RESUMEN

Bisindolylmethane (BIM) and its derivatives are widely used in the pharmaceutical industry due to their significant biological activities. However, most reported synthetic methods are focused on the synthesis of symmetric BIMs, while the synthesis of unsymmetrical BIMs remains a challenge. Herein, an unprecedented two-step one-pot method to afford unsymmetrically substituted 3,3'-BIM frameworks, using methylene chloride (DCM) as the C1-synthon is reported. In this protocol, the formation of two C-C bonds can be achieved via a one-pot reaction. The utility of commercially available phenols and anilines was also demonstrated in the construction of unsymmetrical diarylmethanes. This protocol provides a straightforward approach to access diverse unsymmetrical diarylmethane derivatives under simple and mild conditions. The broad substrate compatibility and good functional group tolerance of the protocol support its practical application potential.

RESUMEN

Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating infectious diseases of pigs globally. The pathogen, porcine reproductive and respiratory syndrome virus (PRRSV), is an enveloped positive-stranded RNA virus, which is considered to be the key triggers for the activation of effective innate immunity through pattern recognition receptor (PRR)-dependent signaling pathways. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs) and Cytoplasmic DNA receptors (CDRs) are used as PRRs to identify distinct but overlapping microbial components. The innate immune system has evolved to recognize RNA or DNA molecules from microbes through pattern recognition receptors (PRRs) and to induce defense response against infections, including the production of type I interferon (IFN-I) and inflammatory cytokines. However, PRRSV is capable of continuous evolution through gene mutation and recombination to evade host immune defenses and exploit host cell mechanisms to synthesize and transport its components, thereby facilitating successful infection and replication. This review presents the research progress made in recent years in the study of these PRRs and their associated adapters during PRRSV infection.

Asunto(s)

Inmunidad Innata , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Receptores de Reconocimiento de Patrones , Animales , Receptores de Reconocimiento de Patrones/metabolismo , Receptores de Reconocimiento de Patrones/inmunología , Virus del Síndrome Respiratorio y Reproductivo Porcino/inmunología , Virus del Síndrome Respiratorio y Reproductivo Porcino/patogenicidad , Porcinos , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/virología , Interacciones Huésped-Patógeno/inmunología , Transducción de Señal , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética

RESUMEN

Immunoassay relies on antibodies, but traditional antibodies such as monoclonal antibody (mAb) require animal immunization and complex procedures. Single-chain variable fragment (scFv) becomes a potential alternative to mAb with advantages of the low cost, rapid and easy prepared. In the present study, we prepared scFvs against dihydroartemisinin (DHA) based on E. coli and HEK293T cell expression system, named MBP-scFv and scFv-Fc, respectively. Their properties were compared with the parent mAb. The calculated affinity constants of mAb, MBP-scFv and scFv-Fc were 2.1 × 108 L mol-1, 2.2 × 107 L mol-1 and 1.6 × 108 L mol-1, respectively. The half inhibitory concentration (IC50) of mAb, MBP-scFv and scFv-Fc were 1.16 ng mL-1, 2.15 ng mL-1 and 6.57 ng mL-1, respectively. Both the scFv showed less sensitive than the mAb based on the IC50. The cross-reactivities of MBP-scFv for artemisinin and artesunate exhibited similarities to the mAb, yet the cross-reactivities of scFv-Fc for these compounds exceeded those of the mAb significantly. The stability of the scFvs was ascertained to be maintained for over 5 days at room temperature, and for more than a month at both 4 °C and - 20 °C. After that, the indirect competitive enzyme-linked immunosorbent assays (icELISAs) based on the scFv from E. coli were used to detect the DHA content in eight drug samples, and the result was consistent with ultra-performance liquid chromatography simultaneously. Although scFv can be used for quantitative determination of drugs, but it still cannot completely replace mAb in immunoassay without evolution and modification.

