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1.
J Neurosci ; 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39054068

RESUMEN

TFEB and TFE3 (TFEB/3), key regulators of lysosomal biogenesis and autophagy, play diverse roles depending on cell type. This study highlights a hitherto unrecognized role of TFEB/3 crucial for peripheral nerve repair. Specifically, they promote the generation of progenitor-like repair Schwann cells after axonal injury. In Schwann cell-specific TFEB/3 double knock-out mice of either sex, the TFEB/3 loss disrupts the transcriptomic reprogramming that is essential for the formation of repair Schwann cells. Consequently, mutant mice fail to populate the injured nerve with repair Schwann cells and exhibit defects in axon-regrowth, target reinnervation, and functional recovery. TFEB/3 deficiency inhibits the expression of injury-responsive repair Schwann cell genes, despite the continued expression of c-Jun, a previously identified regulator of repair Schwann cell function. TFEB/3 binding motifs are enriched in the enhancer regions of injury-responsive genes, suggesting their role in repair gene activation. Autophagy-dependent myelin breakdown is not impaired despite TFEB/3 deficiency. These findings underscore a unique role of TFEB/3 in adult Schwann cells that is required for proper peripheral nerve regeneration.Significance Statement Peripheral nerves have been recognized for their efficient regenerative capabilities compared to the central nervous system neurons. This is due to the remarkable ability of Schwann cells to undergo a reprogramming process, transforming into progenitor-like repair Schwann cells that actively contribute to axon regeneration and overall nerve repair. However, the specific transcriptional regulators responsible for initiating this transformation in the adult peripheral nerve have remained elusive. Our study elucidates a previously undescribed, injury-responsive function of TFEB/3 in adult Schwann cells, showcasing its ability to promote tissue repair. Our findings hold important implications for enhancing nerve regeneration by bolstering the regenerative capacity of glial cells, thereby contributing to advancements in the field of neural tissue repair.

2.
Emerg Infect Dis ; 30(8): 1726-1729, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39043392

RESUMEN

A woman in South Korea who underwent a colonoscopy for occasional gastrointestinal discomfort had 4 adult flukes of Echinostoma cinetorchis showing 37 collar spines around the oral sucker recovered from the terminal ileum through the ascending colon. Partial gene sequencing showed high identity with E. cinetorchis.


Asunto(s)
Echinostoma , Equinostomiasis , Animales , Echinostoma/genética , Echinostoma/aislamiento & purificación , República de Corea , Humanos , Femenino , Equinostomiasis/diagnóstico , Equinostomiasis/parasitología , Equinostomiasis/tratamiento farmacológico , Persona de Mediana Edad , Filogenia
3.
Elife ; 132024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38456457

RESUMEN

Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin . Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.


Asunto(s)
Vaina de Mielina , Nervios Periféricos , Animales , Ratones , Regulación de la Expresión Génica , Ratones Noqueados , Vaina de Mielina/metabolismo , Nervios Periféricos/metabolismo , Células de Schwann/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
4.
bioRxiv ; 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38293102

RESUMEN

Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin (Grove et al., 2017; Grove, Lee, Zhao, & Son, 2020). Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.

