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1.
ACS Omega ; 9(35): 37170-37182, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39246504

RESUMEN

Visceral leishmaniasis is a neglected tropical disease with the highest mortality among different forms of leishmaniasis manifestation in humans. The disease is caused by the parasitic protists Leishmania donovani and Leishmania infantum, and treatments remain unsuitable due to high costs, complicated administration, lack of efficacy, variable patient susceptibility, toxic side effects, and rising parasitic resistance. Herein, we report a structure-activity relationship (SAR) exploration of the diacyl-hydrazide scaffold identified to have antiparasitic activity from a high-throughput screen against L. donovani, Trypanosoma cruzi, and Trypanosoma brucei. This SAR study revealed new structural insights into this scaffold related to bioactivity resulting in a new series of lead compounds with nanomolar activity against L. donovani and no toxicity against human THP-1 macrophages. These optimized diacyl-hydrazide compounds set the stage for future drug development and hold promise for a new treatment avenue for visceral leishmaniasis.

2.
Clin Microbiol Rev ; 37(3): e0013323, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-38995034

RESUMEN

SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.


Asunto(s)
Biopelículas , Microbioma Gastrointestinal , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Humanos , Microbioma Gastrointestinal/fisiología , Disbiosis/microbiología , Animales , Bacterias , Antibacterianos/uso terapéutico , Antibacterianos/farmacología
3.
Gastroenterology ; 167(6): 1098-1112.e5, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38876174

RESUMEN

Gastrointestinal biofilms are matrix-enclosed, highly heterogenic and spatially organized polymicrobial communities that can cover large areas in the gastrointestinal tract. Gut microbiota dysbiosis, mucus disruption, and epithelial invasion are associated with pathogenic biofilms that have been linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel diseases, gastric cancer, and colorectal cancer. Intestinal biofilms are highly prevalent in ulcerative colitis and irritable bowel syndrome patients, and most endoscopists will have observed such biofilms during colonoscopy, maybe without appreciating their biological and clinical importance. Gut biofilms have a protective extracellular matrix that renders them challenging to treat, and effective therapies are yet to be developed. This review covers gastrointestinal biofilm formation, growth, appearance and detection, biofilm architecture and signalling, human host defence mechanisms, disease and clinical relevance of biofilms, therapeutic approaches, and future perspectives. Critical knowledge gaps and open research questions regarding the biofilm's exact pathophysiological relevance and key hurdles in translating therapeutic advances into the clinic are discussed. Taken together, this review summarizes the status quo in gut biofilm research and provides perspectives and guidance for future research and therapeutic strategies.


Asunto(s)
Biopelículas , Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Humanos , Biopelículas/crecimiento & desarrollo , Microbioma Gastrointestinal/fisiología , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/terapia , Enfermedades Gastrointestinales/fisiopatología , Disbiosis , Tracto Gastrointestinal/microbiología , Animales , Antibacterianos/uso terapéutico , Colonoscopía
4.
Beilstein J Org Chem ; 17: 891-907, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33981364

RESUMEN

Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood-brain barrier (BBB) has proven challenging. In an effort to target LNPs composed of an ionizable cationic lipid (DLin-MC3-DMA), cholesterol, the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) to particular cell types, as well as to generate LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB.

5.
ACS Omega ; 4(9): 13889-13895, 2019 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-31497706

RESUMEN

Cancer is a major health risk in the modern society that requires rapid, reliable, and inexpensive diagnostics. Because of the low abundance of cancer DNA in biofluids, current detection methods require DNA amplification. The amplification can be challenging; it provides only relative quantification and extends time and cost of an assay. Herein, we report a new oligonucleotide hybridization platform for amplification-free detection of human cancer DNA. Using a large PEG-capture probe allows rapid separation of the bound (mutant) versus unbound (wild type) DNA. Next, a supramolecular hydrogel forming peptide attached to a detection oligonucleotide probe serves as a signal amplification tool. Having screened multiple short peptides and fluorophores, we identified the system P1 + cyanine 3.5 that allows for sensitive quantitative detection of mutation L858R in EGFR oncogene. The peptide-fluorophore-based assay provides absolute target DNA quantification at the detection limit of 20 ng cancer DNA versus >500 ng for Cy3.5-labeled oligonucleotide in only 1 hour.

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