Asunto(s)

Anticuerpos Monoclonales , Artemisininas , Anticuerpos de Cadena Única , Artemisininas/inmunología , Artemisininas/farmacología , Anticuerpos de Cadena Única/inmunología , Humanos , Anticuerpos Monoclonales/inmunología , Células HEK293 , Afinidad de Anticuerpos , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/inmunología , Reacciones Cruzadas/inmunología , Antimaláricos/inmunología , Ensayo de Inmunoadsorción Enzimática , Especificidad de Anticuerpos

RESUMEN

Bacillus subtilis is a widespread Gram-positive facultative aerobic bacterium that is recognized as generally safe. It has shown significant application value and great development potential in the animal farming industry. As a probiotic, it is frequently used as a feed growth supplement to effectively replace antibiotics due to its favourable effects on regulating the intestinal flora, improving intestinal immunity, inhibiting harmful microorganisms, and secreting bioactive substances. Consequently, the gut health and disease resistance of farmed animals can be improved. Both vegetative and spore forms of B. subtilis have also been utilized as vaccine carriers for delivering the antigens of infectious pathogens for over a decade. Notably, its spore form is regarded as one of the most prospective for displaying heterologous antigens with high activity and stability. Previously published reviews have predominantly focused on the development and applications of B. subtilis spore surface display techniques. However, this review aims to summarize recent studies highlighting the important role of B. subtilis as a probiotic and vaccine carrier in maintaining animal health. Specifically, we focus on the beneficial effects and underlying mechanisms of B. subtilis in enhancing disease resistance among farmed animals as well as its potential application as mucosal vaccine carriers. It is anticipated that B. subtilis will assume an even more prominent role in promoting animal health with in-depth research on its characteristics and genetic manipulation tools.

Asunto(s)

Bacillus subtilis , Probióticos , Probióticos/administración & dosificación , Bacillus subtilis/genética , Animales , Esporas Bacterianas/inmunología , Microbioma Gastrointestinal , Resistencia a la Enfermedad , Vacunas/inmunología

RESUMEN

Salmonella typhimurium (S. typhimurium) is one of the most common Salmonella serotypes in epidemiological surveys of poultry farms in recent years. It causes growth retardation, mortality, and significant economic losses. The extensive use of antibiotics has led to the emergence of multi-drug resistance (MDR) in Salmonella, which has become a significant global problem and long-term challenge. In this study, we investigated the prevalence and features of S. typhimurium strains in duck embryos and cloacal swabs from large-scale duck farms in Shandong, China, including drug resistance and virulence genes and the pathogenicity of an S. typhimurium strain by animal experiment. The results demonstrated that a total of 8 S. typhimurium strains were isolated from 13,621 samples. The drug resistance results showed that three of the eight S. typhimurium strains were MDR with the dominant resistance profile of CTX-DX-CTR-TE-AMX-AMP-CAZ. In particular, the virulence genes invA, hilA, pefA, rck, and sefA showed high positive rates. Based on the analysis of the biological characteristics of bacterial biofilm formation and mobility, a strain of S. typhimurium with the strongest biofilm formation ability, designated 22SD07, was selected for animal infection experiments with broiler ducklings. The results of animal experiments demonstrated that infection with 22SD07 reduced body weight and bursa index but increased heart and liver indexes compared to the control group. Histological examination revealed desquamation of the intestinal villous epithelium, the presence of large aggregates of lymphocytes, and a decrease in goblet cells following infection. Furthermore, the expression of IL-10 was significantly increased in the liver at 3 dpi, while TNF-α was significantly increased in the spleen at 7 dpi. The above results indicate that S. typhimurium may pose a potential threat to human health through the food chain. This helps us to understand the frequency and characteristics of S. typhimurium in duck farms and emphasizes the urgent need to strengthen and implement effective continuous monitoring to control its infection and transmission.