5.
J Ethnopharmacol ; 319(Pt 3): 117285, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-37839769

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus macrocarpa Hance (UmH) bark has been traditionally utilized for medicinal purposes. The bark extract of this plant has diverse health benefits, and its potential role in enhancing bone health is of distinct interest, particularly when considering the substantial health and economic implications of bone-related pathologies, such as osteoporosis. Despite the compelling theoretical implications of UmH bark in fortifying bone health, no definitive evidence at the in vivo level is currently available, thus highlighting the innovative and as-yet-unexplored potential of this field of study. AIM OF THE STUDY: Primarily, our study aims to conduct a meticulous analysis of the disparity in the concentration of active compounds in the UmH root bark (Umrb) and trunk bark (Umtb) extracts and confirm UmH bark's efficacy in enhancing bone health in vivo, illuminating the cellular mechanisms involved. MATERIALS AND METHODS: The Umrb and Umtb extracts were subjected to component analysis using high-performance liquid chromatography and then assessed for their inhibitory effects on osteoclast differentiation through the TRAP assay. An ovariectomized (OVX) mouse model replicates postmenopausal conditions commonly associated with osteoporosis. Micro-CT was used to analyze bone structure parameters, and enzyme-linked immunosorbent assay and staining were used to assess bone formation markers and osteoclast activity. Furthermore, this study investigated the impact of the extract on the expression of pivotal proteins and genes involved in bone formation and resorption using mouse bone marrow-derived macrophages (BMMs). RESULTS: The findings of our study reveal a significant discrepancy in the concentration of active constituents between Umrb and Umtb, establishing Umtb as a superior source for promoting bone health. I addition, a standardized pilot-scale procedure was conducted for credibility. The bone health benefits of Umtb were verified using an OVX model. This validation involved the assessment of various parameters, including BMD, BV/TV, and BS/TV, using micro-CT imaging. Additionally, the activation of osteoblasts was evaluated by Umtb by measuring specific factors such as ALP, OCN, OPG in blood samples and through IHC staining. In the same investigations, diminished levels of osteoclast differentiation factors, such as TRAP, NFATc1, were also observed. The observed patterns exhibited consistency in vitro BMM investigations. CONCLUSIONS: Through verification at both in vitro levels using BMMs and in vivo levels using the OVX-induced mouse model, our research demonstrates that Umtb is a more effective means of improving bone health in comparison to Umrb. These findings pave the way for developing health-functional foods or botanical drugs targeting osteoporosis and other bone-related disorders and enhance the prospects for future research extensions, including clinical studies, in extract applications.


Asunto(s)
Osteoporosis , Ulmus , Femenino , Humanos , Animales , Ratones , Osteoclastos , Corteza de la Planta , Osteoporosis/prevención & control , Modelos Animales de Enfermedad , Ovariectomía
6.
J Med Chem ; 66(20): 14263-14277, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37796116

RESUMEN

Thiopeptides exhibit potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. Micrococcins are among the structurally simpler thiopeptides, but they have not been exploited in detail. This research involved a computational simulation of micrococcin P2 (MP2) docking in parallel with the structure-activity relationship (SAR) studied. The incorporation of particular nitrogen heterocycles in the side chain of MP2 enhances the antimicrobial activity. Micrococcin analogues 6c and 6d thus proved to be more effective against impetigo and C. difficile infection (CDI), respectively, as compared to current first-line treatments. Compound 6c also showed a shorter treatment period than that of a first-line treatment for impetigo. This may be attributed to its ability to downregulate pro-inflammatory cytokines. Compound 6d had no observed recurrence for C. difficile and exerted a minimal impact on the beneficial gut microbiome. Their pharmacokinetic properties and low toxicity profile make these compounds ideal candidates for the treatment of impetigo and CDI and validate their involvement in preclinical development.


Asunto(s)
Clostridioides difficile , Impétigo , Humanos , Antibacterianos/farmacología , Antibacterianos/química
7.
Prev Nutr Food Sci ; 28(3): 370-376, 2023 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-37842259

RESUMEN

The cultivar "Nulichal," a type of naked waxy barley (Hordeum vulgare L.), was developed by the National Institute of Crop Science, Rural Development Administration, Korea, in 2010. In this study, we investigated the anti-inflammatory and antioxidant properties of the "Nulichal" ethanol extract (NRE) using various assays. The NRE exhibited a total phenolic content of 7.55±0.30 mg gallic acid equivalent/g and a flavonoid content of 1.74±0.08 mg rutin equivalent/g. Cell viability assays showed no toxicity of NRE on RAW264.7 macrophage cells up to concentrations of 500 µg/mL. The NRE (300 and 500 µg/mL) significantly reduced nitric oxide (NO) production induced by lipopolysaccharides (LPS). It also down-regulated the mRNA expression and protein levels of inducible NO synthase and cyclooxygenase-2 in a dose-dependent manner. Moreover, the NRE treatment significantly decreased the levels of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, and their mRNA expression compared to LPS treatment alone. The NRE demonstrated strong free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals in a dose-dependent manner. The ferric reducing antioxidant power assay also showed increased antioxidant activity with increasing NRE concentrations. These findings suggest that the NRE can be used as a functional food with anti-inflammatory and antioxidant properties.

