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Understanding the composition and spatial distribution patterns of microbial communities in plateau peatland soils is crucial for preserving the structural and functional stability of highland wetlands. We collected 50 soil samples from the core conservation area of Zoige peatland along horizontal and vertical distributions to analyze the soil bacterial and fungal diversity by using high-throughput sequencing technology, combined with Mantel tests and multiple regression on matrices (MRM) statistical methods, as well as the spatial distribution characteristics of community structure similarity at a local scale. The results showed that the dominant soil bacterial and fungal groups were Chloroflexi (accounting for 33.2% and 25.1% of the total bacterial community in horizontal and vertical directions, respectively) and Ascomycota (54.7% and 76.4%). The similarity of microbial community structure in both horizontal and vertical directions decreased with increasing spatial distance of the sampling points. The turnover rates of bacterial and fungal communities in the vertical direction were 8.8 and 8.6 times as those in the horizontal direction, respectively. Based on the relative abundance of the communities, we classified microbes into six groups. As the number of rare species in the community increased, the slope of community distance decay decreased. The conditionally rare or abundant taxa (CRAT) category group showed the most similar spatial distribution characteristics to the total microbial community. Mantel analysis indicated that soil organic carbon, total nitrogen, and available phosphorus were key factors driving the distribution of bacterial and fungal communities in the horizontal direction, while soil organic carbon, available carbon, pH, and soil bulk density were the main factors determining the vertical distribution. MRM analysis further showed that both soil physicochemical indicators and spatial distance significantly affected the assembly of microbial communities, where soil factors explained more about the vertical distribution of microbial communities than the horizontal distribution. The impact of soil factors on microbial community distribution was much greater than that of spatial factors through diffusion limitation. In summary, the microbial communities in the plateau peatland soils exhibited more pronounced vertical distribution differences and environmental response characteristics.
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Bacterias , Hongos , Microbiología del Suelo , China , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/crecimiento & desarrollo , Bacterias/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Hongos/crecimiento & desarrollo , Humedales , Análisis Espacial , Biodiversidad , Altitud , Suelo/química , Microbiota , Chloroflexi/clasificación , Chloroflexi/crecimiento & desarrollo , Chloroflexi/aislamiento & purificación , Ascomicetos/crecimiento & desarrollo , Ascomicetos/aislamiento & purificaciónRESUMEN
High safety and low cost are essential for energy-storage systems. Here, an aqueous zinc ion battery composed of a hydrogel-based water-in-salt electrolyte prepared by photoinitiated polymerization of acrylamide in ZnCl2 solution (named as PZC) and flexible electrodes is developed. The stable performance in Zn||Zn symmetric cells and high Coulombic efficiency of PZC in Zn||Cu asymmetric cells verify dendrite suppression. VO2 nanobelts coated with polyaniline (PANI) are grown on a carbon cloth (CC). The battery shows a capacity of 221.5 mAh g-1 after 200 cycles. The batteries present high recovery performance after bending/cutting. After bending of 60°, 90°, and 180°, capacities remain at 240.0, 205.4, and 175.2 mAh g-1, respectively; while the battery healed from 1, 2, 3, and 4 times of cutting shows 197.5, 174.3, 124.7, and 101.2 mAh g-1, respectively. Our findings enable the engineering of a quasi-solid-state battery to have good capability for flexible and portable electronics.
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Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 µM to 7.530 µM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 µM and 0.094 µM, being about 4.3-fold superior to EFV (EC50 = 0.132 µM) and 1.9-fold superior to NVP (EC50 = 0.181 µM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 µM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.
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Aminoácidos , Fármacos Anti-VIH , Diseño de Fármacos , Transcriptasa Inversa del VIH , VIH-1 , Pirimidinas , Inhibidores de la Transcriptasa Inversa , Tiofenos , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Humanos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Relación Estructura-Actividad , Aminoácidos/química , Simulación del Acoplamiento MolecularRESUMEN
In addressing the urgent need for novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat drug resistance, we employed CuAAC click chemistry to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. This rapid synthesis approach facilitated the identification of A6N36, demonstrating exceptional HIV-1 RT inhibitory activity. Moreover, it was demonstrated with EC50 values of 1.8-8.7 nM for mutant strains L100I, K103 N, Y181C, and E138K, being equipotent or superior to that of ETR. However, A6N36's efficacy was compromised against specific resistant strains (Y188L, F227L + V106A and RES056), highlighting a need for further optimization. Through scaffold hopping, we optimized this lead to develop 10c, which exhibited broad-spectrum activity with EC50 values ranging from 3.2 to 57.5 nM and superior water solubility. Molecular docking underscored the key interactions of 10c within the NNIBP. Our findings present 10c as a promising NNRTI lead, illustrating the power of click chemistry and rational design in combatting HIV-1 resistance.
