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International Journal of Molecular... Apr 2024Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single...
Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAβ; hyperphosphorylated protein TAU at Ser/Thr; mitochondrial membrane potential (ΔΨ); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser/Ser, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 μM), CU (10 μM), or SP (1 μM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 μM) concentration was efficient in diminishing the iAβ, p-TAU Ser/Thr, DJ-1Cys-SO, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser/Thr, DJ-1Cys-SO, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAβ compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAβ-induced ChLN damage in FAD.
Topics: Curcumin; Alzheimer Disease; Presenilin-1; Anthracenes; Animals; Reactive Oxygen Species; Mice; Amyloid beta-Peptides; Humans; tau Proteins; Neurons; Membrane Potential, Mitochondrial; Taurine
PubMed: 38732141
DOI: 10.3390/ijms25094925 -
Foods (Basel, Switzerland) May 2024Honey is a natural product extensively consumed in the world for its nutritional and healthy properties. However, residues of pesticides and environmental contaminants...
Honey is a natural product extensively consumed in the world for its nutritional and healthy properties. However, residues of pesticides and environmental contaminants can compromise its quality. For this reason, the physicochemical parameters, and the organic contamination of monofloral and multifloral honey from three regions of Algeria (Tiaret, Laghouat, and Tindouf) were monitored to evaluate the quality of the honey and its safety for consumers. In general, the results obtained from the physicochemical analyses were in line with the EU standards. In terms of contamination, pesticides authorised and used in Algerian agriculture (metalaxyl-M and cyromazine), as well as a banned pesticide (carbaryl), were found in almost all the samples. However, only the concentration of cyromazine was higher than the relative EU maximum residue levels. PCB 180, PCB 189, anthracene, fluorene, and phenanthrene were mainly detected. All the honey shows traces of DiBP, DBP, DEHP, and DEHT, but no traces of bisphenols were found. Moreover, according to the dietary exposure assessment, a small amount of Algerian honey can be safely consumed. Overall, the data from this study should motivate the Algerian government to enhance their monitoring activities in beekeeping and to find solutions for implementing more sustainable agricultural practices harmonising with international legislation.
PubMed: 38731784
DOI: 10.3390/foods13091413 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current...
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the , 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against and parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the -substituted BODIPY, with 1-dimethylaminonaphthalene () and anthracene moiety (), were the most active against , displaying IC = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues and exhibited the highest toxicity (IC = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against . Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Topics: Boron Compounds; Trypanosoma brucei brucei; Humans; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania major; Drug Design; Structure-Activity Relationship; Cell Line; Molecular Structure; Trypanocidal Agents; Oxidoreductases
PubMed: 38731562
DOI: 10.3390/molecules29092072 -
Molecules (Basel, Switzerland) Apr 2024The aim of this study was to investigate how dietary modifications with pomegranate seed oil (PSO) and bitter melon aqueous extract (BME) affect mineral content in the...
The aim of this study was to investigate how dietary modifications with pomegranate seed oil (PSO) and bitter melon aqueous extract (BME) affect mineral content in the spleen of rats both under normal physiological conditions and with coexisting mammary tumorigenesis. The diet of Sprague-Dawley female rats was supplemented either with PSO or with BME, or with a combination for 21 weeks. A chemical carcinogen (7,12-dimethylbenz[a]anthracene) was applied intragastrically to induce mammary tumors. In the spleen of rats, the selected elements were determined with a quadrupole mass spectrometer with inductively coupled plasma ionization (ICP-MS). ANOVA was used to evaluate differences in elemental composition among experimental groups. Multivariate statistical methods were used to discover whether some subtle dependencies exist between experimental factors and thus influence the element content. Experimental factors affected the splenic levels of macroelements, except for potassium. Both diet modification and the cancerogenic process resulted in significant changes in the content of Fe, Se, Co, Cr, Ni, Al, Sr, Pb, Cd, B, and Tl in rat spleen. Chemometric analysis revealed the greatest impact of the ongoing carcinogenic process on the mineral composition of the spleen. The obtained results may contribute to a better understanding of peripheral immune organ functioning, especially during the neoplastic process, and thus may help develop anticancer prevention and treatment strategies.
