The aim of this study was to investigate the contribution of lung zinc ions to pathogenesis of lung ischemia/reperfusion (I/R) injury in rats. Male Sprague Dawley (SD) rats were randomly divided into control group, lung I/R group (I/R group), lung I/R + low-dose zinc chloride group (LZnCl₂+I/R group), lung I/R + high-dose ZnCl₂ group (HZnCl₂+I/R group), lung I/R + medium-dose ZnCl₂ group (MZnCl₂+I/R group) and TPEN+MZnCl₂+I/R group (n = 8 in each group). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of zinc ions in lung tissue. The degree of lung tissue injury was analyzed by observing HE staining, alveolar damage index, lung wet/dry weight ratio and lung tissue gross changes. TUNEL staining was used to detect cellular apoptosis in lung tissue. Western blot and RT-qPCR were used to determine the protein expression levels of caspase-3 and ZIP8, as well as the mRNA expression levels of zinc transporters (ZIP, ZNT) in lung tissue. The mitochondrial membrane potential (MMP) of lung tissue was detected by JC-1 MMP detection kit. The results showed that, compared with the control group, the lung tissue damage, lung wet/dry weight ratio and alveolar damage index were significantly increased in the I/R group. And in the lung tissue, the concentration of Zn²⁺ was markedly decreased, while the cleaved caspase-3/caspase-3 ratio and apoptotic levels were significantly increased. The expression levels of ZIP8 mRNA and protein were down-regulated significantly, while the mRNA expression of other zinc transporters remained unchanged. There was also a significant decrease in MMP. Compared with the I/R group, both MZnCl₂+I/R group and HZnCl₂+I/R group exhibited significantly reduced lung tissue injury, lung wet/dry weight ratio and alveolar damage index, increased Zn²⁺ concentration, decreased ratio of cleaved caspase-3/caspase-3 and apoptosis, and up-regulated expression levels of ZIP8 mRNA and protein. In addition, the MMP was significantly increased in the lung tissue. Zn²⁺ chelating agent TPEN reversed the above-mentioned protective effects of medium-dose ZnCl₂ on the lung tissue in the I/R group. The aforementioned results suggest that exogenous administration of ZnCl₂ can improve lung I/R injury in rats.
Animals ; Reperfusion Injury/pathology* ; Male ; Rats, Sprague-Dawley ; Rats ; Chlorides/administration & dosage* ; Lung/pathology* ; Zinc Compounds/administration & dosage* ; Apoptosis/drug effects* ; Caspase 3/metabolism* ; Cation Transport Proteins/metabolism*

Objective To construct a big data sharing platform for clinical scientific research to solve the problems of clinical research in decentralized application systems and data sharing safety.Methods A clinical research information data usage management system was developed through the formulation of management methods in line with the actual situation of the institution,normalized standard data usage processes and a data usage service team.Then a clinical scientific research big data sharing platform including the components for sharing environment construction,research application integration,data desensitization and encryption and file management was established based on the existing hospital systems,the requirements of clinical research data usage management and the habits of clinical researchers.Results The platform realized the balance between open sharing of clinical research data and data security control,which improved the efficiency of clinical researchers while reducing data security risks during data transmission and data analysis.Conclusion The clinical scientific research big data sharing platform meets the needs of clinical scientific research application and data security management,and provides references for the co-construction-sharing of medical big data resources.[Chinese Medical Equipment Journal,2024,45(4):27-31]

