Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress.

The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm-a response regulated by newly identified mTOR-agonistic amino acids-Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.

Lysyl oxidase interactions with transforming growth factor-ß during angiogenesis are mediated by endothelin 1.

Crosstalk between multiple components underlies the formation of mature vessels. Although the players involved in angiogenesis have been identified, mechanisms underlying the crosstalk between them are still unclear. Using the ex vivo aortic ring assay, we set out to dissect the interactions between two key angiogenic signaling pathways, vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGFß), with members of the lysyl oxidase (LOX) family of matrix modifying enzymes. We find an interplay between VEGF, TGFß, and the LOXs is essential for the formation of mature vascular smooth muscle cells (vSMC)-coated vessels. RNA sequencing analysis further identified an interaction with the endothelin-1 pathway. Our work implicates endothelin-1 downstream of TGFß in vascular maturation and demonstrate the complexity of processes involved in generating vSMC-coated vessels.

Protective mechanisms of Tuina therapy against lipopolysaccharide-induced fever in young rabbits based on untargeted metabolomics analysis.

OBJECTIVE: To investigate the effect of Tuina on the plasma metabolites of lipopolysaccharide-induced febrile in infant rabbits. METHODS: Twenty-four infant New Zealand rabbits were selected and randomly divided into three groups: saline, model, and Tuina. The fever model was established by injecting LPS intravenously through the ear margin vein in the model group and Tuina group, respectively. The modeling was considered successful when the anal temperature increased by 0.5℃ or above within 1 h. In the Tuina group, six Tuina techniques (i.e., opening Tianmen / the heaven gate, pushing Kangong / the superciliary arch, kneading Taiyang and the prominent bone behind the ears, clearing Tianheshui, spine pinching) that alleviate fever were performed on the young rabbits 1 h after the modeling, whereas the model and saline groups were not given Tuina treatment, with the real-time anal temperature monitored during the experiment. The plasma was taken 3 h after the modeling for liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics study. RESULTS: Our results showed a fever-reducing effects of Tuina therapy on lipopolysaccharide-induced fever in young rabbits, as indicated by a significantly lower anal temperature, maximum rise in body temperature, and body response index at 2 and 3 h after modeling in the Tuina group compared to the model group, with reductions in the PGE2 expression observed in the blood and hypothalamus. The differential metabolites including riboflavin, nicotinamide N-oxide, porphobilinogen, 5-hydroxyindoleacetic acid, gamma-aminobutyric acid, and lysoPC (16:1 (9Z)/0:0) were found following the Tuina intervention. Tuina primarily involves glycine-serine-threonine, arginine-proline, porphyrin-chlorophyll, pyrimidine, primary bile acid biosynthesis, and cyanoamino acid metabolic pathways. CONCLUSION: Tuina therapy has proven to be effective in reducing body temperature and down-regulating PGE2 expression in LPS-induced febrile young rabbits, with its mechanism of fever-reducing action possibly associated with the changes in plasma metabolites and metabolic pathways.

Differences in health behavior and nutrient intake status between diabetes-aware and unaware Korean adults based on the Korea national health and nutrition examination survey 2016-18 data: A cross-sectional study.

Background: The aim of this study was to investigate the nutritional intakes and treatment regimens of Korean patients with type 2 diabetes who were aware of their condition. Methods: Participants (n = 16582) aged ≥ 19 years from the 2016-18 National Health and Nutrition Survey were divided into diabetes-aware and unaware groups and the variables were compared. Results: Among 1,906 (11.5%) diabetic adults, 1,433 (75.2%) were aware of their condition; 130 (9.1%) had nutrition education, and 1,340 (93.5%) were in the diabetes-aware treatment group. The diabetes-aware group had higher average age (P < 0.0001) and lower average BMI (P = 0.0015) than the unaware group. Intake of total fat (P = 0.0034), saturated fatty acids (P = 0.0021), riboflavin (P = 0.0035) and niacin (P = 0.0228) was significantly higher in the unaware group than in the diabetes-aware group, after adjusting energy intake for age and sex. Current smoking (P = 0.0046) and heavy drinking (P < 0.0001) rates were higher in the unaware group, whereas fiber intake (P = 0.0054) was lower in the unaware group. Higher levels of glycated hemoglobin were found in the group treated for diabetes (7.2%) than in the no-treatment (6.8%) group (P = 0.0048). Diabetes control was significantly better in the high income group. Conclusions: There is a need to strengthen nutritional education to prevent diabetes and improve the health status of diabetic patients in Korea.

TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review.

The gut microbiota and its metabolites have become a hotspot of recent research. Trimethylamine N-oxide (TMAO) metabolized by the gut microbiota is closely related to many diseases such as cardiovascular disease, chronic kidney disease, type 2 diabetes, etc. Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from non-communicable diseases. Recently, increasing focus has been put on the role of TMAO in the development and progress of chronic kidney disease. The level of TMAO in patients with chronic kidney disease is significantly increased, and a high level of TMAO deteriorates chronic kidney disease. This article describes the relationship between TMAO and chronic kidney disease and the research progress of drugs targeted TMAO, providing a reference for the development of anti-chronic kidney disease drugs targeted TMAO.

New Advances in Dato-DXd Treatment for Advanced Non-Small-Cell Lung Cancer / 肿瘤防治研究

Approximately 50% of patients with non-small-cell lung cancer (NSCLC) are diagnosed at advanced stages and face a challenging prognosis despite the integration of targeted therapies, immunotherapy, and systemic chemotherapy into current standard care. A key factor in this context is trophoblast cell-surface antigen 2 (TROP2), which is widely expressed in NSCLC and strongly associated with poor patient outcomes. This article examines the latest developments in the application of datopotamab deruxtecan (Dato-DXd, DS-1062), a novel antibody-drug conjugate targeting TROP2, in the treatment of NSCLC. It provides a detailed assessment of Dato-DXd’s technical design, evaluates its efficacy by using recent clinical trial data, and discusses its safety profile.

Study of labor Process Management and Perinatal Outcome in Pregnant Women Colonized with Group B Streptococcus / 医学研究杂志

Objective To study the labor process management and perinatal outcome in full-term pregnant women colonized with group B streptococcus.Methods The clinical data of 355 full-term pregnant women with positive GBS screening(the positive GBS group)and 355 full-term pregnant women with negative GBS screening(the negative GBS group)from October 2020 to November 2021,in the department of obstetrics and gynecology of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical Uni-versity were collected.The labor characteristics,duration of rupture of membranes and perinatal outcome were compared between the two groups.Results In the positive GBS group,the incidences of intrapartum fever,postpartum fever,hospital stays,histological chorioam-nionitis,neonatal admission to neonatal intensive care unit(NICU),and neonatal sepsis were higher than those in the negative GBS group(P＜0.05).There was no significant difference between the two groups with mode of initiation of labor,mode of delivery,premature rup-ture of membrane,clinical chorioamnionitis,duration of rupture of membranes,the first stage of labor,the active stage,the second stage of labor,birth weight of newborn,gender of newborn,fetal distress,and neonatal jaundice(P＞0.05).According to the difference of in-terval between rupture of the fetal membranes,the positive GBS group was divided into three groups:＜12 hours group,≥12 and＜24 hours group,and ≥ 24 hours group.The＜12 hours group was selected as the control group.In the ≥ 12 and＜24 hours group,the first stage of labor,active stage,second stage of labor,and hospital stay were longer than those in the control group.The incidence of prema-ture rupture of membranes of term and forceps delivery was higher than that in the control group(P＜0.05).In the ≥ 24 hours group,the first stage of labor,second stage of labor,and hospital stay were longer than those in the control group.The incidence of premature rup-ture of membranes of term,intrapartum fever,postpartum fever,histological chorioamnionitis,and cesarean section was higher than that in the control group(P＜0.05).In the GBS positive group,there was no significant difference between neonatal sepsis and neonatal no-sepsis of mode of initiation of labor,mode of delivery,type of rupture of membranes,histological chorioamnionitis,duration of rupture of membranes,and duration of labor(P＞0.05).Conclusion The labor process is not affected by GBS.However,GBS increases the risk of maternal and infant infection.The full-term women colonized with group B streptococcus delivery within 24 hours after rupture of membranes,which can shorten labor,reduce labor complications,and improve adverse perinatal outcomes.