Topics: Animals; Spleen; Female; Rats; Pomegranate; Plant Extracts; Momordica charantia; Rats, Sprague-Dawley; Plant Oils; Dietary Supplements; Seeds; Breast Neoplasms; Mammary Neoplasms, Experimental
PubMed: 38731433
DOI: 10.3390/molecules29091942 -
Chemical Science May 2024Triplet excited state generation plays a pivotal role in photosensitizers, however the reliance on transition metals and heavy atoms can limit the utility of these...
Triplet excited state generation plays a pivotal role in photosensitizers, however the reliance on transition metals and heavy atoms can limit the utility of these systems. In this study, we demonstrate that an interplay of competing quantum effects controls the high triplet quantum yield in a prototypical boron dipyrromethene-anthracene (BD-An) donor-acceptor dyad photosensitizer, which is only captured by an accurate treatment of both inner and outer sphere reorganization energies. Our -derived model provides excellent agreement with experimentally measured spectra, triplet yields and excited state kinetic data, including the triplet lifetime. We find that rapid triplet state formation occurs primarily high-energy triplet states through both spin-orbit coupled charge transfer and El-Sayed's rule breaking intersystem crossing, rather than direct spin-orbit coupled charge transfer to the lowest lying triplet state. Our calculations also reveal that competing effects of nuclear tunneling, electronic state recrossing, and electronic polarizability dictate the rate of non-productive ground state recombination. This study sheds light on the quantum effects driving efficient triplet formation in the BD-An system, and offers a promising simulation methodology for diverse photochemical systems.
PubMed: 38725521
DOI: 10.1039/d4sc01369g -
Physical Chemistry Chemical Physics :... May 2024Strong light-matter interactions have attracted much attention as a means to control the physical/chemical properties of organic semiconducting materials with...
Strong light-matter interactions have attracted much attention as a means to control the physical/chemical properties of organic semiconducting materials with light-matter hybrids called polaritons. To unveil the processes under strong coupling, studies on the dynamics of polaritons are of particular importance. While highly condensed molecular materials with large dipole density are ideal to achieve strong coupling, the emission properties of such films often become a mixture of monomeric and excimeric components, making the role of excimers unclear. Here, we use amorphous neat films of a new bis(phenylethynyl anthracene) derivative showing only excimer emission and investigate the excited-state dynamics of a series of strongly coupled microcavities, with each cavity being characterised by a different exciton-photon detuning. A time-resolved photoluminescence study shows that the excimer radiatively pumps the lower polariton in the relaxation process and the decay profile reflects the density of states. The delayed emission derived from triplet-triplet annihilation is not sensitive to the cavity environment, possibly due to the rapid excimer formation. Our results highlight the importance of controlling intermolecular interactions towards rational design of organic exciton-polariton devices, whose performance depends on efficient polariton relaxation pathways.
PubMed: 38716658
DOI: 10.1039/d4cp00255e -
Environmental Science and Pollution... May 2024Peatlands records can be used to reconstruct and understand the history of environmental evolution, as well as a more accurate reflection of human activities. The black...