RESUMEN

Background: Influenza A (H1N1) virus is a highly contagious respiratory disease that causes severe illness and death. Vaccines and antiviral drugs are limited by viral variation and drug resistance, so developing efficient integrated theranostic options appears significant in anti-influenza virus infection. Methods: In this study, we designed and fabricated covalent organic framework (COF) based theranostic platforms (T705@DATA-COF-Pro), which was composed of an RNA polymerase inhibitor (favipiravir, T705), the carboxyl-enriched COF (DATA-COF) nano-carrier and Cy3-labeled single DNA (ssDNA) probe. Results: The multi-porosity COF core provided an excellent micro-environment and smooth delivery for T705. The ssDNA probe coating bound to the nucleic acids of H1N1 selectively, thus controlling drug release and allowing fluorescence imaging. The combination of COF and probe triggered the synergism, promoting drug further therapeutic outcomes. With the aid of T705@DATA-COF-Pro platforms, the H1N1-infected mouse models lightly achieved diagnosis and significantly prolonged survival. Conclusion: This research underscores the distinctive benefits and immense potential of COF materials in nano-preparations for virus infection, offering novel avenues for the detection and treatment of H1N1 virus infection.

Asunto(s)

Antivirales , Subtipo H1N1 del Virus de la Influenza A , Estructuras Metalorgánicas , Infecciones por Orthomyxoviridae , Nanomedicina Teranóstica , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Animales , Nanomedicina Teranóstica/métodos , Antivirales/química , Antivirales/farmacología , Antivirales/uso terapéutico , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Humanos , Amidas/química , Amidas/farmacología , Pirazinas/química , Pirazinas/farmacología , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Gripe Humana/tratamiento farmacológico , Ratones Endogámicos BALB C , Células de Riñón Canino Madin Darby , Portadores de Fármacos/química , Perros , Liberación de Fármacos

RESUMEN

Porcine epidemic diarrhea virus (PEDV), porcine transmissible gastroenteritis virus (TGEV), porcine deltacoronavirus (PDCoV), and porcine rotavirus-A (PoRVA) are the four main pathogens that cause viral diarrhea in pigs, and they often occur in mixed infections, which are difficult to distinguish only according to clinical symptoms. Here, we developed a multiplex TaqMan-probe-based real-time RT-PCR method for the simultaneous detection of PEDV, TGEV, PDCoV, and PoRVA for the first time. The specific primers and probes were designed for the M protein gene of PEDV, N protein gene of TGEV, N protein gene of PDCoV, and VP7 protein gene of PoRVA, and corresponding recombinant plasmids were constructed. The method showed extreme specificity, high sensitivity, and excellent repeatability; the limit of detection (LOD) can reach as low as 2.18 × 102 copies/µL in multiplex real-time RT-PCR assay. A total of 97 clinical samples were used to compare the results of the conventional reverse transcription PCR (RT-PCR) and this multiplex real-time RT-PCR for PEDV, TGEV, PDCoV, and PoRVA detection, and the results were 100% consistent. Subsequently, five randomly selected clinical samples that tested positive were sent for DNA sequencing verification, and the sequencing results showed consistency with the detection results of the conventional RT-PCR and our developed method in this study. In summary, this study developed a multiplex real-time RT-PCR method for simultaneous detection of PEDV, TGEV, PDCoV, and PoRVA, and the results of this study can provide technical means for the differential diagnosis and epidemiological investigation of these four porcine viral diarrheic diseases.