8.
Cell Rep ; 42(9): 113068, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37656624

RESUMEN

Primary somatosensory axons stop regenerating as they re-enter the spinal cord, resulting in incurable sensory loss. What arrests them has remained unclear. We previously showed that axons stop by forming synaptic contacts with unknown non-neuronal cells. Here, we identified these cells in adult mice as oligodendrocyte precursor cells (OPCs). We also found that only a few axons stop regenerating by forming dystrophic endings, exclusively at the CNS:peripheral nervous system (PNS) borderline where OPCs are absent. Most axons stop in contact with a dense network of OPC processes. Live imaging, immuno-electron microscopy (immuno-EM), and OPC-dorsal root ganglia (DRG) co-culture additionally suggest that axons are rapidly immobilized by forming synapses with OPCs. Genetic OPC ablation enables many axons to continue regenerating deep into the spinal cord. We propose that sensory axons stop regenerating by encountering OPCs that induce presynaptic differentiation. Our findings identify OPCs as a major regenerative barrier that prevents intraspinal restoration of sensory circuits following spinal root injury.


Asunto(s)
Células Precursoras de Oligodendrocitos , Ratones , Animales , Médula Espinal/fisiología , Axones/fisiología , Raíces Nerviosas Espinales , Ganglios Espinales/fisiología , Regeneración Nerviosa/fisiología
9.
Microbiol Spectr ; : e0182523, 2023 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-37594284

RESUMEN

Unsatisfactory outcomes following long-term multidrug treatment in patients with Mycobacterium avium complex (MAC) pulmonary disease have urged us to develop novel antibiotics. Thiopeptides, a class of peptide antibiotics derived from natural products, have potential as drug candidates that target bacterial ribosomes, but drug development has been hampered due to their extremely poor solubility. Here, we evaluated three new compounds (AJ-037, AJ-039, and AJ-206) derived from the thiopeptide micrococcin P2 with enhanced aqueous solubility; the derivatives were generated based on structure-activity relationship analysis. We conducted in vitro drug susceptibility and intracellular antimycobacterial activity testing of the three thiopeptide derivatives against various MAC strains, including macrolide-resistant MAC clinical isolates. These compounds showed low MICs against MAC, similar to that of clarithromycin (CLR). In particular, two compounds, AJ-037 and AJ-206, had intracellular antimycobacterial activities, along with synergistic effects with CLR, and inhibited the growth of MAC inside macrophages. Moreover, these two compounds showed in vitro and intracellular anti-MAC activities against macrolide-resistant MAC strains without showing cross-resistance with CLR. Taken together, the results of the current study suggest that AJ-037 and AJ-206 can be promising anti-MAC agents for the treatment of MAC infection, including for macrolide-resistant MAC strains. IMPORTANCE Novel antibiotics for the treatment of MAC infection are urgently needed because the treatment outcomes using the standard regimen for Mycobacterium avium complex (MAC) pulmonary disease remain unsatisfactory. Here, we evaluated three novel thiopeptide derivatives (AJ-037, AJ-039, and AJ-206) derived from the thiopeptide micrococcin P2, and they were confirmed to be effective against macrolide-susceptible and macrolide-resistant MAC. Our thiopeptide derivatives have enhanced aqueous solubility through structural modifications of poorly soluble thiopeptides. The thiopeptide derivatives showed minimal inhibitory concentrations against MAC that were comparable to clarithromycin (CLR). Notably, two compounds, AJ-037 and AJ-206, exhibited intracellular antimycobacterial activities and acted synergistically with CLR to hinder the growth of MAC within macrophages. Additionally, these compounds demonstrated in vitro and intracellular anti-MAC activities against macrolide-resistant MAC strains without showing any cross-resistance with CLR. We believe that AJ-037 and AJ-206 can be promising anti-MAC agents for the treatment of MAC infections, including macrolide-resistant MAC strains.

