Rational modification of melatonin for broad-spectrum antifungal agents discovery.

Natural products, known for their environmental safety, are regarded as a significant basis for the modification and advancement of fungicides. Melatonin, as a low-cost natural indole, exhibits diverse biological functions, including antifungal activity. However, its potential as an antifungal agent has not been fully explored. In this study, a series of melatonin derivatives targeting the mitogen-activated protein kinase (Mps1) protein of fungal pathogens were synthesized based on properties of melatonin, among which the trifluoromethyl-substituted derivative Mt-23 exhibited antifungal activity against seven plant pathogenic fungi, and effectively reduced the severity of crop diseases, including rice blast, Fusarium head blight of wheat and gray mold of tomato. In particular, its EC50 (5.4 µM) against the rice blast fungus Magnaporthe oryzae is only one-fourth that of isoprothiolane (22 µM), a commercial fungicide. Comparative analyzes revealed that Mt-23 simultaneously targets the conserved protein kinase Mps1 and lipid protein Cap20. Surface plasmon resonance assays showed that Mt-23 directly binds to Mps1 and Cap20. In this study, we provide a strategy for developing antifungal agents by modifying melatonin, and the resultant melatonin derivative Mt-23 is a commercially valuable, eco-friendly and broad-spectrum antifungal agent to combat crop disease.

Electroacupuncture and Growth Hormone for Quadriceps Atrophy Management Post-Anterior Cruciate Ligament Reconstruction: A Prospective Study.

Objective: This study aimed to investigate the efficacy of electroacupuncture (EA) combined with growth hormone in alleviating quadriceps atrophy and enhancing knee function following anterior cruciate ligament reconstruction. Methods: A prospective study was conducted, and a total of 90 patients exhibiting quadriceps atrophy after anterior cruciate ligament reconstruction were recruited between July 2020 and July 2022 from Shenzhen Pingle Orthopedic Hospital. They were randomly assigned to either the control group or the observation group , with 45 patients in each. The control group received routine rehabilitation training along with growth hormone treatment, while the observation group received routine rehabilitation training in addition to EA and growth hormone treatment. The study assessed the visual analogue score (VAS) for postoperative pain, knee function, and clinical outcomes in both groups. Results: The total effective rate in the observation group was significantly higher compared to the control group, with a statistically significant difference (P < .05). Initially, there were no significant differences between the two groups in peri-thigh atrophy index, VAS score, Lysholm score, knee swelling, knee stability, and range of motion (ROM) score (P > .05). However, after 3 and 6 months of treatment, significant reductions were observed in peri-thigh atrophy index, VAS score, knee swelling, and ROM score in the observation group compared to the control group (P < .05). Moreover, Lysholm score and knee stability significantly increased in the observation group (P < .05), with changes significantly higher than those in the control group (P < .05). Conclusions: EA combined with growth hormone treatment significantly reduces quadriceps atrophy and knee joint function in patients undergoing anterior cruciate ligament reconstruction. This combination therapy holds promise for enhancing rehabilitation outcomes in this patient population.

Association between gut microbiota and diabetic microvascular complications: a two-sample Mendelian randomization study.

Background: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). Methods: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. Results: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. Conclusion: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Design, Synthesis, and Antifungal Activities of Novel Potent Fluoroalkenyl Succinate Dehydrogenase Inhibitors.

The development of new fungicide molecules is a crucial task for agricultural chemists to enhance the effectiveness of fungicides in agricultural production. In this study, a series of novel fluoroalkenyl modified succinate dehydrogenase inhibitors were synthesized and evaluated for their antifungal activities against eight fungi. The results from the in vitro antifungal assay demonstrated that compound 34 exhibited superior activity against Rhizoctonia solani with an EC50 value of 0.04 µM, outperforming commercial fluxapyroxad (EC50 = 0.18 µM) and boscalid (EC50 = 3.07 µM). Furthermore, compound 34 showed similar effects to fluxapyroxad on other pathogenic fungi such as Sclerotinia sclerotiorum (EC50 = 1.13 µM), Monilinia fructicola (EC50 = 1.61 µM), Botrytis cinerea (EC50 = 1.21 µM), and also demonstrated protective and curative efficacies in vivo on rapeseed leaves and tomato fruits. Enzyme activity experiments and protein-ligand interaction analysis by surface plasmon resonance revealed that compound 34 had a stronger inhibitory effect on succinate dehydrogenase compared to fluxapyroxad. Additionally, molecular docking and DFT calculation confirmed that the fluoroalkenyl unit in compound 34 could enhance its binding capacity with the target protein through p-π conjugation and hydrogen bond interactions.

