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Histone deacetylase 6 (HDAC6) was a potential target for Alzheimer's disease (AD). In this study, a series of novel oxyevodiamine-based HDAC6 inhibitors with a variety of linker moieties were designed, synthesized and evaluated. Compound 12 with a benzyl linker was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 value of 6.2 nM and was more than 200 fold selectivity over HDAC1. It also had lower cytotoxicity and higher anti-H2O2 activity in vitro comparing with other derivatives. Compound 12 might be a good lead as novel HDAC6 inhibitor for the treatment of AD. [ABSTRACT FROM AUTHOR]

Rifaximin and rifampicin are good broad-spectrum antimicrobials. The irrational use of antimicrobial drugs in veterinary clinics could threaten public health and food safety. It is necessary to develop a reliable detection method of the residue for enhancing the rational supervision of the use of such drugs, reducing and slowing down the generation of bacterial resistance, and promoting animal food safety and human health. So, this study developed an LC-MS/MS method for the detection of rifaximin and rifampicin residues in animal-origin foods. The residual rifaximin and rifampicin of homogenized test materials were extracted with acetonitrile-dichloromethane solution or acetonitrile in the presence of anhydrous sodium sulfate and vitamin C, purified by dispersible solid phase extraction, determined by LC-MS/MS, and quantified by the internal standard method. The specificity, sensitivity, matrix effect, accuracy, and precision of the method were investigated in the edible tissues of cattle, swine, or chicken. In addition, the stability of the standard stock solution and the standard working solution was also investigated. The method was suitable for the muscle, liver, kidney, fat, milk, and eggs of cattle, swine, or chicken, as well as fish and shrimp. The specificity of the method was good, and the detection of the analytes was not affected by different matrices. Both the LOD and LOQ of the two analytes were 5 μg/kg and 10 μg/kg, respectively. The results of matrix effects in each tissue were in the range of 80–120%; there were no significant matrix effects. The average accuracy of rifaximin and rifampicin in different foodstuffs of animal origin was between 80% and 120%, and the method precision was below 20% (RSD). The proposed method showed good performance for determination, which could be employed for the extraction, purification, and detection of residual rifaximin and rifampicin in edible animal tissues. The pretreatment procedure of tissue samples was simple and feasible. The method was highly specific, stable, reliable, and with high sensitivity, accuracy, and precision, which met the requirements of quantitative detection of veterinary drug residues. [ABSTRACT FROM AUTHOR]

Platelet activation is closely related to thrombosis. Aspirin eugenol ester (AEE) is a novel medicinal compound synthesized by esterifying aspirin with eugenol using the pro-drug principle. Pharmacological and pharmacodynamic experiments showed that AEE has excellent anti-inflammatory, antioxidant, and inhibitory platelet activation effects, preventing thrombosis. However, the regulatory network and action target of AEE in inhibiting platelet activation remain unknown. This study aimed to investigate the effects of AEE on platelets of thrombosed rats to reveal its regulatory mechanism via a multi-omics approach. The platelet proteomic results showed that 348 DEPs were identified in the AEE group compared with the model group, of which 87 were up- and 261 down-regulated. The pathways in this result were different from previous results, including mTOR signaling and ADP signaling at P2Y purinoceptor 12. The metabolomics of heart and abdominal aortic tissue results showed that the differential metabolites were mainly involved in steroid biosynthesis, the citric acid cycle, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and glutathione metabolism. Molecular docking results showed that AEE had a better binding force to both the COX-1 and P2Y12 protein. AEE could effectively inhibit platelet activation by inhibiting COX-1 protein and P2Y12 protein activity, thereby inhibiting platelet aggregation. Therefore, AEE can have a positive effect on inhibiting platelet activation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]

Background: Surgical patients often experience intraoperative hypothermia or hyperthermia. However, the relationship of intraoperative hypothermia and hyperthermia with postoperative pulmonary infection (PPI) and surgical site infection (SSI) is unclear. Here, we conducted a retrospective cohort study to address these issues., Methods: Adult patients who underwent major non-cardiac surgery under general anesthesia were eligible for the study and were recruited. Three indices of core body temperature under hypothermia (<36°C) and hyperthermia (>37.3°C) were calculated as mentioned in the following: absolute value ( 0 C), duration of exposure (min), and area under the curve (AUC,°C× min). The outcomes were in-hospital PPI and SSI. The risk-adjusted association of intraoperative hypothermia and hyperthermia with PPI and SSI was determined., Results: The absolute value (the nadir value of hypothermia and the peak value of hyperthermia) was not associated with PPI and SSI. PPI was associated with (1) duration: hypothermia >90 min [adjusted odds ratio (aOR): 1.425, 95% confidence interval (CI): 1.131-1.796] and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >3,198 (aOR: 1.390, 95%CI: 1.128-1.731) and hyperthermia >7,945 (aOR: 2.045, 95%CI: 1.138-3.676). SSI was associated with (1) duration: hypothermia > 195 min (aOR: 2.900, 95%CI: 1.703-4.937) and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >6,946 (aOR: 2.665, 95%CI: 1.618-4.390), hyperthermia >7,945 (aOR: 2.619, 95%CI: 1.625-4.220). Interactions were not observed between hyperthermia and hypothermia on the outcomes., Conclusions: It was observed that intraoperative hypothermia and hyperthermia are associated with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pang, Yang, Feng, Sun and Liu.)

Klebsiella pneumoniae ( K. pneumoniae ) infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on K. pneumoniae when combined with colistin, both in vitro and in vivo . The checkerboard method was employed to assess the in vitro synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The in vitro concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with K. pneumoniae was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of K. pneumoniae ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Geng, Zhang, Li, Hao, Yang, Liu and Li.)

Southwest China is home to numerous ethnic minorities, as well as many geographically and genetically isolated groups. However, the genetic substructure of these ethnic groups, especially the paternal genetic structure between groups, has not been comprehensively analyzed. In this study, we used Y chromosome capture and Illumina sequencing technologies to investigate the paternal genetic structure of three isolated groups of male unrelated individuals, including Baima in Pingwu, Sichuan Province, Muya in Shimian, Sichuan Province, and Kongge in Jinghong, Yunnan Province. We calculated the frequencies of related haplogroups by the fixed-point compound amplification method and direct counting method, and used the Past3.0 software to perform principal component analysis to draw a population clustering tree. we observed that Kongge had 3 Y chromosome haplogroups, Baima had 4 Y chromosome haplogroups, and Muya had 5 Y chromosome haplogroups. The results showed that Kongge was most closely related to the Wa, and the Y chromosome types of the Baima and Muya were mainly concentrated in the D haplogroup and its lower reaches. It has the closest relationship with the Tibetans in Qamdo and Nyingchi. The study on the genetic structure of different ethnic groups has enriched the genetic relationship of isolated populations and provided a new perspective for understanding Chinese ethnic groups.