RESUMEN

Background: The development and marketing of Bedaquiline (BDQ) represent significant advancements in treating tuberculosis, particularly multidrug-resistant forms. However, comprehensive research into BDQ's real-world safety remains limited. Purpose: We obtained BDQ related adverse event (AE) information from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess its safety and inform drug usage. Methods: The AE data for BDQ from 2012 Q4 to 2023 Q3 was collected and standardized. Disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN) was used to quantify signals of BDQ-related AEs. Logistic regression was used to analyze the individual data of hepatotoxicity and drug-induced liver injury, and multiple linear regression models were established. Additionally, network pharmacology was employed to identify the potential biological mechanisms of BDQ-induced liver injury. Results: We identified 2017 case reports directly related to BDQ. Our analysis identified 341 Preferred Terms (PTs) characterizing these AEs across 27 System Organ Classes (SOC). An important discovery was the identification of AEs associated with ear and labyrinth disorders, which had not been documented in the drug's official leaflet before. Subgroup analysis revealed a negative correlation between BDQ-related liver injury and females (OR: 0.4, 95%CI: 0.3-0.6). In addition, via network pharmacology approach, a total of 76 potential targets for BDQ related liver injury were predicted, and 11 core target genes were selected based on the characterization of protein-protein interactions. The pathway linked to BDQ-induced liver injury was identified, and it was determined that the PI3K-Akt signaling pathway contained the highest number of associated genes. Conclusion: The analysis of the FAERS database revealed adverse events linked to BDQ, prompting the use of a network pharmacology approach to study the potential molecular mechanism of BDQ-induced liver injury. These findings emphasized the significance of drug safety and offered understanding into the mechanisms behind BDQ-induced liver injury. BDQ demonstrated distinct advantages, including reduced incidence of certain adverse events compared to traditional treatments such as injectable agents and second-line drugs. However, it is important to acknowledge the limitations of this analysis, including potential underreporting and confounding factors. This study provides valuable insights into the safety of BDQ and its role in the management of MDR-TB, emphasizing the need for continued surveillance and monitoring to ensure its safe and effective use.

RESUMEN

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Homeostasis , Ácidos Hidroxámicos , Hierro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Hierro/metabolismo , Hierro/química , Proliferación Celular/efectos de los fármacos , Homeostasis/efectos de los fármacos , Relación Estructura-Actividad , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/síntesis química , Estructura Molecular , Apoptosis/efectos de los fármacos , Aniones/química , Aniones/farmacología , Relación Dosis-Respuesta a Droga , Animales , Línea Celular Tumoral , Ratones , Quinina/análogos & derivados

RESUMEN

Introduction: Early detection of the virus in the environment or in infected pigs is a critical step to stop African swine fever virus (ASFV) transmission. The p22 protein encoded by ASFV KP177R gene has been shown to have no effect on viral replication and virulence and can serve as a molecular marker for distinguishing field virus strains from future candidate KP177R deletion vaccine strains. Methods: This study established an ASFV detection assay specific for the highly conserved ASFV KP177R gene based on recombinase polymerase amplification (RPA) and the CRISPR/Cas12 reaction system. The KP177R gene served as the initial template for the RPA reaction to generate amplicons, which were recognized by guide RNA to activate the trans-cleavage activity of Cas12a protein, thereby leading to non-specific cleavage of single-stranded DNA as well as corresponding color reaction. The viral detection in this assay could be determined by visualizing the results of fluorescence or lateral flow dipstick (LFD) biotin blotting for color development, and was respectively referred to as fluorescein-labeled RPA-CRISPR/Cas12a and biotin-labeled LFD RPA-CRISPR/Cas12a. The clinical samples were simultaneously subjected to the aforementioned assay, while real-time quantitative PCR (RT-qPCR) was employed as a control for determining the diagnostic concordance rate between both assays. Results: The results showed that fluorescein- and biotin-labeled LFD KP177R RPA-CRISPR/Cas12a assays specifically detected ASFV, did not cross-react with other swine pathogens including PCV2, PEDV, PDCoV, and PRV. The detection assay established in this study had a limit of detection (LOD) of 6.8 copies/µL, and both assays were completed in 30 min. The KP177R RPA-CRISPR/Cas12a assay demonstrated a diagnostic coincidence rate of 100% and a kappa value of 1.000 (p < 0.001), with six out of ten clinical samples testing positive for ASFV using both KP177R RPA-CRISPR/Cas12a and RT-qPCR, while four samples tested negative in both assays. Discussion: The rapid, sensitive and visual detection assay for ASFV developed in this study is suitable for field application in swine farms, particularly for future differentiation of field virus strains from candidate KP177R gene-deleted ASFV vaccines, which may be a valuable screening tool for ASF eradication.