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Fármacos Anti-VIH , Química Clic , Transcriptasa Inversa del VIH , VIH-1 , Inhibidores de la Transcriptasa Inversa , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , VIH-1/efectos de los fármacos , VIH-1/enzimología , Relación Estructura-Actividad , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Estructura Molecular , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Descubrimiento de Drogas , Cobre/química , Cobre/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de MedicamentosRESUMEN
The rapid emergence of drug resistance severely reduces the clinical response of human immunodeficiency virus-1 (HIV-1) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, a series of 2,4,6-trisubstituted pyrimidine derivatives was designed and synthesized, with the aim to identify novel anti-HIV-1 agents with improved drug resistance profiles. The antiviral activity results demonstrated that all compounds showed excellent potency to wild-type (WT) HIV-1 strain (EC50 = 3.61-15.5 nM). Moreover, 13c was proved to be the most potent inhibitor against the whole tested viral panel, with EC50 ranging from 4.68 to 229 nM. In addition, 13c yielded moderate HIV-1 RT inhibition with IC50 value of 0.231 µM, which demonstrated it was a classical NNRTI. Molecular docking was further conducted to illustrate its binding mode with HIV-1 RT. These encouraging results indicated that 13c can be used as a lead compound for further study.
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Fármacos Anti-VIH , Transcriptasa Inversa del VIH , VIH-1 , Simulación del Acoplamiento Molecular , Pirimidinas , Inhibidores de la Transcriptasa Inversa , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , VIH-1/efectos de los fármacos , VIH-1/enzimología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Relación Estructura-Actividad , Humanos , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Relación Dosis-Respuesta a Droga , Descubrimiento de DrogasRESUMEN
In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.
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Antivirales , Sinergismo Farmacológico , Virus de la Influenza A , Oseltamivir , Pirazinas , Proteínas Virales , Replicación Viral , Oseltamivir/farmacología , Oseltamivir/análogos & derivados , Animales , Antivirales/farmacología , Humanos , Replicación Viral/efectos de los fármacos , Pirazinas/farmacología , Virus de la Influenza A/efectos de los fármacos , Embrión de Pollo , Proteínas Virales/metabolismo , Proteínas Virales/antagonistas & inhibidores , Amidas/farmacología , Dibenzotiepinas/farmacología , Virus de la Influenza B/efectos de los fármacos , Virus de la Influenza B/fisiología , Zanamivir/farmacología , Triazinas/farmacología , Piridonas/farmacología , Gripe Aviar/tratamiento farmacológico , Gripe Aviar/virología , Morfolinas/farmacología , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Perros , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Línea Celular , Células de Riñón Canino Madin DarbyRESUMEN
Capsid assembly modulators (CAMs) have the potential to cure chronic hepatitis B, as demonstrated in clinical trials. Lead compounds NVR3-778 and 5a were found to exist in normal and flipped conformations through induced fit docking. Therefore, we designed and synthesized series I and II compounds by interchanging the amide and sulfonamide bonds of 5a to modify both the tolerance region and solvent-opening region. Among them, compound 4a (EC50 = 0.24 ± 0.10 µM, CC50 > 100 µM) exhibited potent anti-HBV activity with low toxicity, surpassing the lead compounds NVR3-778 (EC50 = 0.29 ± 0.03 µM, CC50 = 20.78 ± 2.29 µM) and 5a (EC50 = 0.50 ± 0.07 µM, CC50 = 48.16 ± 9.15 µM) in HepAD38 cells. Additionally, compared with the lead compound, 4a displayed a stronger inhibitory effect on HBV capsid protein assembly. Molecular dynamics (MD) simulations confirmed that the normal conformation of 4a had relatively stable conformation at different frames of binding modes. Furthermore, 4a showed better metabolic stability in human plasma than positive control drugs. Therefore, compound 4a could be further structurally modified as a potent lead compound.
