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The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK.
Zhang, T, Xu, L, Guo, X, Tao, H, Liu, Y, Liu, X, Zhang, Y, Meng, X
Journal of pharmaceutical analysis. 2024;(2):157-176
Abstract
Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicine (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).
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Preoperative prognostic nutritional index value as a predictive factor for postoperative delirium in older adult patients with hip fractures: a secondary analysis.
Mi, X, Jia, Y, Song, Y, Liu, K, Liu, T, Han, D, Yang, N, Wang, G, Guo, X, Yuan, Y, et al
BMC geriatrics. 2024;(1):21
Abstract
BACKGROUND Malnutrition is a common geriatric syndrome and can be targeted preoperatively to decrease the risk of postoperative delirium (POD) in older adult patients. To analyze the value of the prognostic nutritional index (PNI) to predict the incidence of POD in older adult patients with hip fractures. METHODS This was a prospective, observational, cohort study of older adult patients with hip fractures. Preoperative PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (/μL) using preoperative laboratory results. Patients were divided into POD and non-POD groups using the Confusion Assessment Method (CAM). The risk factors associated with POD as well as the relationship between PNI values and the incidence of POD were analyzed using univariate and multivariate logistic regression analyses. The predictive value of PNI for POD was assessed using receiver operating characteristic curve analysis. RESULTS In this cohort of 369 patients who underwent hip fracture surgery, 67 patients (18.2%) were diagnosed with POD by the CAM results. Low PNI increased the risk of POD (odds ratio (OR) = 0.928, 95% confidence interval (CI): 0.864-0.997). General anesthesia (OR = 2.307, 95% CI: 1.279-4.162) and Mini-Mental State Examination (MMSE) score (OR = 0.956, 95% CI: 0.920-0.994) were also identified as risk factors for POD. Receiver operating characteristic curve analysis suggested that PNI combined with the anesthetic method and MMSE score may be used as a potential predictive indicator of POD after hip fracture surgery. CONCLUSION Preoperative PNI value is related to POD in older adult patients with hip fractures. TRIAL REGISTRATION This secondary analysis study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (approval No. M2022578) and registered in the Chinese Clinical Trial Registry (ChiCTR2300070569).
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Short-term effects of ambient gaseous air pollution on blood platelet mitochondrial DNA methylation and myocardial ischemia.
Jiang, Y, Chen, J, Guo, L, Lan, Y, Li, G, Liu, Q, Li, H, Deng, F, Guo, X, Wu, S
Environment international. 2024;:108533
Abstract
BACKGROUND The potential effects of short-term exposure to major ambient gaseous pollutants (ozone: O3, carbon monoxide: CO, and sulfur dioxide: SO2) on platelet mitochondrial DNA (mtDNA) methylation have been uncertain and no studies have examined whether platelet mtDNA methylation levels could modify the associations between ambient gaseous pollutants and the risks of ST-segment depression (STDE) and T-wave inversion events (TIE), two indicators of myocardial ischemia. METHODS This study used data from a randomized, double-blind, placebo-controlled intervention study with a standardized 24-hour exposure protocol among 110 participants in Beijing. Absolute changes in platelet mtDNA methylation (ACmtDNAm) levels were determined by two repeated measurements on platelet mtDNA methylation levels in blood samples collected before and after the 24-hour exposure period. A multivariable linear regression model and a generalized linear model with a Poisson link function were used to investigate the associations of ambient gaseous pollutants with platelet mtDNA methylation levels, STDE, and TIE, respectively. RESULTS Short-term O3 exposure was significantly associated with decreased ACmtDNAm at ATP6_P1 but increased ACmtDNAm at mt12sRNA, MT-COX1, and MT-COX1_P2; short-term CO and SO2 exposures were significantly associated with decreased ACmtDNAm at D-loop, MT-COX3- and ATP-related genes. Moreover, short-term O3 exposure was significantly associated with increased risks of STDE and TIE, and ACmtDNAm at MT-COX1 and MT-COX1_P2 modified the association between short-term O3 exposure and STDE events. L-Arg supplementation attenuated the effects of ambient gaseous pollutants, particularly O3, on ACmtDNAm and STDE. CONCLUSIONS Platelet mtDNA methylation levels are promising biomarkers of short-term exposure to ambient gaseous air pollution, and are likely implicated in the mechanism behind the association of ambient O3 pollution with adverse cardiovascular effects. L-Arg supplementation showed the potential to mitigate the adverse effects of ambient O3 pollution.
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[Role of Ferroptosis in Non-small Cell Lung Cancer and Progress
of Traditional Chinese Medicine Intervention].