Glycyrrhizae radix et rhizoma processing ameliorates adverse reactions of polygalae radix in zebra fish and rabbit models.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala tenuifilia Willd (Polygalaceae), a traditional Chinese medicine, has been used for a long time to treat various illnesses with serious adverse reactions. Glycyrrhizae radix et rhizoma processing is generally used to reduce the adverse reactions. AIM OF THE STUDY: The aim of this study was to validate the irritation caused by raw Polygalaceae (RPA), to investigate whether processed Polygalaceae (PGA) was less irritating, and to screen and validate irritant properties of virgaureagenin G (polygala acid, PA), 3,6'-disinapoylsucrose (DSS), Tenuifolia (TEN) and polygalaxanthone III (POL), which had pharmacologically active in Polygalaceae. Zebrafish model, Draize test and High-Performance Liquid Chromatography (HPLC) were utilized to achieve the aim. MATERIALS AND METHODS: Scanning Electron Microscopy (SEM) and optical microscope were used to determine the presence of calcium oxalate needle crystal in RPA and PGA. Zebrafish egg spinning changes and zebrafish embryo behavior were used for irritation validation, irritation comparison and irritant screening. For additional evidence, the Draize test, HE staining of rabbit eyes and ELISA kit were used. Finally, changes in the composition of RPA and PGA were investigated using HPLC. RESULTS: SEM and optical microscopy revealed no calcium oxalate needle crystals in Polygalaceae. RPA, PGA, PA and DSS were able to accelerate the spinning of zebrafish eggs and the movement of embryos, while TEN and POL were not. RPA, PGA, DSS and PA may cause rabbit eyes to become hyperemic and swollen, resulting in damage to the iris, cornea and conjunctiva and increased levels of interleukin-6 (IL-6) and interleukin-10 (IL-10). Comparatively, the effects caused by PGA were less severe than those caused by RPA. In addition, compared to RPA, PGA had lower levels of DSS and PA. CONCLUSIONS: RPA, PGA, DSS, and PA were irritating. However, processing and curing could reduce the irritation by reducing the levels of DSS and PA. DSS and PA could be two potential irritants of Polygalaceae.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway.

BACKGROUND: Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain. AIM: To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism. METHODS: Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA. RESULTS: In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1ß induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002. CONCLUSION: This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Evaluating the effects of S-ketamine on postoperative delirium in elderly patients following total hip or knee arthroplasty under intraspinal anesthesia: a single-center randomized, double-blind, placebo-controlled, pragmatic study protocol.

Introduction: Postoperative delirium (POD) is an acute, transient brain disorder associated with decreased postoperative quality of life, dementia, neurocognitive changes, and mortality. A small number of trials have explored the role of S-ketamine in the treatment of POD due to its neuroprotective effects. Surprisingly, these trials have failed to yield supportive results. However, heterogeneity in delirium assessment methodologies, sample sizes, and outcome settings as well as deficiencies in S-ketamine use methods make the evidence provided by these studies less persuasive. Given the severe impact of POD on the health of elderly patients and the potential for S-ketamine to prevent it, we believe that designing a large sample size, and rigorous randomized controlled trial for further evaluation is necessary. Methods: This is a single-center, randomized, double-blind, placebo-controlled, pragmatic study. Subjects undergoing total hip or knee arthroplasty will be randomized in a 1:1 ratio to intervention (n = 186) and placebo (n = 186) groups. This trial aims to explore the potential role of S-ketamine in the prevention of POD. Its primary outcome is the incidence of POD within 3 postoperative days. Secondary outcomes include the number of POD episodes, the onset and duration of POD, the severity and subtype of POD, pain scores and opioid consumption, sleep quality, clinical outcomes, and safety outcomes. Discussion: To our knowledge, this is the first pragmatic study that proposes to use S-ketamine to prevent POD. We reviewed a large body of literature to identify potential preoperative confounding variables that may bias associations between the intervention and primary outcome. We will use advanced statistical methods to correct potential confounding variables, improving the test's power and external validity of test results. Of note, the patient population included in this trial will undergo intraspinal anesthesia. Although large, multicenter, randomized controlled studies have found no considerable difference in the effects of regional and general anesthesia on POD, patients receiving intraspinal anesthesia have less exposure to at-risk drugs, such as sevoflurane, propofol, and benzodiazepines, than patients receiving general anesthesia. At-risk drugs have been shown to negatively interfere with the neuroprotective effects of S-ketamine, which may be the reason for the failure of a large number of previous studies. There is currently a lack of randomized controlled studies evaluating S-ketamine for POD prevention, and our trial helps to fill a gap in this area.Trial registration: http://www.chictr.org.cn, identifier ChiCTR2300075796.