This study aims to explore the mechanism of Zhuanggu Jianxi Decoction in reducing synovial tissue inflammation in human knee osteoarthritis(KOA) via the liver X receptors(LXRs)/nuclear factor(NF)-κB signaling pathway. The synovial tissue samples were collected from 5 healthy volunteers and 30 KOA synovitis patients and cultured in vitro. The samples from the heathy volunteers were set as the normal group, and those from KOA synovitis patients were randomized into synovitis, Zhuanggu Jianxi Decoction, LXRα inhibitor, and N-CoR inhibitor groups. The synovitis tissue samples of the 5 groups were treated with 10% blank serum, 10% blank serum, 10% drug-containing serum, 10% drug-containing serum+LXRα inhibitor, and 10% drug-containing serum+N-CoR inhibitor, respectively, for 7 days. After intervention, the synovial tissue samples of each group were collected and stained with hematoxylin-eosin for observation and scoring of the pathological changes. The expression intensity of the fibroblast-specific marker α-smooth musle actin(α-SMA) in the synovial tissue was observed by immunofluorescence staining. The levels of interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), matrix metalloproteinase-3(MMP-3), and matrix metalloproteinase-13(MMP-13) in the supernatant of synovium homogenate were determined by ELISA. The mRNA and protein levels of LXRα, N-CoR, P50, and P65 in the synovial tissue were determined by RT-qPCR and Western blot, respectively. The results showed that compared with the normal group, the synovitis group showcased obvious synovial lining cell proliferation, inflammatory cell infiltration, synovial cell disarrangement, increased histopathological score(P<0.05), enhanced α-SMA fluorescence intensity and increased number of synovial fibroblasts(P<0.05), elevated levels of IL-1β, TNF-α, MMP-3, and MMP-13 in the synovial tissue(P<0.05), down-regulated mRNA and protein levels of LXRα and N-CoR, and up-regulated mRNA and protein levels of P50 and P65(P<0.05). Compared with the synovitis group, the Zhuanggu Jianxi Decoction group showed alleviated pathological changes, declined histopathological score of the synovial tissue(P<0.05), decreased α-SMA fluorescence intensity and number of synovial fibroblasts(P<0.05), lowered levels of IL-1β, TNF-α, MMP-3, and MMP-13(P<0.05), up-regulated mRNA and protein levels of LXRα and N-CoR, and down-regulated mRNA and protein levels of P50 and P65(P<0.05) in the synovial tissue. Compared with the Zhuanggu Jianxi Decoction group, the LXRα inhibitor group and N-CoR inhibitor group showed aggravated pathological changes, risen histopathological score of the synovial tissue(P<0.05), enhanced α-SMA fluorescence intensity and increased number of synovial fibroblasts(P<0.05), elevated levels of IL-1β, TNF-α, MMP-3, and MMP-13(P<0.05), down-regulated mRNA and protein levels of LXRα and N-CoR, and up-regulated mRNA and protein levels of P50 and P65(P<0.05). The results above indicated that Zhuanggu Jianxi Decoction could alleviate the synovial tissue inflammation in KOA patients by upregulating the mRNA and protein levels of LXRα and N-CoR in the LXRs/NF-κB pathway to downregulate the mRNA and protein levels of P50 and P65 and reduce the activity of the NF-κB pathway in the synovial tissue.
Humans ; Osteoarthritis, Knee/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; Male ; Liver X Receptors/immunology* ; Middle Aged ; NF-kappa B/metabolism* ; Female ; Synovial Membrane/metabolism* ; Aged ; Adult

Asialoglycoprotein receptor (ASGPR) is highly expressed on the surface of parenchymal liver cells. It can specifically recognize and bind to desialylated glycoproteins which contain terminal galactose or N-acetylgalactosamine residues, and endocytosed by clathrin-mediated endocytosis, transported and then degraded in lysosome. Based on this character, ASGPR mediated liver-targeted drug delivery is likely to increase drug distribution, reduce potential side effects and lower dose. This article reviewed the expression, structure, ligand binding and endocytosis of ASGPR, and summarized the design and optimization of ASGPR ligands and the release strategies. Finally, we put forward some expects about the clinical drug development for ASGPR.

Advances in science and technology promote the rapid development of toxicological detection technologies. However, there is still a lack of decision-making tools for toxicological risk assessment, such as the lack of transparent schemes to evaluate current toxicological research and practice and the lag of toxicological testing tools to evaluate toxicity, resulting in difficulties in toxicity verification and hindering the transformation of toxicological research paradigm. Some scholars have proposed to integrate the concept of evidence-based medicine with the toxicological practice to improve the technical methods of toxicological research concept and risk assessment decision-making. With the promotion of relevant scholars and academic organizations, the concept and connotation of evidence-based toxicology have gradually become clear and a framework for research and practice has been initially formed. Although there are still many challenges, it also provides a new idea for the toxicity risk assessment and safe medication decision-making of traditional Chinese medicine(TCM). The era of digital intelligence has brought new opportunities and broad space for the development of TCM evidence-based toxicology. The exploration of TCM evidence-based toxicology from concept to method is an important embodiment of the development of TCM evidence-based toxicology, and will also promote the continuous enrichment and improvement of the research and practice system of TCM evidence-based toxicology.
Drugs, Chinese Herbal/toxicity* ; Evidence-Based Medicine ; Medicine, Chinese Traditional ; Research Design

