Protective effect of rutin on spinal motor neuron in rats exposed to acrylamide and the underlying mechanism.

The present study aimed to investigate the protective effect of rutin on the injury of spinal motor neuron in rats exposed to acrylamide (ACR) the underlying mechanism. Fifty male Sprague-Dawley rats, aged 7-8 weeks, were randomly divided into control group, ACR group (20 mg/kg), low dose(100 mg/kg), medium dose (200 mg/kg) and high dose(400 mg/kg) rutin groups, ten rats in each group. The rats were given intragastric administration for 21 days. Every week, a neurobehavioral test was conducted. Nissl staining was used to observe the morphological changes in motor neurons in the L4-L6 segment of the spinal cord. Immunohistochemistry was used to identify AChE and ChAT in the rat spinal cord. Western blot was used to identify the expression of AChE, ChAT, P-ERK, ERK, and Nrf2 proteins in the rat spinal cord. The commercial kits were used to detect the presence of SOD, GSH, and LDH in the rat spinal cord. At the start of the second week, the medium and high dosage rutin group's rats' gait scores significantly decreased as compared to those of the ACR group. When rutin dosage was increased, the Nissl staining revealed that Nissl bodies was staining intensified compared to the ACR group. Immunohistochemistry and Western blot analysis revealed that AChE and ChAT expression changed when rutin dose was raised, but P-ERK and Nrf2 expression steadily increased in the spinal cord of rats in the medium and high dose groups compared to the ACR group. In the spinal cord of rats in each dosage group compared to the ACR group, the findings of the oxidative stress indices demonstrated that the expression levels of SOD and GSH rose with the increase of rutin dose, while the expression of LDH reduced with the rise of rutin dose. Rutin has an anti-oxidative impact through up-regulating the expression of P-ERK and Nrf2 proteins in the ERK/Nrf2 pathway, which may be connected to its protective action on motor neurons in the spinal cord of rats exposed to ACR.

Analysis of Prevalence, Influencing Factors, and Countermeasures of Short Stature in Children and Adolescents Aged 6∼14 in Furong District, Changsha City, in 2020.

In recent years, children's and adolescents' growth and development issues have received increasing attention with the socioeconomic development. The etiology of child short stature involves heredity, race, sex, nutrition, and a variety of endocrine hormones, which is very complex. The age of 6∼14 is the key period of children's development. Understanding the height characteristics, the prevalence of short stature, and its influencing factors at this stage and formulating preventive measures as soon as possible are conducive to improving the average height of children and reducing the incidence of short stature. In this study, cluster sampling was used to select 56,865 children and adolescents aged 6∼14 years old from 40 primary and secondary schools in Furong District of Changsha City, and the height of each child and adolescent was measured. The results showed that the overall crude prevalence of short stature in children aged 6∼14 in Furong District of Changsha is 2.82%. Growth hormone level <10 µg/L, pubertal retardation, familial short stature, low egg intake, and intrauterine growth retardation are independent risk factors affecting the occurrence of short stature. In order to improve the status quo of short stature of children aged 6∼14 in Furong District, Changsha City, targeted intervention should be strengthened for people with combined high risk factors.

Gold nanoparticle-modified black phosphorus nanosheets with improved stability for detection of circulating tumor cells.

Gold nanoparticle (AuNP)-anchored BP nanosheets were synthesized through in situ growth of AuNPs onto BP. Due to the strong chelating ability of P or phosphorus oxides with AuNPs, the stability of BP is improved. As proof-of-concept demonstration of the functionalized BP, electrochemical detection of circulating tumor cells (CTCs) based on BP@AuNPs@aptamer as a probe combined with immunomagnetic separation is reported. The aptamer can specifically bind with CTCs, while the phosphorus oxides including phosphite ion and phosphate ion (PxOy species) on BP and aptamer can react with molybdate to generate an electrochemical current, leading to dual signal amplification. The biosensor is applied to MCF-7 cell detection and displays good analytical performance with a detection limit of 2 cell mL-1. Furthermore, the practicality of this biosensor was validated through sensitive determination of MCF-7 cells in human blood. Therefore, the reported biosensor could be applied to detect other biomarkers, offering an ultrasensitive strategy for clinical diagnostics. Graphical abstract Electrochemical detection of circulating tumor cells based on gold nanoparticle-modified black phosphorus nanosheets is reported.

Mutations of Mycobacterium tuberculosis induced by anti-tuberculosis treatment result in metabolism changes and elevation of ethambutol resistance.

Selective pressure from antibiotic use is one of the most important risk factors associated with the development of drug resistance in Mycobacterium tuberculosis (MTB). However, the mechanisms underlying drug resistance at the molecular level remain partly unclear. Therefore, the purpose of this study was to investigate the potential functional effect of novel mutations arising from anti-tuberculosis treatment. We analyzed two multidrug-resistant TB (MDR-TB) isolates from the same patient; one collected before and one almost a year after commencing MDR-TB treatment. The post-treatment isolate exhibited elevated ethambutol resistance. We sequenced the whole genomes of the two clinical isolates and detected six novel polymorphisms affecting the genes Rv1026, nc0021, Rv2155c, Rv2437, and Rv3696c, and the intergenic region between Rv2764c and Rv2765. Metabolomics approach was used to reveal the effect of the found variation on the metabolic pathways of MTB. Partial least squares-discriminant analysis showed a clear differentiation between the two isolates, involving a total of 175 metabolites. Pathway analysis showed that these metabolites are mainly involved in amino sugar and nucleotide sugar metabolism, ß-alanine metabolism, sulfur metabolism, and galactose metabolism. The increased ethambutol resistance exhibited by the post-treatment MDR-TB strain could speculatively be linked to the identified genetic variations, which affected the synthesis of a number of metabolites associated with sources of carbon and energy. This may have been the main factor underlying the increased ethambutol resistance of this isolate.