Research progress in the metabolism of branched-chain amino acids and obesity related insulin resistance / 中国糖尿病杂志

Obese patients may have abnormal metabolism of branched-chain amino acids(BCAA).Elevated levels of BCAA can lead to insulin resistance(IR)through various mechanisms,which may make it a sensitive indicator for predicting the occurrence of diabetes mellitus.This article reviews the research progress on the correlation between BCAA metabolism,obesity and IR.

Research progress of the endoplasmic reticulum-mitochondrial interactions in post-stroke cognitive impair-ment / 实用医学杂志

Post-stroke cognitive impairment(PSCI),refers to a range of clinical syndromes of cognitive impairment caused by stroke.Although its specific pathogenesis is still unclear,many studies have confirmed that endoplasmic reticulum-mitochondria interaction has become a key hub for intracellular signal transduction and substance metabolism,and its regulation of various biological processes,such as Ca2+ balance,lipid metabolism,mitochondrial dynamics,autophagy,and neuroinflammation,is closely related to the development of PSCI.There-fore,in this paper,we will review the various functions of endoplasmic reticulum-mitochondrial interactions and explore their specific roles in PSCI,in order to discover new therapeutic targets and provide new theoretical basis and references for the development of PSCI-targeted drugs in the future.

Regulatory Mechanism of Mitochondrial Apoptosis in Gastric Cancer and Intervention of Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Gastric cancer （GC） is one of the most common cancers in the world， with hidden symptoms， complex pathogenesis， high morbidity， high mortality， and poor prognosis. As one of the classical apoptosis pathways， mitochondrial apoptosis has been widely described in the apoptosis escape by GC cells. Mitochondrial apoptosis can regulate the proliferation， invasion， and metastasis of GC cells via oxidative stress， cell cycle， mitochondrial membrane potential， mitochondrial translocation and other mechanisms， and it is one of the potential targets of traditional Chinese medicine （TCM） intervention to restore the mitochondrial function in GC. The theory of spleen-mitochondria in correlation explains that spleen deficiency and cancer toxin are the root causes of mitochondrial apoptosis. Accordingly， the TCM treatment should follow the basic principle of invigorating spleen to restore healthy Qi and removing cancer toxin to eliminate the root cause. Mitochondrial apoptosis can be promoted by inhibiting oxidative stress， promoting cell cycle arrest， and reducing mitochondrial membrane potential. This therapy can improve the energy metabolism， restore the mitochondrial structure and function， and prevent the occurrence and development of GC， with mild side effects and low drug resistance. However， the mechanism of mitochondrial apoptosis in GC and the target of TCM intervention in GC have not been systematically reviewed. Therefore， this paper systematically summarized the effects of mitochondrial apoptosis on the occurrence and development of GC and the role of TCM in the treatment of GC by intervening in mitochondrial apoptosis， aiming to provide a theoretical reference for the treatment and further research of GC.