Guo, X, Wang, T, Xia, J, Zeng, H, Shi, W
Zhongguo fei ai za zhi = Chinese journal of lung cancer. 2024;(3):216-230
Abstract
Non-small cell lung cancer (NSCLC) is one of the malignant tumors with high morbidity and mortality worldwide. Ferroptosis is a new type of programmed cell death caused by abnormal accumulation of iron-dependent reactive oxygen species (ROS) leading to lipid peroxidation. It involves the balance between iron metabolism, lipid metabolism, oxygen free radical reaction and lipid peroxidation. Recent studies have found that ferroptosis is closely related to the occurrence and development of NSCLC. Due to the emergence of chemotherapy resistance and radiotherapy resistance in the treatment of NSCLC, there is an urgent need to develop new effective drugs and treatment strategies. Traditional Chinese medicine has unique advantages in the prevention and treatment of NSCLC due to its multi-targets and minimal side effects. In this review, we summarize the mechanism of ferroptosis in NSCLC, and discuss the research status of active ingredients of traditional Chinese medicine, single-herb traditional Chinese medicine and Chinese herbal compounds in the intervention of NSCLC through ferroptosis, in order to provide a new theoretical basis for the research of ferroptosis pathway and the prevention and treatment of NSCLC by targeted ferroptosis of traditional Chinese medicine.
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Upregulation of Wheat Heat Shock Transcription Factor TaHsfC3-4 by ABA Contributes to Drought Tolerance.
Ma, Z, Zhao, B, Zhang, H, Duan, S, Liu, Z, Guo, X, Meng, X, Li, G
International journal of molecular sciences. 2024;(2)
Abstract
Drought stress can seriously affect the yield and quality of wheat (Triticum aestivum). So far, although few wheat heat shock transcription factors (Hsfs) have been found to be involved in the stress response, the biological functions of them, especially the members of the HsfC (heat shock transcription factor C) subclass, remain largely unknown. Here, we identified a class C encoding gene, TaHsfC3-4, based on our previous omics data and analyzed its biological function in transgenic plants. TaHsfC3-4 encodes a protein containing 274 amino acids and shows the basic characteristics of the HsfC class. Gene expression profiles revealed that TaHsfC3-4 was constitutively expressed in many tissues of wheat and was induced during seed maturation. TaHsfC3-4 could be upregulated by PEG and abscisic acid (ABA), suggesting that this Hsf may be involved in the regulation pathway depending on ABA in drought resistance. Further results represented that TaHsfC3-4 was localized in the nucleus but had no transcriptional activation activity. Notably, overexpression of TaHsfC3-4 in Arabidopsis thaliana pyr1pyl1pyl2pyl4 (pyr1pyl124) quadruple mutant plants complemented the ABA-hyposensitive phenotypes of the quadruple mutant including cotyledon greening, root elongation, seedling growth, and increased tolerance to drought, indicating positive roles of TaHsfC3-4 in the ABA signaling pathway and drought tolerance. Furthermore, we identified TaHsfA2-11 as a TaHsfC3-4-interacting protein by yeast two-hybrid (Y2H) screening. The experimental data show that TaHsfC3-4 can indeed interact with TaHsfA2-11 in vitro and in vivo. Moreover, transgenic Arabidopsis TaHsfA2-11 overexpression lines exhibited enhanced drought tolerance, too. In summary, our study confirmed the role of TaHsfC3-4 in response to drought stress and provided a target locus for marker-assisted selection breeding to improve drought tolerance in wheat.
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Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.
Zhan, Y, Lin, Z, Liang, J, Sun, R, Li, Y, Lin, B, Ge, F, Lin, L, Lu, H, Su, L, et al
EClinicalMedicine. 2024;:102359
Abstract
BACKGROUND Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. METHODS This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. FINDINGS Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. INTERPRETATION Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. FUNDING This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.
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7.
Latest assessment methods for mitochondrial homeostasis in cognitive diseases.
You, W, Li, Y, Liu, K, Mi, X, Li, Y, Guo, X, Li, Z
Neural regeneration research. 2024;(4):754-768
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Abstract
Mitochondria play an essential role in neural function, such as supporting normal energy metabolism, regulating reactive oxygen species, buffering physiological calcium loads, and maintaining the balance of morphology, subcellular distribution, and overall health through mitochondrial dynamics. Given the recent technological advances in the assessment of mitochondrial structure and functions, mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, and postoperative cognitive dysfunction. This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences, from the perspectives of energy metabolism, oxidative stress, calcium homeostasis, and mitochondrial dynamics (including fission-fusion, transport, and mitophagy).
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8.
Physiological response of anthocyanin synthesis to different light intensities in blueberry.