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Antivirales , Diseño de Fármacos , Virus de la Hepatitis B , Virus de la Hepatitis B/efectos de los fármacos , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Humanos , Relación Estructura-Actividad , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/antagonistas & inhibidores , Simulación de Dinámica Molecular , Estructura Molecular , Cápside/efectos de los fármacos , Cápside/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period circadian regulator 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.
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Senescencia Celular , Hipertensión , Ratones Noqueados , Oxiesteroles , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratones , Hipertensión/metabolismo , Hipertensión/fisiopatología , Oxiesteroles/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Células Endoteliales/metabolismo , Transducción de Señal , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Acetato de Desoxicorticosterona , Células CultivadasRESUMEN
BACKGROUND: Advanced knee osteoarthritis (KOA) impacts both knees, resulting in pain, deformity, and substantial restrictions in joint mobility. OBJECTIVE: This study aims to examine the effectiveness of combining arthroscopic debridement with functional exercise in treating advanced KOA. METHODS: A total of 296 patients diagnosed with advanced KOA were divided into two groups: the observation group (n= 152) received arthroscopic debridement combined with functional exercise, while the control group (n= 144) underwent arthroscopic debridement only. The study compared and observed the outcomes between the two groups. RESULTS: There were no significant differences in knee joint function, inflammation level, and oxidative stress between the two groups before treatment (P> 0.05). Following treatment for six months, the observation group exhibited significantly lower visual analog scale (VAS) score, tissue inhibitors of metalloproteinase-1 (TIMP-1), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), matrix metalloproteinase-3 (MMP-3), and malondialdehyde (MDA) levels compared to the control group (P< 0.05). Meanwhile, the observation group showed significantly higher levels of Lysholm score, hospital for special surgery (HSS) score, range of motion (ROM) of knee, peak torque (PT) and total work (TW) for knee extension and flexion, superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione (GSH) compared to the control group (P< 0.05). Besides, the effective treatment rate in the observation group was notably higher than that in the control group (80.92% vs. 69.44%, P< 0.05). CONCLUSION: The combination of arthroscopic debridement with functional exercise is an effective treatment for advanced KOA. This approach not only enhances the function and strength of knee joint and reduces inflammatory response but also boosts the body's antioxidant capacity. The treatment exhibits encouraging outcomes and warrants broad implementation.
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To explore the prevalence and source of antibiotic resistant genes ï¼ARGsï¼ and pathogenic antibiotic resistant bacteria ï¼PARBï¼ associated with bioaerosols in wastewater treatment plants ï¼WWTPsï¼, metagenomic sequencing and assembly were applied to elucidate the antibiotic resistome of bioaerosols and wastewater in WWTPs. The results showed that more subtypes of ARGs and a higher abundance of PARB were found in bioaerosols from WWTPs and downwind than those from upwind. Multidrug and macB were respectively the most dominant type and subtype of ARGs in bioaerosols from WWTPs. In total, 37 types of PARB carried at least two or more ARG types and were characterized by multiple drug resistance. At the fine grid, aerated tank, and sludge dewatering room, wastewater was the main source of bioaerosol ARGs and PARB. A total of 32 PARB were easily aerosolized in at least one wastewater treatment unit, such as Pseudomonas aeruginosa and Escherichia coli. This study will provide theoretical support for the risk assessment and health protection of antibiotic resistant pollution associated with bioaerosols from WWTPs.
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Aerosoles , Microbiología del Aire , Eliminación de Residuos Líquidos , Aguas Residuales , Aguas Residuales/microbiología , Aerosoles/análisis , Eliminación de Residuos Líquidos/métodos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Genes Bacterianos , Escherichia coli/aislamiento & purificación , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Farmacorresistencia Microbiana/genética , Antibacterianos , Farmacorresistencia Bacteriana/genética , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genéticaRESUMEN
OBJECTIVES: To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI. METHODS: The rat models of the sham surgery group, AMI group and hyperlipidemia + acute myocardial infarction (HAMI) group were established. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats. Principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites. The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites. RESULTS: A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened, respectively. Among them, 22 metabolites were common in both rat models. These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways. Within the 95% confidence interval, the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetylspermidine, 3-methylhistamine, and thymine were greater than 0.95. CONCLUSIONS: N8-acetylspermidine, 3-methylhistamine, and thymine can be used as potential biomarkers for AMI diagnosis, and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI. This study can provide reference for the mechanism and causes of AMI identification.