Role of autophagy in orthodontic tooth movement / 中国组织工程研究

BACKGROUND:The application of orthodontic force triggers autophagy in the periodontal tissue via diverse signaling pathways,augmenting or attenuating the activity of relevant cell types such as periodontal ligament cells,osteocytes,osteoclasts,and osteoblasts,thus facilitating the process of periodontal remodeling. OBJECTIVE:To review the research progress in orthodontic force mediated autophagy in periodontal tissue and its impact on orthodontic tooth movement. METHODS:The PubMed,Web of Science,China Biology Medicine disc and CNKI were searched for literature published from 2010 to 2023 to summarize the progress in orthodontics-related autophagy.And 76 papers were finally included in the analysis and discussion. RESULTS AND CONCLUSION:Orthodontic force can trigger a series of biochemical signal changes through periodontal mechanical receptors and aseptic inflammation they cause,leading to autophagy in periodontal tissue.Subsequently,autophagy generates corresponding feedback through cascaded amplified signaling pathways such as Phosphoinositide 3-kinase/protein kinase B,Hippo,and mitogen-activated protein kinase pathways,promoting periodontal tissue remodeling and ultimately achieving tooth movement and stability.Orthodontic force-induced autophagy can differentially regulate bone resorption on the tooth pressure side and bone formation on the tension side.Related targets have good prospects in the clinical application of orthodontic treatment.Orthodontics and autophagy have complex mechanisms.However,existing research has only focused on exploring the role of autophagy in orthodontic tooth movement.Further exploration is needed to investigate the mutual regulatory effects between autophagy and orthodontic tooth movement,as well as the interactions between upstream mechanical receptors and signaling pathways involved in related pathways.

The Association between Educational Attainment and the Risk of Nonalcoholic Fatty Liver Disease among Chinese Adults: Findings from the REACTION Study

Background/Aims@#Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. @*Methods@#A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. @*Results@#Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. @*Conclusions@#In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Analysis of the factors of acute ischemic stroke patients after endovascular treatment in the real world / 安徽医科大学学报

Objective @# To investigate the 90 day prognosis of acute ischemic stroke patients treated with mechanical thrombectomy in the real world and analyze the related factors of prognosis．@*Methods@#A total of 1 033 acute ischemic stroke patients treated with mechanical thrombectomy in tertiary hospitals of Anhui province were retrospectively investigated．The 90 day modified Rankin Scale (mRS) score was evaluated by follow-up telephone，0 ～2 points were good prognosis and 3 ～6 points were poor prognosis. @*Results @#A total of 770 patients were followed up，with an average age of (67. 7 ± 11. 8) years．The good prognosis rate was 32. 1% and the mortality rate was 31. 8% . With the increase of age，the good prognosis rate showed a downward trend while the mortality rate showed an upward trend．The best cut-off value for age prediction of 90-day mortality was 69 years old．There was no gender difference in the good prognosis rate between women (70. 6 ± 10. 6) years and men (65. 6 ± 12. 2) years，but females experienced a higher mortality than males (37. 1% vs 27. 9% ) before adjusting for age． Comparison was made among provincial，municipal and county hospitals，only the good prognosis rate of provincial hospitals was significantly higher than that of county hospitals (37．2% vs 15. 6% ) ．In the grouping of annual number of endovascular treatment cases，the good prognosis rate of only ≥40 cases group was significantly higher．There was no significant difference in mortality among the groups．@*Conclusion @#At present，the good prognosis is low and the mortality is high for the whole acute ischemic stroke patients treated with mechanical thrombectomy．Age was positively correlated with poor prognosis and mortality．The higher mortality rate in women than in men is due to the higher average age of onset in women．The good prognosis rate of provincial hospitals and hospitals with annual number of endovascular treatment ≥40 cases is higher than that of other hospitals.

[Seizure outcome after surgery for medically intractable mesial temporal lobe epilepsy and its predictors].