Peatlands records can be used to reconstruct and understand the history of environmental evolution, as well as a more accurate reflection of human activities. The black carbon (BC) and polycyclic aromatic hydrocarbons (PAHs) are ideal natural archives of anthropogenic activities. To identify the information of anthropogenic activities recorded by peatlands in the middle and high latitudes of the alpine mountains in the arid and semi-arid regions of China. this study analyzed the concentrations of BC, δC ratios of BC, PAHs, and molecular diagnostic ratios of PHAs (including Benzo(a) anthracene (BaA), Chrysene (Chr), fluoranthene (Flt), anthracene (Ant), phenanthrene (Phe), Benzo(a) pyrene (BaP), and pyrene (Pyr) in a 30-cm peat profile from the Altay Mountain, northwestern China. Our results revealed concentrations of BC from 11.71 to 67.5 mg·g, and PAHs from 168.09 to 263.53 ng·g. The δC value ranged from - 31.37 to - 26.27‰, with an average of - 29.54‰, indicating that the BC mainly comes from biomass combustion. The ratios of BaA/(BaA + Chr), Flt/(Flt + Pyr), and Ant/(Ant + Phe) exceeded 0.35, 0.5, and 0.1, respectively, revealing that the PAHs pollutants mainly originated from the combustion of biomass and fossil fuel burning. Furthermore, based on these findings and our knowledge of social development in Altay, industrial transport and tourism have influenced the emission, transport, and deposition of BC and PAH in peatlands in the Altay mountains since the 1980s. After 1980, pollutant concentrations decreased with the implementation of environmental policies. The results not only reveal the influence of anthropogenic activities on the sedimentary characteristics of peatlands in the Altay Mountains, but also provide an important theoretical basis for the conservation of fragile mountain peatlands.
Topics: China; Environmental Monitoring; Polycyclic Aromatic Hydrocarbons; Soil; Humans; Soil Pollutants
PubMed: 38709407
DOI: 10.1007/s11356-024-33498-1 -
The Journal of Biological Chemistry Jun 2024Rieske nonheme iron aromatic ring-hydroxylating oxygenases (RHOs) play pivotal roles in determining the substrate preferences of polycyclic aromatic hydrocarbon (PAH)...
Rieske nonheme iron aromatic ring-hydroxylating oxygenases (RHOs) play pivotal roles in determining the substrate preferences of polycyclic aromatic hydrocarbon (PAH) degraders. However, their potential to degrade high molecular weight PAHs (HMW-PAHs) has been relatively unexplored. NarA2B2 is an RHO derived from a thermophilic Hydrogenibacillus sp. strain N12. In this study, we have identified four "hotspot" residues (V236, Y300, W316, and L375) that may hinder the catalytic capacity of NarA2B2 when it comes to HMW-PAHs. By employing structure-guided rational enzyme engineering, we successfully modified NarA2B2, resulting in NarA2B2 variants capable of catalyzing the degradation of six different types of HMW-PAHs, including pyrene, fluoranthene, chrysene, benzo[a]anthracene, benzo[b]fluoranthene, and benzo[a]pyrene. Three representative variants, NarA2B2, NarA2B2, and NarA2B2, not only maintain their abilities to degrade low-molecular-weight PAHs (LMW-PAHs) but also exhibited 2 to 4 times higher degradation efficiency for HMW-PAHs in comparison to another isozyme, NarAaAb. Computational analysis of the NarA2B2 variants predicts that these modifications alter the size and hydrophobicity of the active site pocket making it more suitable for HMW-PAHs. These findings provide a comprehensive understanding of the relationship between three-dimensional structure and functionality, thereby opening up possibilities for designing improved RHOs that can be more effectively used in the bioremediation of PAHs.
Topics: Polycyclic Aromatic Hydrocarbons; Molecular Weight; Bacterial Proteins; Substrate Specificity; Biodegradation, Environmental; Oxygenases; Hydroxylation
PubMed: 38705395
DOI: 10.1016/j.jbc.2024.107343 -
Microbial Cell Factories May 2024Anthraquinone-fused enediynes (AFEs) are excellent payloads for antibody-drug conjugates (ADCs). The yields of AFEs in the original bacterial hosts are extremely low....
BACKGROUND
Anthraquinone-fused enediynes (AFEs) are excellent payloads for antibody-drug conjugates (ADCs). The yields of AFEs in the original bacterial hosts are extremely low. Multiple traditional methods had been adopted to enhance the production of the AFEs. Despite these efforts, the production titers of these compounds are still low, presenting a practical challenge for their development. Tiancimycins (TNMs) are a class of AFEs produced by Streptomyces sp. CB03234. One of their salient features is that they exhibit rapid and complete cell killing ability against various cancer cell lines.