10.
Sci Rep ; 13(1): 11102, 2023 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-37423923

RESUMEN

Ulmus macrocarpa Hance bark (UmHb) has been used as a traditional herbal medicine in East Asia for bone concern diseases for a long time. To find a suitable solvent, we, in this study, compared the efficacy of UmHb water extract and ethanol extract which can inhibit osteoclast differentiation. Compared with two ethanol extracts (70% and 100% respectively), hydrothermal extracts of UmHb more effectively inhibited receptor activators of nuclear factor κB ligand-induced osteoclast differentiation in murine bone marrow-derived macrophages. We identified for the first time that (2R,3R)-epicatechin-7-O-ß-D-apiofuranoside (E7A) is a specific active compound in UmHb hydrothermal extracts through using LC/MS, HPLC, and NMR techniques. In addition, we confirmed through TRAP assay, pit assay, and PCR assay that E7A is a key compound in inhibiting osteoclast differentiation. The optimized condition to obtain E7A-rich UmHb extract was 100 mL/g, 90 °C, pH 5, and 97 min. At this condition, the content of E7A was 26.05 ± 0.96 mg/g extract. Based on TRAP assay, pit assay, PCR, and western blot, the optimized extract of E7A-rich UmHb demonstrated a greater inhibition of osteoclast differentiation compared to unoptimized. These results suggest that E7A would be a good candidate for the prevention and treatment of osteoporosis-related diseases.


Asunto(s)
Catequina , Ulmus , Ratones , Animales , Osteoclastos , Catequina/farmacología , Corteza de la Planta , Extractos Vegetales/farmacología , Extractos Vegetales/química , Etanol/farmacología , Diferenciación Celular , Ligando RANK/farmacología
11.
J Enzyme Inhib Med Chem ; 38(1): 2191164, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36950944

RESUMEN

Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.


Asunto(s)
Enfermedades por Prión , Priones , Humanos , Priones/metabolismo , Proteínas Priónicas/metabolismo , Encéfalo , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Células Cultivadas
12.
ACS Chem Biol ; 18(2): 265-272, 2023 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-36693003

RESUMEN

Micrococcin P1 and P2 are thiopeptides with a wide range of biological functions including antibacterial and antimalarial activities. We previously demonstrated optimized enzymatic sequences for the exclusive and scalable biosynthesis of micrococcin P2. Thiocillin IV is predicted to be the congener of O-methylated micrococcin P2, but the exact structure has not been elucidated. In this study, we report the first scalable biosynthesis and full structural characterization of thiocillin IV, a 26-membered thiopeptide. This was achieved by generating a recombinant plasmid by inserting tclO, a gene encoding an O-methyltransferase, and genes responsible for micrococcin P2 production and incorporating them into a Bacillus strain. With the incorporation of precursor peptide genes and optimal culture conditions, production reached 2.4 mg/L of culture. The purified thiocillin IV structure was identified as O-methylated micrococcin P2 at the 8-Thr position, and its promising biological activity toward various Gram-positive pathogens was observed. This study provides tclO-mediated site-selective methylation and opens a biotechnological opportunity to produce selective thiopeptides.


Asunto(s)
Bacillus , Péptidos , Péptidos/química , Antibacterianos/química , Bacillus/metabolismo
13.
Sci Transl Med ; 15(677): eabq6885, 2023 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-36599003

RESUMEN

Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF-MAP2K signaling plays a key role in axon elongation during nervous system development. Here, we show that conditional expression of a constitutively kinase-activated BRAF in mature corticospinal neurons elicited the expression of a set of transcription factors previously implicated in the regeneration of zebrafish retinal ganglion cell axons and promoted regeneration and sprouting of corticospinal tract (CST) axons after spinal cord injury in mice. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, resulting in improved recovery of motor function. Noninvasive suprathreshold high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) activated the BRAF canonical downstream effectors MAP2K1/2 and modulated the expression of a set of regeneration-related transcription factors in a pattern consistent with that induced by BRAF activation. HF-rTMS enabled CST axon regeneration and sprouting, which was abolished in MAP2K1/2 conditional null mice. These data collectively demonstrate a central role of MAP2K signaling in augmenting the growth capacity of mature corticospinal neurons and suggest that HF-rTMS might have potential for treating spinal cord injury by modulating MAP2K signaling.