Asunto(s)

Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Proteínas Bacterianas , Sistemas CRISPR-Cas , Virus de la Fiebre Porcina Africana/genética , Animales , Porcinos , Fiebre Porcina Africana/virología , Fiebre Porcina Africana/diagnóstico , Proteínas Asociadas a CRISPR/genética , Recombinasas/genética , Recombinasas/metabolismo , Proteínas Virales/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Endodesoxirribonucleasas/genética , Sensibilidad y Especificidad

RESUMEN

Osteoporosis is a prevalent chronic metabolic bone disease that poses a significant risk of fractures or mortality in elderly individuals. Its pathophysiological basis is often attributed to postmenopausal estrogen deficiency and natural aging, making the progression of primary osteoporosis among elderly people, especially older women, seemingly inevitable. The treatment and prevention of osteoporosis progression have been extensively discussed. Recently, as researchers delve deeper into the molecular biological mechanisms of bone remodeling, they have come to realize the crucial role of posttranscriptional gene control in bone metabolism homeostasis. RNA-binding proteins, as essential actors in posttranscriptional activities, may exert influence on osteoporosis progression by regulating the RNA life cycle. This review compiles recent findings on the involvement of RNA-binding proteins in abnormal bone metabolism in osteoporosis and describes the impact of some key RNA-binding proteins on bone metabolism regulation. Additionally, we explore the potential and rationale for modulating RNA-binding proteins as a means of treating osteoporosis, with an overview of drugs that target these proteins.

Asunto(s)

Osteoporosis , Femenino , Humanos , Anciano , Osteoporosis/tratamiento farmacológico , Envejecimiento , Huesos , Homeostasis

RESUMEN

Indole-3-carbinol, bisindolylmethanes (BIMs) and indole-3-methanamines exhibit diverse therapeutic activities. Fluorinated molecules are widely used in pharmaceuticals. Herein we report a facile and straightforward method for the successful synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines by a Friedel-Crafts reaction. The reaction involves the in situ generation of difluoroacetaldehyde from difluoroacetaldehyde ethyl hemiacetal in the presence of a base or an acid. This protocol is distinguished by its good to excellent yields, broad substrate compatibility, good functional group tolerance and scalability.

RESUMEN

Porcine epidemic diarrhea virus (PEDV) belongs to the coronavirus family and the coronavirus genus, causing contact enteric infection in pigs. It is one of the most serious diseases that threatens the pig industry. However, there is currently no specific drug to prevent and treat the disease, indicating that we need to be vigilant about the spread of the disease and the development of anti-PEDV drugs. The dried aerial parts of the plant Portulaca oleracea in the family Portulacaceous, whose decoction can be used to treat acute enteritis, dysentery, diarrhea, and other diseases. This study explored the potential mechanism of water extract of Portulaca oleracea (WEPO) in PEDV-induced pyroptosis in Vero cells. PEDV decreased the viability of Vero cells in a dose- and time-dependent manner, causing cell damage, upregulating the level of intracellular Nlrp3, and inhibiting the level of Gasdermin D (GSDMD) and the activation of Caspase-1. WEPO can inhibit PEDV-induced pyroptosis, reduce the elevation of inflammatory factors caused by infection, and exhibit a dose-dependent effect. Knockdown of Caspase-1 and GSDMD separately can induce the production of the inflammatory factor IL-1ß to significantly decrease and increase, respectively. These results suggest that WEPO can inhibit cell pyroptosis caused by PEDV and that the Caspase-1 and GSDMD pathways play an important role in this process.