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.

Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

HGSD attenuates neuronal apoptosis through enhancing neuronal autophagy in the brain of diabetic mice: The role of AMP-activated protein kinase.

AIMS: Berberine (BBR) holds promising effect for neuronal injury in diabetes because its anti-apoptotic activity and our laboratory developed the Huang-Gui Solid Dispersion (HGSD) to improve oral bioavailability of BBR. However, anti-apoptotic effect and the mechanism of HGSD in the brain of diabetic mice are not clear. We hypothesized that the AMPK/mTOR signaling pathway could exert a protective role in high glucose induced cellular apoptotic death via inducing autophagy and HGSD could inhibit apoptosis by activating AMPK/mTOR pathway. MAIN METHODS: In vivo, we established C57/BL6 mice diabetic model by STZ and detected apoptosis, autophagy and AMPK/mTOR to explore the effect of HGSD. In vitro, we established high glucose-induced apoptotic death model, treating cells with 3-MA, compound C and AICAR to explore the anti-apoptotic mechanism of BBR. KEY FINDINGS: HGSD significantly inhibited cell apoptosis, enhanced cell autophagy and activated the AMPK/mTOR pathway in the hippocampi of diabetic C57/BL6 mice, and the function of BBR is not obvious at the same dosage. Moreover, BBR significantly attenuated apoptotic death, enhanced autophagy and activated the AMPK/mTOR pathway in high glucose-treated SH-SY5Y cells. Pretreated cells with 3-MA, an inhibitor of autophagy, abolished BBR-inhibited apoptosis. Pretreated cells with Compound C, an AMPK inhibitor, blocked BBR-inhibited apoptotic and BBR-induced cell autophagy. AICAR, an AMPK activator, strengthened the function of BBR. SIGNIFICANCE: HGSD protected against neurotoxicity induced by high glucose through activating autophagy and eventually inhibiting neuronal apoptosis, which was activated by the AMPK/mTOR signaling pathway.

Effects of dietary L-glutamine supplementation on specific and general defense responses in mice immunized with inactivated Pasteurella multocida vaccine.

Little is known about effects of dietary glutamine supplementation on specific and general defense responses in a vaccine-immunized animal model. Thus, this study determined roles for dietary glutamine supplementation in specific and general defense responses in mice immunized with inactivated Pasteurella multocida vaccine. The measured variables included: (1) the production of pathogen-specific antibodies; (2) mRNA levels for pro-inflammatory cytokines, toll-like receptors and anti-oxidative factors; and (3) the distribution of P. multocida in tissues and the expression of its major virulence factors in vivo. Dietary supplementation with 0.5 % glutamine had a better protective role than 1 or 2 % glutamine against P. multocida infection in vaccine-immunized mice, at least partly resulting from its effects in modulation of general defense responses. Dietary glutamine supplementation had little effects on the production of P. multocida-specific antibodies. Compared to the non-supplemented group, dietary supplementation with 0.5 % glutamine had no effect on bacterial burden in vivo but decreased the expression of major virulence factors in the spleen. Collectively, supplementing 0.5 % glutamine to a conventional diet provides benefits in vaccine-immunized mice by enhancing general defense responses and decreasing expression of specific virulence factors.

Dietary L-glutamine supplementation increases Pasteurella multocida burden and the expression of its major virulence factors in mice.

This study was conducted to determine the effects of graded doses of L-glutamine supplementation on the replication and distribution of Pasteurella multocida, and the expression of its major virulence factors in mouse model. Mice were randomly assigned to the basal diet supplemented with 0, 0.5, 1.0 or 2.0 % glutamine. Pasteurella multocida burden was detected in the heart, liver, spleen, lung and kidney after 12 h of P. multocida infection. The expression of major virulence factors, toll-like receptors (TLRs), proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha) and anti-oxidative factors (GPX1 and CuZnSOD) was analyzed in the lung and spleen. Dietary 0.5 % glutamine supplementation has little significant effect on these parameters, compared to those with basal diet. However, results showed that a high dose of glutamine supplementation increased the P. multocida burden (P < 0.001) and the expression of its major virulence factors (P < 0.05) as compared to those with a lower dose of supplementation. In the lung, high dose of glutamine supplementation inhibited the proinflammatory responses (P < 0.05) and TLRs signaling (P < 0.05). In the spleen, the effect of glutamine supplementation on different components in TLR signaling depends on glutamine concentration, and high dose of glutamine supplementation activated the proinflammatory response. In conclusion, glutamine supplementation increased P. multocida burden and the expression of its major virulence factors, while affecting the functions of the lung and spleen.