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Biomarcadores , Modelos Animales de Enfermedad , Metabolómica , Infarto del Miocardio , Animales , Infarto del Miocardio/metabolismo , Infarto del Miocardio/orina , Ratas , Metabolómica/métodos , Masculino , Biomarcadores/orina , Biomarcadores/metabolismo , Cromatografía Líquida de Alta Presión , Ratas Sprague-Dawley , Análisis de Componente Principal , Análisis Discriminante , Espectrometría de Masas/métodos , Niacina/metabolismo , Niacina/orina , Hiperlipidemias/metabolismo , Niacinamida/orina , Niacinamida/metabolismo , Niacinamida/análogos & derivados , Redes y Vías Metabólicas , Curva ROC , Análisis de los Mínimos Cuadrados , Medicina Legal/métodos , MetabolomaRESUMEN
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
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Fármacos Anti-VIH , Diseño de Fármacos , VIH-1 , Simulación del Acoplamiento Molecular , Inhibidores de la Transcriptasa Inversa , Sulfonas , VIH-1/efectos de los fármacos , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Estructura-Actividad , Sulfonas/farmacología , Sulfonas/síntesis química , Sulfonas/química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismoRESUMEN
Pathogenic viruses are a profound threat to global public health, underscoring the urgent need for the development of efficacious antiviral therapeutics. The advent of RNA-targeting antiviral strategies has marked a significant paradigm shift in the management of viral infections, offering a potent means of control and potential cure. In this review, we delve into the cutting-edge progress in RNA-targeting antiviral agents, encompassing antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), small and bifunctional molecules. We provide an in-depth examination of their strategic molecular design and elucidate the underlying mechanisms of action that confer their antiviral efficacy. By synthesizing recent findings, we shed light on the innovative potential of RNA-targeting approaches and their pivotal role in advancing the frontiers of antiviral drug discovery.
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Antivirales , Diseño de Fármacos , Oligonucleótidos Antisentido , ARN Interferente Pequeño , ARN Viral , Virosis , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Antisentido/farmacología , Virosis/tratamiento farmacológico , Virosis/virología , Animales , Descubrimiento de Drogas/métodosRESUMEN
HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared via structural modifications of the leads K-5a2 and 25a. Among them, 15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC50 = 1.75 nmol/L), 3.0-fold (L100I, EC50 = 2.84 nmol/L), 2.4-fold (K103N, EC50 = 1.27 nmol/L), 3.3-fold (Y181C, EC50 = 5.38 nmol/L), 2.9-fold (Y188L, EC50 = 7.96 nmol/L), 2.5-fold (E138K, EC50 = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC50 = 3.76 nmol/L) and 5.3-fold (RES056, EC50 = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound 15a and WT, F227L/V106A, and RES056 RT. Moreover, 15a·HCl carried outstanding pharmacokinetic (t 1/2 = 1.32 h, F = 40.8%) and safety profiles (LD50 > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.
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Chronic hyperglycemia can result in damage to the hippocampus and dysfunction of the blood-brain barrier (BBB), potentially leading to neurological disorders. This study examined the histological structure of the hippocampus and the expression of critical genes associated with the BBB at 2 early stage time points in a streptozotocin-induced diabetes mellitus (DM) mouse model. Routine histology revealed vascular congestion and dilation of Virchow-Robin spaces in the hippocampal CA1 region of the DM group. Neuronal alterations included rounding and swelling and reduction in Nissl bodies and increased apoptosis. Compared to the control group, TJP1 mRNA expression in the DM group was significantly lower (P < .05 or P < .01), while mRNA levels of JAM3, TJP3, CLDN5, CLDN3, and OCLN initially increased and then decreased. At 7, 14, and 21 days, mRNA levels of the receptor for advanced glycation end products (AGER) were greater in the DM group than in the control group (P < .05 or P < .01). These findings indicate that early-stage diabetes may cause structural and functional impairments in hippocampal CA1 in mice. These abnormalities may parallel alterations in the expression of key BBB tight junction molecules and elevated AGER expression in early DM patients.