RESUMEN

Objective: To explore the feasibility and early effectiveness of computer-simulated osteotomy based on the health-side combined with guide plate technique in the treatment of cubitus varus deformity in adolescents. Methods: The clinical data of 23 patients with cubitus varus deformity who met the selection criteria between June 2019 and February 2023 were retrospectively analyzed. There were 17 males and 6 females, ranging in age from 4 to 16 years with an average of 8.5 years. The time from injury to operation was 1-4 years. The angle of distal humerus rotation was defined by humeral head posterior inclination angle using low radiation dose CT to scan the patient's upper extremity data at one time, and the preoperative rotation of the distal humerus on the affected side was (33.82±4.39)°. The CT plain scan data were imported into 9yuan3D digital orthopaedic system (V3.34 software) to reconstruct three-dimensional images of both upper extremities. The simulated operation was performed with the healthy upper extremity as the reference, the best osteotomy scheme was planned, overlapped and compared, and the osteotomy guide plate was prepared. The patients were followed up regularly after operation, and the formation of callus in the osteotomy area was observed by X-ray examination. Before and after operation, the carrying angle of both upper extremities (the angle of cubitus valgus was positive, and the angle of cubitus varus was negative) and anteversion angle were measured on X-ray and CT images. At the same time, the flexion and extension range of motion of elbow joint and the external rotation range of motion of upper extremity were measured, and Mayo score was used to evaluate the function of elbow joint. Results: The operation time ranged from 34 to 46 minutes, with an average of 39 minutes. All patients were followed up 5-26 months, with a mean of 14.9 months. All the incisions healed by first intention after the operation; 2 patients had nail path irritation symptoms after Kirschner wire fixation, which improved after dressing change; no complication such as breakage and loosening of internal fixators occurred after regular X-ray review. Continuous callus formed at the osteotomy end at 4 weeks after operation, and the osteotomy end healed at 8-12 weeks after operation. At last follow-up, the carrying angle, anteversion angle, external rotation range of motion, and extension and flexion range of motion of the elbow joint of the affected side significantly improved when compared with preoperative ones ( P<0.05). Except for the extension range of motion of the healthy elbow joint ( P<0.05), there was no significant difference in other indicators between the two sides ( P>0.05). At last follow-up, the Mayo elbow score was 85-100, with an average of 99.3; 22 cases were excellent, 1 case was good, and the excellent and good rate was 100%. Conclusion: Computer-simulated osteotomy based on health-side combined with guide plate technique for treating cubitus varus deformity in adolescents can achieve precise osteotomy, which has the advantages of short operation time and easy operation, and the short-term effectiveness is satisfactory.

Asunto(s)

Articulación del Codo , Fracturas del Húmero , Deformidades Adquiridas de la Articulación , Deformidades Congénitas de las Extremidades , Masculino , Femenino , Humanos , Adolescente , Preescolar , Niño , Codo , Fracturas del Húmero/cirugía , Estudios Retrospectivos , Deformidades Adquiridas de la Articulación/etiología , Deformidades Adquiridas de la Articulación/cirugía , Articulación del Codo/cirugía , Osteotomía/métodos , Cabeza Humeral , Rango del Movimiento Articular , Computadores , Resultado del Tratamiento

RESUMEN

Preclinical and clinical studies have demonstrated the synergistic effect of microtubule-targeting agents in combination with Janus kinase 2 (JAK2) inhibitors, prompting the development of single agents with enhanced therapeutic efficacy by dually inhibiting tubulin polymerization and JAK2. Herein, we designed and synthesized a series of substituted 2-amino[1,2,4]triazolopyrimidines and related heterocycles as dual inhibitors for tubulin polymerization and JAK2. Most of these compounds exhibited potent antiproliferative activity against the selected cancer cells, with compound 7g being the most active. This compound effectively inhibits both tubulin assembly and JAK2 activity. Furthermore, phosphorylated compound 7g (i.e., compound 7g-P) could efficiently convert to compound 7g in vivo. Compound 7g, whether it was administered directly or in the form of a phosphorylated prodrug (i.e., compound 7g-P), significantly inhibited the growth of A549 xenografts in nude mice. The present findings strongly suggest that compound 7g represents a promising chemotherapeutic agent with high antitumor efficacy.

