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Molecules (Basel, Switzerland) Jun 2024Ammonium polyphosphate (APP), a pivotal constituent within environmentally friendly flame retardants, exhibits notable decomposition susceptibility and potentially...
Ammonium polyphosphate (APP), a pivotal constituent within environmentally friendly flame retardants, exhibits notable decomposition susceptibility and potentially engenders ecological peril. Consequently, monitoring the APP concentration to ensure product integrity and facilitate the efficacious management of wastewater from production processes is of great significance. A fluorescent assay was devised to swiftly discern APP utilizing 4',6'-diamino-2-phenylindole (DAPI). With increasing APP concentrations, DAPI undergoes intercalation within its structure, emitting pronounced fluorescence. Notably, the flame retardant JLS-PNA220-A, predominantly comprising APP, was employed as the test substrate. Establishing a linear relationship between fluorescence intensity (F-F0) and JLS-PNA220-A concentration yielded the equation y = 76.08x + 463.2 (R = 0.9992), with a LOD determined to be 0.853 mg/L. The method was used to assess the degradation capacity of APP-degrading bacteria. Strain D-3 was isolated, and subsequent analysis of its 16S DNA sequence classified it as belonging to the genus. D-3 demonstrated superior APP degradation capabilities under pH 7 at 37 °C, with degradation rates exceeding 85% over a four-day cultivation period. It underscores the sensitivity and efficacy of the proposed method for APP detection. Furthermore, D-3 exhibits promising potential for remediation of residual APP through environmental biodegradation processes.
Topics: Biodegradation, Environmental; Acinetobacter; Polyphosphates; Indoles; Ammonium Compounds; Flame Retardants
PubMed: 38893541
DOI: 10.3390/molecules29112667 -
Molecules (Basel, Switzerland) May 2024Metronidazole (MTZ) is the most common drug used against () infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported,...
Metronidazole (MTZ) is the most common drug used against () infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in to MTZ. Therefore, research into new therapeutic options against infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC values in the nanomolar range and AGR-2 being the most potent (IC 400 nM). To gain insight into molecular events related to AGR-induced cell death in , we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (, , , and ) and genes involved in metabolism (, , , , , and ), suggesting that disturbing these key metabolic genes alters the survival of the parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against .
Topics: Trichomonas vaginalis; Imidazoles; Humans; Carbamates; Metronidazole; Gene Expression Regulation; Trophozoites
PubMed: 38893461
DOI: 10.3390/molecules29112585 -
Molecules (Basel, Switzerland) May 2024Kallopterolides A-I (-), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were...
Kallopterolides A-I (-), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume . The structures and relative configurations of - were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.
Topics: Diterpenes; Animals; Anthozoa; Antiprotozoal Agents; Caribbean Region; Molecular Structure; Anti-Inflammatory Agents; Magnetic Resonance Spectroscopy; Antitubercular Agents
PubMed: 38893370
DOI: 10.3390/molecules29112493 -
Molecules (Basel, Switzerland) May 2024m6A methylation, a ubiquitous modification on circRNAs, exerts a profound influence on RNA function, intracellular behavior, and diverse biological processes, including...
m6A methylation, a ubiquitous modification on circRNAs, exerts a profound influence on RNA function, intracellular behavior, and diverse biological processes, including disease development. While prediction algorithms exist for mRNA m6A modifications, a critical gap remains in the prediction of circRNA m6A modifications. Therefore, accurate identification and prediction of m6A sites are imperative for understanding RNA function and regulation. This study presents a novel hybrid model combining a convolutional neural network (CNN) and a bidirectional long short-term memory network (BiLSTM) for precise m6A methylation site prediction in circular RNAs (circRNAs) based on data from HEK293 cells. This model exploits the synergy between CNN's ability to extract intricate sequence features and BiLSTM's strength in capturing long-range dependencies. Furthermore, the integrated attention mechanism empowers the model to pinpoint critical biological information for studying circRNA m6A methylation. Our model, exhibiting over 78% prediction accuracy on independent datasets, offers not only a valuable tool for scientific research but also a strong foundation for future biomedical applications. This work not only furthers our understanding of gene expression regulation but also opens new avenues for the exploration of circRNA methylation in biological research.
Topics: RNA, Circular; Humans; Neural Networks, Computer; Methylation; HEK293 Cells; Computational Biology; Algorithms; Adenosine
PubMed: 38893304
DOI: 10.3390/molecules29112429 -
International Journal of Molecular... Jun 2024Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World...
Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist , which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.