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Barrera Hematoencefálica , Diabetes Mellitus Experimental , Animales , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/metabolismo , Ratones , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Hipocampo/patología , Hipocampo/metabolismoRESUMEN
Culture-dependent and metagenomic binning techniques were employed to gain an insight into the diversification of gut bacteria in Rhinopithecius bieti, a highly endangered primate endemic to China. Our analyses revealed that Bacillota_A and Bacteroidota were the dominant phyla. These two phyla species are rich in carbohydrate active enzymes, which could provide nutrients and energy for their own or hosts' survival under different circumstances. Among the culturable bacteria, one novel bacterium, designated as WQ 2009T, formed a distinct branch that had a low similarity to the known species in the family Sphingobacteriaceae, based on the phylogenetic analysis of its 16S rRNA gene sequence or phylogenomic analysis. The ANI, dDDH and AAI values between WQ 2009T and its most closely related strains S. kitahiroshimense 10CT, S. pakistanense NCCP-246T and S. faecium DSM 11690T were significantly lower than the accepted cut-off values for microbial species delineation. All results demonstrated that WQ 2009T represent a novel genus, for which names Rhinopithecimicrobium gen. nov. and Rhinopithecimicrobium faecis sp. nov. (Type strain WQ 2009T = CCTCC AA 2021153T = KCTC 82941T) are proposed.
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Microbioma Gastrointestinal , Metagenómica , Filogenia , ARN Ribosómico 16S , Animales , Microbioma Gastrointestinal/genética , Metagenómica/métodos , ARN Ribosómico 16S/genética , Bacteroidetes/genética , Bacteroidetes/aislamiento & purificación , Bacteroidetes/clasificaciónRESUMEN
Multi-target drug treatment has become popular as a substitute for traditional monotherapy. Monotherapy can lead to resistance and side effects. Multi-target drug discovery is gaining importance as data on bioactivity becomes more abundant. The design of multi-target drugs is expected to be an important development in the pharmaceutical industry in the near future. This review presents multi-target compounds against trypanosomatid parasites (Trypanosoma cruzi, T. brucei, and Leishmania sp.) and tuberculosis (Mycobacterium tuberculosis), which mainly affect populations in socioeconomically unfavorable conditions. The article analyzes the studies, including their chemical structures, viral strains, and molecular docking studies, when available. The objective of this review is to establish a foundation for designing new multi-target inhibitors for these diseases.
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Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.
Asunto(s)
Alcaloides , Antineoplásicos , Benzodioxoles , Proliferación Celular , Dihidroorotato Deshidrogenasa , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos , Ferroptosis , Piperidinas , Alcamidas Poliinsaturadas , Humanos , Alcaloides/farmacología , Alcaloides/química , Alcaloides/síntesis química , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Benzodioxoles/farmacología , Benzodioxoles/síntesis química , Benzodioxoles/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Ferroptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Línea Celular TumoralRESUMEN
INTRODUCTION: Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims to provide an overview of the HyT literature and future outlook to offer guidance for drug design. AREAS COVERED: In this review, the authors introduce the composition, mechanisms and advantages of HyT technology, as well as summarize the detailed applications of HyT technology in anti-cancer, neurodegenerative diseases (NDs), autoimmune disorders, cardiovascular diseases (CVDs), and other fields. Furthermore, this review discusses key aspects of the future development of HyT molecules. EXPERT OPINION: HyT emerges as a highly promising targeted protein degradation (TPD) strategy, following the successful development of proteolysis targeting chimeras (PROTAC) and molecular glue. Based on exploring new avenues, modification of the HyT molecule itself potentially enhances the technology. Improved synthetic pathways and emphasis on pharmacokinetic (PK) properties will facilitate the development of HyT. Furthermore, elucidating the biochemical basis by which the compound's hydrophobic moiety recruits the protein homeostasis network will enable the development of more precise assays that can guide the optimization of the linker and hydrophobic moiety.