An, X, Tan, T, Song, Z, Guo, X, Zhang, X, Zhu, Y, Wang, D
PloS one. 2023;(6):e0283284
Abstract
Fruit color is an important economic character of blueberry, determined by the amount of anthocyanin content. Anthocyanin synthesis within the blueberry fruits is significantly affected by light. To reveal the physiological response mechanism of anthocyanin synthesis in blueberry fruits in different light intensities, four light intensities (100% (CK), 75%, 50% and 25%) were set for the 'O'Neal' southern highbush blueberry as the experimental material in our study. The relationship between endogenous hormones content, associated enzyme activities, and variations with the anthocyanin content in blueberry fruits under various light intensities during the white fruit stage (S1), purple fruit stage (S2), and blue fruit stage (S3) were studied. The results showed that adequate light could significantly promote anthocyanin synthesis in blueberry fruits (P < 0.05). Blueberry fruits had an anthocyanin content that was 1.76~24.13 times higher under 100% light intensity than it was under non-full light intensity. Different light intensities significantly affected the content of endogenous hormones and the activity of associated enzymes in anthocyanin synthesis pathway (P < 0.05). Among them, the JA (jasmonic acid) content and PAL (phenylalanine ammonia lyase) activity of fruits under 100% light intensity were 2.49%~41.83% and 2.47%~48.48% higher than those under other light intensity, respectively. And a significant correlation was found between the variations in anthocyanin content in fruits and the content or activities of JA, ABA (abscisic acid), ETH (ethylene), GA3 (gibberellin 3), IAA (indoleacetic acid), PAL, CHI (chalcone isomerase), DFR (dihydroflavonol reductase) and UFGT (UDP-glucose: flavonoid 3-glucosyltransferase) (P < 0.05). It indicated that 100% light intensity significantly promoted anthocyanin synthesis in blueberry fruits by affecting endogenous hormones content and associated enzyme activities in the anthocyanin synthesis pathway. This study will lay a foundation for further research on the molecular mechanism of light intensity regulating anthocyanin synthesis in blueberry.
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The impact of serum magnesium and calcium on the risk of epilepsy: A mendelian randomization study.
Guo, X, Zhu, Y, Ying, C, Xu, K, Hong, Y
CNS neuroscience & therapeutics. 2023;(10):3062-3067
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Abstract
AIMS: To investigate the causal role of serum magnesium and calcium in epilepsy or any of its subtypes through Mendelian randomization (MR) approach. METHODS Single nucleotide polymorphisms (SNPs) associated with serum magnesium and calcium were used as the instrumental variables. MR analyses were performed using the summary-level data for epilepsy extracted from International League Against Epilepsy Consortium (15,212 cases and 29,677 controls) to obtain the causal estimates. The analyses were replicated using FinnGen data (7224 epilepsy cases and 208,845 controls), and a meta-analysis was then conducted. RESULTS The result of combined analyses showed that higher serum magnesium concentrations was associated with a reduced risk of overall epilepsy (odds ratios [OR] = 0.28, 95% confidence interval [CI], 0.12-0.62, p = 0.002). In ILAE, higher serum magnesium was suggestively associated with reduced risks of focal epilepsy (OR = 0.25, 95% CI 0.10-0.62, p = 0.003). However, the results cannot be repeated in sensitivity analyses. As for serum calcium, the results did not reach statistical significance with overall epilepsy (OR = 0.60, 95% CI, 0.31-1.17, p = 0.134). However, genetically predicted serum calcium concentrations showed an inverse association with risk of generalized epilepsy (OR = 0.35, 95% CI, 0.17-0.74, p = 0.006). CONCLUSION The current MR analysis did not support a causal relationship between serum magnesium and epilepsy, but showed a causally negative association between genetically determined serum calcium and generalized epilepsy.
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High-frequency and functional mitochondrial DNA mutations at the single-cell level.
Guo, X, Xu, W, Zhang, W, Pan, C, Thalacker-Mercer, AE, Zheng, H, Gu, Z
Proceedings of the National Academy of Sciences of the United States of America. 2023;(1):e2201518120
Abstract
Decline in mitochondrial function underlies aging and age-related diseases, but the role of mitochondrial DNA (mtDNA) mutations in these processes remains elusive. To investigate patterns of mtDNA mutations, it is particularly important to quantify mtDNA mutations and their associated pathogenic effects at the single-cell level. However, existing single-cell mtDNA sequencing approaches remain inefficient due to high cost and low mtDNA on-target rates. In this study, we developed a cost-effective mtDNA targeted-sequencing protocol called single-cell sequencing by targeted amplification of multiplex probes (scSTAMP) and experimentally validated its reliability. We then applied our method to assess single-cell mtDNA mutations in 768 B lymphocytes and 768 monocytes from a 76-y-old female. Across 632 B lymphocyte and 617 monocytes with medium mtDNA coverage over >100×, our results indicated that over 50% of cells carried at least one mtDNA mutation with variant allele frequencies (VAFs) over 20%, and that cells carried an average of 0.658 and 0.712 such mutation for B lymphocytes and monocytes, respectively. Surprisingly, more than 20% of the observed mutations had VAFs of over 90% in either cell population. In addition, over 60% of the mutations were in protein-coding genes, of which over 70% were nonsynonymous, and more than 50% of the nonsynonymous mutations were predicted to be highly pathogenic. Interestingly, about 80% of the observed mutations were singletons in the respective cell populations. Our results revealed mtDNA mutations with functional significance might be prevalent at advanced age, calling further investigation on age-related mtDNA mutation dynamics at the single-cell level.