Quality in balance sensitivity through martial arts applied to children / Qualidade na sensibilidade do equilíbrio pelas artes marciais aplicadas às crianças / Calidad en la sensibilidad del equilibrio a través de las artes marciales aplicadas a los niños

ABSTRACT Introduction: Martial arts training focuses on science, methodology, and practice. Martial arts are a symbol of physical fitness. The academic analysis of the influence of martial arts training on children's physical health is of great importance for promoting traditional Chinese culture. It can enrich sports intervention programs to improve children's physical health. Objective: Analyze the effect of sensory quality training on martial arts balance training in children. Methods: Children aged 8 to 12 years were selected as research subjects. After repeated deliberations, a children's martial arts set was designed and implemented. The pilot project analyzes the importance of sensory quality in the essential stage of children's martial arts training. Results: After the experiment, there was a significant difference in balance quality in the experimental group (p<0.01). After the experiment, the difference in balance sense between the experimental and control groups was significant (p<0.01). Conclusion: In the basic training phase of children's martial arts, coaches should require athletes to master basic martial arts skills more comprehensively. All movement combinations in martial arts require comprehensive physical fitness and balance sensitivity, including speed, flexibility, and coordination. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O treinamento em artes marciais concentra-se na ciência, na metodologia e na prática. As artes marciais são um símbolo de aptidão física. A análise acadêmica da influência do treinamento de artes marciais na saúde física das crianças é de grande importância para a promoção da cultura tradicional chinesa e pode enriquecer os programas de intervenção esportiva para melhorar a saúde física infantil. Objetivo: Analisar o efeito do treinamento de qualidade sensitiva no treinamento de equilíbrio das artes marciais em crianças. Métodos: Selecionou-se crianças de 8 a 12 anos como objetos de pesquisa. Após repetidas deliberações, foi elaborado e implementado um conjunto de artes marciais infantis. O projeto piloto analisa a importância da qualidade sensitiva na etapa essencial do treinamento das artes marciais infantis. Resultados: Após o experimento, houve uma diferença significativa na qualidade do equilíbrio no grupo experimental (p<0,01). Após o experimento, a diferença no sentido de equilíbrio entre os grupos experimental e de controle foi significativa (p<0,01). Conclusão: Na fase de treinamento básico das artes marciais infantis, os treinadores devem exigir que os atletas dominem as habilidades básicas das artes marciais de forma mais abrangente. Todas as combinações de movimentos nas artes marciais exigem aptidão física e sensibilidade de equilíbrio abrangentes, incluindo velocidade, flexibilidade e coordenação. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El entrenamiento de las artes marciales se centra en la ciencia, la metodología y la práctica. Las artes marciales son un símbolo de la condición física. El análisis académico de la influencia del entrenamiento de artes marciales en la salud física de los niños es de gran importancia para la promoción de la cultura tradicional china y puede enriquecer los programas de intervención deportiva para mejorar la salud física de los niños. Objetivo: Analizar el efecto del entrenamiento de la calidad sensorial en el entrenamiento del equilibrio en artes marciales en niños. Métodos: Se seleccionaron niños de 8 a 12 años como sujetos de la investigación. Tras repetidas deliberaciones, se diseñó y puso en marcha un conjunto de artes marciales para niños. El proyecto piloto analiza la importancia de la calidad sensorial en la etapa esencial del entrenamiento de artes marciales de los niños. Resultados: Después del experimento, hubo una diferencia significativa en la calidad del equilibrio en el grupo experimental (p<0,01). Tras el experimento, la diferencia en el sentido del equilibrio entre los grupos experimental y de control fue significativa (p<0,01). Conclusión: En la fase de formación básica de las artes marciales infantiles, los entrenadores deberían exigir a los deportistas un dominio más completo de las habilidades marciales básicas. Todas las combinaciones de movimientos en las artes marciales requieren una amplia aptitud física y sensibilidad al equilibrio, incluidas la velocidad, la flexibilidad y la coordinación. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.