcriptomic endpoints. Zebrafish were exposed to four treatments: control (contaminant-free), 50 µg/L 6PPDq, 3 mg/L polystyrene (PS)-NPs, and a combination of 50 µg/L 6PPDq and 3 mg/L PS-NPs. We did not observe locomotory dysregulation in zebrafish exposed to NPs. However, we found significant hyperlocomotion in zebrafish exposed to 6PPDq and this effect was even more substantial after co-exposure with PS-NPs. This study explores the molecular mechanisms behind these effects, identifying genes associated with neurotransmitters and fatty acid metabolism that were dysregulated by the co-exposure. Transcriptomic analysis further showed that both 6PPDq and PS-NPs impacted cellular processes associated with sterol biosynthesis, cholesterol metabolism, and muscle tissue development. The effects on these mechanisms were stronger in co-exposed zebrafish, indicating a heightened risk to cellular integrity and mitochondrial dysfunction. These results highlight the significance of mixture toxicity when studying the effects of NPs and associated chemicals like 6PPDq.

Two New Benzoquinone Derivatives from Vietnamese Knema globularia Stems.

The chemical investigation of the stems of Knema globularia led to the isolation of two new benzoquinones derivatives, embenones A and B (1 and 2), along with three known compounds (3-5). The structures of the isolated compounds were determined using spectroscopic techniques, including HRESIMS, 1D and 2D NMR, in conjunction with comparison to existing literature data. Compounds 1 and 2 represent new carbon skeletons in nature. Furthermore, all isolated compounds were evaluated for their α-glucosidase inhibitory activity, with compounds 1-3 exhibiting superior potency relative to the positive control (acarbose, IC50 331 µM). Their IC50 values ranged from 1.40 to 96.1 µM.

Computational and in vitro analyses on synergistic effects of paclitaxel and thymoquinone in suppressing invasive breast cancer cells.

BACKGROUND: In the present experiment, we evaluated the impact of thymoquinone (TQ) and paclitaxel (PTX) treatment on MDA-MB-231 cell line growth inhibition via controlling apoptosis/autophagy. MATERIALS AND RESULTS: MDA-MB-231cells were exposed to PTX (0, 25, 50, 75, and 100 nM), TQ (0, 25, 50, 75, and 100 µM), and combinations for 48 h. After the MTT assessment, dose-response curves and IC50 values were calculated, and the combination synergism was evaluated using the Compusyn software. Following the treatment with PTX, TQ, and combinations at IC50 doses, the expression of apoptosis and autophagy genes was assessed in cells. The GraphPad Prism program was used to analyze the data, and Tukey's test at p < 0.05 was then run. PTX, TQ, and their combinations inhibited MDA-MB-231cell proliferation and viability dose-dependently. TQ reduced the effective concentration (IC50) of PTX in co-treatment groups. PTX and TQ showed antagonistic effects when cell proliferation declined above 70%. Antagonistic effects shifted into additive and synergistic effects upon increasing PTX concentration, indicated by diminished cell proliferation below 70%. PTX-TQ co-treatment significantly enhanced P53 and BAX expression while reducing Bcl-2 expression. Also, their combination increased Beclin-1, ATG-5, and ATG-7 expression in treated cells. CONCLUSION: Effective concentrations of TQ and PTX had synergic effects and inhibited breast cancer cells via prompting apoptosis and autophagy in vitro.

Electrochemical Analysis for Total Alkalinity of Water by the Measurement of Cathodic Prepeak of Quinone Caused by Surplus Acid.

In this study, an electrochemical analysis, coupled with the concept of back neutralization titration and the voltammetric determination of surplus acid, is proposed for determining the total alkalinity of water samples. When linear sweep voltammetry of 3,5-di-tert-butyl-1,2-benzoquinone (DBBQ) with H2SO4 in a water and ethanol (44 : 56, v/v) mixture was carried out using a bare glassy carbon working electrode, a cathodic prepeak of DBBQ caused by H2SO4 was observed on the voltammogram at a more positive potential than when compared with the original cathodic peak of DBBQ. When similar voltammetry was carried out in the presence of Na2CO3 and H2SO4, the cathodic prepeak height of DBBQ was decreased with an increase in the Na2CO3 concentration. The decrease of the cathodic prepeak height of DBBQ was found to be linearly related to the Na2CO3 concentration ranging from 0.025 to 2.5 mM (r2 = 0.998). The total equivalent concentrations of inorganic bases in samples of mineral water and tap water were determined, and then the results were converted to the total alkalinities of the water samples (mg/L CaCO3). The total alkalinities of the water samples determined by the present electrochemical analysis were essentially the same compared with those by the neutralization titration method. From these results, we were able to demonstrate that the present electrochemical analysis with accuracy and precision could be applied to determine the total alkalinity, which is one of the indicators to examine water quality. The present electrochemical analysis would contribute to achieving the sustainable development goals (SDGs) of #6 and #14.