Asunto(s)

Antineoplásicos , Tubulina (Proteína) , Animales , Ratones , Humanos , Tubulina (Proteína)/metabolismo , Relación Estructura-Actividad , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Polimerizacion , Janus Quinasa 2 , Ratones Desnudos , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Microtúbulos

RESUMEN

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Asunto(s)

Lesión Pulmonar Aguda , Lipopolisacáridos , Animales , Ratones , Lipopolisacáridos/toxicidad , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Inflamación , Citocinas , Modelos Animales de Enfermedad

RESUMEN

Diet is a critical regulator for physiological metabolism and tissue homeostasis, with a close relation to health and disease. As an important organ for digestion and absorption, the intestine comes into direct contact with many dietary components. The rapid renewal of its mucosal epithelium depends on the continuous proliferation and differentiation of intestinal stem cells (ISCs). The function and metabolism of ISCs can be controlled by a variety of dietary patterns including calorie restriction, fasting, high-fat, ketogenic, and high-sugar diets, as well as different nutrients including vitamins, amino acids, dietary fibre, and probiotics. Therefore, dietary interventions targeting ISCs may make it possible to prevent and treat intestinal disorders such as colon cancer, inflammatory bowel disease, and radiation enteritis. This review summarised recent research on the role and mechanism of diet in regulating ISCs, and discussed the potential of dietary modulation for intestinal diseases.

Asunto(s)

Enfermedades Inflamatorias del Intestino , Intestinos , Humanos , Intestinos/fisiología , Dieta , Células Madre/metabolismo , Fibras de la Dieta/metabolismo , Mucosa Intestinal/metabolismo

RESUMEN

Oral ulcer is a common inflammatory disease of oral mucosa, causing severe burning pain and great inconvenience to daily life. In this study, compound 3J with anti-inflammatory activity was synthesized beforehand. Following that, an intelligent composite hydrogel supported 3J was designed with sodium alginate, carboxymethyl chitosan, and chitosan quaternary ammonium salt as the skeleton, and its therapeutic effect on the rat oral ulcer model was investigated. The results show that the composite hydrogel has a dense honeycomb structure, which is conducive to drug loading and wound ventilation, and has biodegradability. It has certain antibacterial effects and good anti-inflammatory activity. When loaded with 3J, it reduced levels of TNF-α and IL-6 in inflammatory cells by up to 50.0%. It has excellent swelling and water retention properties, with a swelling rate of up to 765.0% in a pH 8.5 environment. The existence of a large number of quaternary ammonium groups, carboxyl groups, and hydroxyl groups makes it show obvious differences in swelling in different pH environments, which proves that it has double pH sensitivity. It is beneficial to adapt to the highly dynamic changes of the oral environment. Compared with single hydrogel or drug treatment, the drug-loaded hydrogel has a better effect on the treatment of oral ulcers.

RESUMEN

Obesity is a disease commonly associated with urbanization and can also be characterized as a systemic, chronic metabolic condition resulting from an imbalance between energy intake and expenditure. The World Health Organization (WHO) has identified obesity as the most serious chronic disease that is increasingly prevalent in the world population. If left untreated, it can lead to dangerous health issues such as hypertension, hyperglycemia, hyperlipidemia, hyperuricemia, nonalcoholic steatohepatitis, atherosclerosis, and vulnerability to cardiovascular and cerebrovascular events. The specific mechanisms by which obesity affects the development of these diseases can be refined to the effect on immune cells. Existing studies have shown that the development of obesity and its associated diseases is closely related to the balance or lack thereof in the number and function of various immune cells, of which neutrophils are the most abundant immune cells in humans, infiltrating and accumulating in the adipose tissues of obese individuals, whereas NETosis, as a newly discovered type of neutrophil-related cell death, its role in the development of obesity and related diseases is increasingly emphasized. The article reviews the significant role that NETosis plays in the development of obesity and related diseases, such as diabetes and its complications. It discusses the epidemiology and negative impacts of obesity, explains the mechanisms of NETosis, and examines its potential as a targeted drug to treat obesity and associated ailments.

Asunto(s)

Enfermedades Transmisibles , Aves de Corral , Animales , Humanos , Ganado , Enfermedades Transmisibles/etiología , Enfermedades Transmisibles/veterinaria