Objective:This study was to investigate the expression of long noncoding RNA (lncRNA) KCNQ1OT1 during the differentiation program of human preadipocyte and to look for the changes of its expression in adipose tissue in obese subject, as well as to clarify the correlation between KCNQ1OT1 and obesity, and to provide clues for further understanding the role of lncRNA in the development of obesity.Methods:Quantitative PCR was used to detect the expression of KCNQ1OT1 in human preadipocyte at day 0, 1, 3, 5, 9, and 12 during differentiation program, quantitative PCR was also used to detect KCNQ1OT1 expression in white adipose tissue of obese and normal people, which related to PPIA internal reference gene. Pearson correlation analyses were used to explore the relationships of KCNQ1OT1 with body mass index, triglyceride, and total cholesterol.Results:During differentiation program, the relative expression of KCNQ1OT1 levels at day of 1, 3, 5, 9, and 12 were (25.89±3.10), (24.78±5.58), (15.53±2.11), (6.75±0.71), (4.81±0.84), which showed an upward trend compared with day 0. This difference was significant ( P<0.01), especially in the early stage of differentiation (day 1 and day 3). The relative expression of KCNQ1OT1 in visceral adipose tissue of obese subjects was 0.79±0.05, which was significantly higher than that of normal people ( P<0.01). KCNQ1OT1 was positively correlated with body mass index ( r=0.569, P<0.01), triacylglycerol content ( r=0.489, P<0.05), and total cholesterol content( r=0.591, P<0.01). Conclusion:KCNQ1OT1 expression level, which was up-regulated in adipose tissue from obese subjects, increased during the differentiation program of preadipocytes, and also positively correlated with body mass index and serum triglyceride content. These results suggest that KCNQ1OT1 may be an important regulator of human preadipocyte differentiation and a potential target for prevention and treatment of obesity.

Polymyxin B and polymyxin E (colistin) are increasingly used as last-resort drugs for treatment of infections caused by multidrug-resistant gram-negative pathogens. Unfortunately, the application was limited due to the serious side effects, especially nephrotoxicity. Very recently, the need for developing more tolerated and more effective polymyxin analogues has grown. This study details the design, synthesis, and evaluation of two classes of polymyxin B analogues with varying hydrophobicity and bulkiness at the N-terminal fatty acyl chain or position 6 amino acid. 20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and ¹H NMR spectra. Compounds 7e (MIC: 0.5-4 μg·mL^-1) and 7l (MIC: 0.25-2 μg·mL^-1) showed similar or better antimicrobial activity against both susceptible and resistant strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to polymyxin B (MIC: 0.5-2 μg·mL^-1). Besides, compound 7l (CC₅₀: 217.1±13.2 μg·mL^-1) displayed noticeably decreased renal cytotoxicity compared to polymyxin B (CC₅₀: 120.3±6.0 μg·mL^-1). This work establishes the base of further study on the structure-activity relationship of polymyxin B.

Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in AngiotensionⅡ(AngⅡ)-treated cardiomyocytes and in hearts of AngⅡ-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy.In particular,SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3.Specifically,SIRT3 physically interacts with and deacety-lates NMNAT3,thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects.Moreover,NMNAT3 regulates the activity of SIRT3 via synthesis of mitochon-dria NAD.Taken together,these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Sirtuin 3(SIRT3),a mitochondrial deacetylase that may play an impor-tant role in regulating cardiac function and a potential target for CHF

Blood Circulation ; Coronary Disease ; diagnosis ; physiopathology ; Humans ; Integrative Medicine ; Societies, Medical