RESULTS
In this study, a combinatorial metabolic engineering strategy guided by the CB03234-S genome and transcriptome was employed to improve the titers of TNMs. First, re-sequencing of CB03234-S (Ribosome engineered mutant strains) genome revealed the deletion of a 583-kb DNA fragment, accounting for about 7.5% of its genome. Second, by individual or combined inactivation of seven potential precursor competitive biosynthetic gene clusters (BGCs) in CB03234-S, a double-BGC inactivation mutant, S1009, was identified with an improved TNMs titer of 28.2 ± 0.8 mg/L. Third, overexpression of five essential biosynthetic genes, including two post-modification genes, and three self-resistance auxiliary genes, was also conducted, through which we discovered that mutants carrying the core genes, tnmE or tnmE10, exhibited enhanced TNMs production. The average TNMs yield reached 43.5 ± 2.4 mg/L in a 30-L fermenter, representing an approximately 360% increase over CB03234-S and the highest titer among all AFEs to date. Moreover, the resulting mutant produced TNM-W, a unique TNM derivative with a double bond instead of a common ethylene oxide moiety. Preliminary studies suggested that TNM-W was probably converted from TNM-A by both TnmE and TnmE10.
CONCLUSIONS
Based on the genome and transcriptome analyses, we adopted a combined metabolic engineering strategy for precursor enrichment and biosynthetic pathway reorganization to construct a high-yield strain of TNMs based on CB03234-S. Our study establishes a solid basis for the clinical development of AFE-based ADCs.
Topics: Streptomyces; Metabolic Engineering; Anthraquinones; Enediynes; Multigene Family; Biosynthetic Pathways
PubMed: 38704580
DOI: 10.1186/s12934-024-02399-w -
Applied Microbiology and Biotechnology May 2024Perylenequinones (PQs) are natural photosensitizing compounds used as photodynamic therapy, and heat stress (HS) is the main limiting factor of mycelial growth and...
Perylenequinones (PQs) are natural photosensitizing compounds used as photodynamic therapy, and heat stress (HS) is the main limiting factor of mycelial growth and secondary metabolism of fungi. This study aimed to unravel the impact of HS-induced Ca and the calcium signaling pathway on PQ biosynthesis of Shiraia sp. Slf14(w). Meanwhile, the intricate interplay between HS-induced NO and Ca and the calcium signaling pathway was investigated. The outcomes disclosed that Ca and the calcium signaling pathway activated by HS could effectively enhance the production of PQs in Shiraia sp. Slf14(w). Further investigations elucidated the specific mechanism through which NO signaling molecules induced by HS act upon the Ca/CaM (calmodulin) signaling pathway, thus propelling PQ biosynthesis in Shiraia sp. Slf14(w). This was substantiated by decoding the downstream positioning of the CaM/CaN (calcineurin) pathway in relation to NO through comprehensive analyses encompassing transcript levels, enzyme assays, and the introduction of chemical agents. Concurrently, the engagement of Ca and the calcium signaling pathway in heat shock signaling was also evidenced. The implications of our study underscore the pivotal role of HS-induced Ca and the calcium signaling pathway, which not only participate in heat shock signal transduction but also play an instrumental role in promoting PQ biosynthesis. Consequently, our study not only enriches our comprehension of the mechanisms driving HS signaling transduction in fungi but also offers novel insights into the PQ synthesis paradigm within Shiraia sp. Slf14(w). KEY POINTS: • The calcium signaling pathway was proposed to participate in PQ biosynthesis under HS. • HS-induced NO was revealed to act upon the calcium signaling pathway for the first time.
Topics: Ascomycota; Quinones; Perylene; Calcium Signaling; Nitric Oxide; Heat-Shock Response; Calcium; Hot Temperature
PubMed: 38700737
DOI: 10.1007/s00253-024-13142-1