Asunto(s)
Axones , Traumatismos de la Médula Espinal , Animales , Ratones , Axones/fisiología , Ingeniería Genética , Regeneración Nerviosa/fisiología , Proteínas Proto-Oncogénicas B-raf/metabolismo , Tractos Piramidales/metabolismo , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/metabolismo , Estimulación Magnética Transcraneal , Factores de Transcripción/metabolismo , Pez Cebra
14.
Plant Foods Hum Nutr ; 78(1): 146-153, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36380140

RESUMEN

Cold plasma treatment has been studied to enhance the germination, growth, and bioactive phytochemical production in crops. Here, we aimed to investigate the effects of cold plasma treatment on the growth, bioactive metabolite production, and protein expression related to the physiological and osteogenic activities of oat sprouts. Oat seeds were soaked for 12 h, and then exposed to plasma for 6 min/day for 3 days after sowing. Plasma exposure did not significantly change the growth of oat sprouts; however, increased the content of bioactive metabolites. A single exposure for 6 min on the first day (T-1) increased the content of free amino acids (39.4%), γ-aminobutyric acid (53%), and avenacoside B (23%) compared to the control. Hexacosanol content was the highest in T-3 (6 min exposure on each day for 3 days), 28% higher than that in the control. Oat sprout extracts induced the phosphorylation of adenosine 5'-monophosphate-activated protein kinase and osteoblast differentiation was enhanced by increasing the alkaline phosphatase (ALP) activity; all these effects were induced by plasma treatment. Avenacoside B content was positively correlated with ALP activity (r = 0.911, p < 0.1). These results suggest that plasma treatment has the potential to improve the value of oat sprouts and that it may be used in food fortification to enhance nutritional value for promoting human health.


Asunto(s)
Avena , Gases em Plasma , Humanos , Avena/química , Avena/metabolismo , Gases em Plasma/análisis , Gases em Plasma/metabolismo , Germinación , Antioxidantes/farmacología , Fitoquímicos/análisis , Semillas/química
15.
Life (Basel) ; 12(11)2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36431021

RESUMEN

(1) Background: Osteoporosis is a disease in which bones are weakened and fractured easily because of various factors. It is mainly observed in elderly and postmenopausal women, and it continues to carry high economic costs in aging societies. Normal bone maintains a healthy state through a balanced process of osteoclast suppression and osteoblast activation; (2) Methods: In this study, osteoclast inhibition was induced by inhibiting osteoclast differentiation using ginseng protopanaxadiol-enriched rice (PPD-rice) seed extract. To analyze the effect of PPD-rice extract on the inhibition of osteoclast differentiation, bone marrow macrophages extracted from mice were treated with PPD-rice and Dongjin seed (non-transformed rice) extracts and analyzed for the inhibition of osteoclast differentiation; (3) Results: The results illustrated that PPD-rice extract reduced the transcription and translation of NFATc1, a modulator of osteoclast formation, decreased the mRNA expression of various osteoclast differentiation marker genes, and reduced osteoclast activity. Moreover, the bone resorptive activity of osteoclasts was diminished by PPD-rice extract on Osteo Assay plates; (4) Conclusions: Based on these results, PPD-rice extract is a useful candidate therapeutic agent for suppressing osteoclasts, an important component of osteoporosis, and it could be used as an ingredient in health supplements.

16.
J Nat Prod ; 85(8): 1928-1935, 2022 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-35816693

RESUMEN

Clostridioides difficile infection is a global public health threat. Extensive in vitro assays using clinical isolates have identified micrococcin P2 (MP2, 1) as a particularly effective anti-C. difficile agent. MP2 possesses a mode of action that differs from other antibiotics and pharmacokinetic properties that render it especially promising. Its time-kill studies have been investigated using hypervirulent C. difficile ribotype 027. DSS (dextran sulfate sodium)-induced in vivo mouse studies with that strain indicate that 1 is better than vancomycin and fidaxomicin. Thus, micrococcin P2 is a valuable platform to be exploited for the development of new anti-C. difficile antibiotics.


Asunto(s)
Clostridioides difficile , Animales , Antibacterianos/farmacología , Bacteriocinas , Clostridioides , Ratones , Pruebas de Sensibilidad Microbiana
17.
Pharmaceuticals (Basel) ; 15(5)2022 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-35631450

RESUMEN

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.