Topics: Giardiasis; Giardia lamblia; Molecular Docking Simulation; Antiprotozoal Agents; United States; United States Food and Drug Administration; Humans; Protozoan Proteins; Molecular Dynamics Simulation
PubMed: 38892424
DOI: 10.3390/ijms25116238 -
International Journal of Molecular... May 2024Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on... (Review)
Review
Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development of new efficient drugs, and the emergence of resistant fungal strains. Niclosamide is currently applied for the treatment of worm infections. Its mechanisms of action, which include the suppression of mitochondrial oxidative phosphorylation (also known as mitochondrial uncoupling), among others, has led to a repurposing of this promising anthelmintic drug for the therapy of further human diseases such as cancer, diabetes, and microbial infections. Given the urgent need to develop new drugs against fungal infections, the considerable antifungal properties of niclosamide are highlighted in this review. Its chemical and pharmacological properties relevant for drug development are also briefly mentioned, and the described mitochondria-targeting mechanisms of action add to the current arsenal of approved antifungal drugs. In addition, the activities of further salicylanilide-based niclosamide analogs against fungal pathogens, including agents applied in veterinary medicine for many years, are described and discussed for their feasibility as new antifungals for humans. Preliminary structure-activity relationships are determined and discussed. Various salicylanilide derivatives with antifungal activities showed increased oral bioavailabilities when compared with niclosamide. The simple synthesis of salicylanilide-based drugs also vouchsafes a broad and cost-effective availability for poorer patient groups. Pertinent literature is covered until 2024.
Topics: Niclosamide; Salicylanilides; Antifungal Agents; Humans; Animals; Structure-Activity Relationship; Fungi; Mycoses; Mitochondria
PubMed: 38892165
DOI: 10.3390/ijms25115977 -
Cells May 2024Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth,...
Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes.
Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis, whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis, with the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.
Topics: Humans; Ferroptosis; Pinocytosis; Colonic Neoplasms; Tumor Suppressor Protein p53; Proto-Oncogene Proteins p21(ras); Cell Line, Tumor; Niclosamide; Antineoplastic Agents; Amino Acid Transport System y+; Mutation
PubMed: 38891084
DOI: 10.3390/cells13110951 -
Journal of Medical Case Reports Jun 2024Schistosomiasis is one of the endemic parasitic diseases in many developing countries. Despite this, appendicitis secondary to schistosomiasis is an uncommon condition...
BACKGROUND
Schistosomiasis is one of the endemic parasitic diseases in many developing countries. Despite this, appendicitis secondary to schistosomiasis is an uncommon condition even in some endemic areas. Schistosomal appendicitis, an incidentally discovered appendicitis associated with schistosomiasis histological findings, affects young males predominantly. Timely diagnosis and treatment, including appendectomy and anti-helminthic therapy, are crucial.
CASE REPORT
A 24-year-old Sudanese male patient presented with abdominal pain. Diagnosed with acute appendicitis, he underwent appendectomy, revealing appendix inflammation with Schistosoma ova in histopathology. Abdominal ultrasound detected no complications. Weakly positive Schistosoma serology was noted, but stool and urine analysis showed no infection evidence. Prescribed praziquantel, patient had 3-year post-op follow-up without complications.
CONCLUSIONS
This case report underscores the significance of including schistosomiasis in the differential diagnosis of appendicitis, particularly in regions where the disease is endemic. It underscores the necessity of histopathological evaluations for accurate diagnosis, emphasizing the potential implications for clinical practice in similar settings.
Topics: Humans; Appendicitis; Male; Young Adult; Praziquantel; Appendectomy; Anthelmintics; Schistosomiasis; Diagnosis, Differential; Abdominal Pain; Ultrasonography; Animals; Treatment Outcome; Appendix
PubMed: 38890741
DOI: 10.1186/s13256-024-04610-3 -
BMC Complementary Medicine and Therapies Jun 2024The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo...
The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo experiments. CUR-NE was successfully prepared via the spontaneous emulsification method. The in vitro effect of various concentrations of CUR-NE against L. major promastigotes was assessed using the flow cytometry method. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 10L. major promastigotes. Mice were treated with topical CUR-NE (2.5 mg/ml), intra-lesion injection of CUR-NE (2.5 mg/ml), topical CUR suspension (CUR-S, 2.5 mg/ml), topical NE without CUR (NE-no CUR), amphotericin B as the positive control group, and infected untreated mice as the negative control group. In vitro exposure of promastigotes to CUR-NE showed a dose-dependent anti-leishmanial effect, with a 67.52 ± 0.35% mortality rate at a concentration of 1250 µg/ml and an IC50 of 643.56 µg/ml. In vivo experiments showed that topical CUR-NE and CUR-S significantly decreased the mean lesion size in mice after four weeks from 4.73 ± 1.28 to 2.78 ± 1.28 mm and 4.45 ± 0.88 to 3.23 ± 0.59 mm, respectively (p = 0.001). Furthermore, CUR-NE significantly decreased the parasite load in treated mice compared with the negative control group (p = 0.001). Results from the current study demonstrated the promising activity of CUR-NE against L. major in both in vitro and in vivo experiments. Moreover, CUR-NE was more efficient than CUR-S in healing and reducing parasite burden in mouse models. Future studies should aim to identify molecular mechanisms as well as the pharmacologic and pharmacokinetic aspects of CUR-NE.
Topics: Animals; Curcumin; Mice, Inbred BALB C; Leishmania major; Mice; Emulsions; Leishmaniasis, Cutaneous; Antiprotozoal Agents; Female; Nanoparticles
PubMed: 38890586
DOI: 10.1186/s12906-024-04522-1 -
Communications Biology Jun 2024Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA...
Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
Topics: Plasmodium falciparum; Lysine-tRNA Ligase; Protein Kinase Inhibitors; Anaplastic Lymphoma Kinase; Antimalarials; Structure-Activity Relationship; Humans; Protozoan Proteins
PubMed: 38890421
DOI: 10.1038/s42003-024-06455-4