18.
Front Mol Neurosci ; 15: 891463, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35557554

RESUMEN

Primary sensory axons in adult mammals fail to regenerate after spinal cord injury (SCI), in part due to insufficient intrinsic growth potential. Robustly boosting their growth potential continues to be a challenge. Previously, we showed that constitutive activation of B-RAF (rapidly accelerated fibrosarcoma kinase) markedly promotes axon regeneration after dorsal root and optic nerve injuries. The regrowth is further augmented by supplemental deletion of PTEN (phosphatase and tensin homolog). Here, we examined whether concurrent B-RAF activation and PTEN deletion promotes dorsal column axon regeneration after SCI. Remarkably, genetically targeting B-RAF and PTEN selectively in DRG neurons of adult mice enables many DC axons to enter, cross, and grow beyond the lesion site after SCI; some axons reach ∼2 mm rostral to the lesion by 3 weeks post-injury. Co-targeting B-RAF and PTEN promotes more robust DC regeneration than a pre-conditioning lesion, which additively enhances the regeneration triggered by B-RAF/PTEN. We also found that post-injury targeting of B-RAF and PTEN enhances DC axon regeneration. These results demonstrate that co-targeting B-RAF and PTEN effectively enhances the intrinsic growth potential of DC axons after SCI and therefore may help to develop a novel strategy to promote robust long-distance regeneration of primary sensory axons.

19.
Biomed Pharmacother ; 150: 112976, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35447553

RESUMEN

Saechalssal barley is Korea's representative naked waxy barley. This study investigated the anti-diabetic effect of the extract derived from saechalssal and its mechanism. The prethanol extract of saechalssal (SPE) showed greater α-glucosidase inhibitory activity in vitro and a more significant lowering of the postprandial blood glucose levels in normal mice compared to its water extract (SWE). When mice with type 2 diabetes (T2DM) induced by a high-fat diet and streptozotocin were fed SPE (200 mg/kg/day) for six weeks, the fasting blood glucose and serum free fatty acid levels were significantly lower than those of the control group. SPE significantly elevated the hepatic glycogen accumulation with increasing glycogen synthesis-related gene (GYS2 and UGP2) levels compared to the control group. SPE stimulated the expression of the hepatic glycolysis-related genes (GK, PFK1, and PK) and suppressed the gluconeogenesis-related genes (G6Pase, FBP1, and PEPCK). SPE up-regulated the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), whereas it down-regulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) compared to the control. The major flavonoids of SPE were naringin, prunin, and catechin, while its phenolic acids were ferulic acid and vanillic acid. These phytochemical compounds may contribute to the anti-hyperglycemic effects of SPE in diabetes. Overall, these results suggest that SPE has potential anti-diabetic activity through the regulating the PI3K/Akt/GSK3ß pathway.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hordeum , Resistencia a la Insulina , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hordeum/química , Hordeum/metabolismo , Ratones , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , República de Corea , Ceras
20.
ACS Omega ; 7(6): 4840-4849, 2022 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-35187304

RESUMEN

The aim of this study was to isolate and identify chemical components with osteoclast differentiation inhibitory activity from Ulmus macrocarpa Hance bark. Spectroscopic analyses, including nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD), resulted in the unequivocal elucidation of active compounds such as (2S)-naringenin-6-C-ß-d-glucopyranoside (1), (2R)-naringenin-6-C-ß-d-glucopyranoside (2), (2R,3S)-catechin-7-O-ß-d-xylopyranoside (3), (2R,3S)-catechin-7-O-ß-d-apiofuranoside (6), (2R,3R)-taxifolin-6-C-ß-d-glucopyranoside (7), and (2S,3S)-taxifolin-6-C-ß-d-glucopyranoside (8). Mechanistically, the compounds may exhibit osteoclast differentiation inhibitory activity via the downregulation of NFATc1, a master regulator involved in osteoclast formation. This is the first report of their inhibitory activities on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in murine bone marrow-derived macrophages. These findings provide further scientific evidence for the rational application of the genus Ulmus for the amelioration or treatment of osteopenic diseases.

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