OBJECTIVE: To evaluate seizure outcome in patients receiving surgery for chronic medically intractable mesial temporal lobe epilepsy (MTLE) and analyze its possible predictors. METHODS: This retrospective study was conducted in patients with chronic medically intractable MTLE undergoing anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH) in our department between September, 2011 and October, 2013. The patients were followed up for 3.5 to 5.5 years, during which the seizure outcome was evaluated according to Engel's classification. The clinical data were collected from the patients to identify the possible predictors that affected the outcome of the patients using Mann-Whitney U test or Kruskal-Wallis test. RESULTS: Atotal of 34 patients were included in this study with a definite diagnosis of chronic medically intractable MTLE after preoperative noninvasive and invasive evaluation. In 4 of these patients, invasive EEG monitoring confirmed that epileptic discharges originated from the bilateral mesial temporal lobe, and hence surgical resection of the epileptogenic zone was not performed. The other 30 patients underwent surgical resection of the epileptogenic zone with ALT or SAH, and favorable outcomes were achieved in 23 (76.7%) of the patients. Of the 7 (23.3%) patients with poor outcomes, 6 patients presented with typical automatism and aura with frequent secondary generalized tonic-clonic seizure, and the other one patient exhibited impaired intelligence. Statistical analysis suggested that the patients without a special disease history (trauma, febrile seizure, or encephalitis) tended to have a more favorable seizure outcome. CONCLUSIONS: Surgical interventions can achieve good therapeutic effect on chronic medically intractable MTLE, and patients without a special disease history may have more favorable outcomes after the surgery. SAH via the superior temporal sulcus approach can be a better surgical option for intractable MTLE.

Toxicity Mechanism of Artesunate-Induced Cardiotoxic Injury:Based on Network Toxicology and Serum Metabolomics / 世界科学技术-中医药现代化

Objective This study aimed to investigate the mechanism of artesunate-induced cardiotoxicity by using network toxicology and serum untargeted metabolomics.Methods The key targets and signaling pathways of artesunate-induced cardiotoxicity were expored by network toxicology technique.The toxic effect of artesunate on Healthy C57BL/6J mice was evaluated according to the pathological morphology of the heart and the levels of serum biochemical indexes included LDH and CKMB.Serum untargeted metabolomics analysis was combined with multivariate statistical analysis to search the key endogenous metabolites of artesunate cardiotoxic injury and related metabolic pathways.Results 64 targets including AKT1,EGFR,CASP3,VEGFA and 165 signaling pathways including Apoptosis,PI3K-Akt,FoxO were screened out by network toxicology,.Serum metabolomics analysis identified the serum metabolites affected by artesunate-induced cardiotoxicity included lysophosphatidylcholine,lysophosphatidylethanolamine,indoleacetaldehyde,etc.The results of metabolic pathways enrichment analysis were glycerophosphatidylcholine metabolism and tryptophan metabolism.Conclusion Artesunate 600 mg·kg-1 can induce cardiotoxicity in C57BL/6J mice after 1-week administration,and the mechanism is related to glycerophosphatidylcholine metabolism disorder and tryptophan metabolism disorder.This study provides a reference for the early prediction and evaluation of artesunate induced drug-induced cardiotoxicity.

Isoleucine and energy metabolism / 中华内分泌代谢杂志

The prevalence of energy metabolism-related metabolic diseases, such as diabetes, fatty liver, and cardiovascular diseases, is trending upwards over years. Not only glucose and lipid metabolism but also amino acid metabolism are involved in the pathogenesis, among which branched-chain amino acids are most widely studied. Isoleucine is an important branched-chain amino acid. Its relevance to metabolic diseases has caught more attention in recent years. This review is to highlight advances in isoleucine and energy metabolism.

Application of mixed TBL teaching method in practical teaching of critical obstetric diseases / 中华医学教育探索杂志

Objective:To evaluate the mixed team-based learning (TBL) teaching method in the practical teaching of critical obstetric diseases.Methods:A total of 72 undergraduate students majoring in "5+3" clinical medicine who practiced in The First Affiliated Hospital of Chongqing Medical University from April to June 2019 were selected in the study. The typical cases of obstetric critical illness were selected, and the students were taught by TBL teaching combined with flipped classroom. After the class, a questionnaire survey was conducted to evaluate the teaching effect.Results:Totally 72 questionnaires were recovered and the results showed that all the students thought this kind of mixed TBL teaching method was helpful to develop clinical thinking ability, and the process of "group discussion" and "extra-curricular preparation" was very helpful to understand the learning. A percentage of 93 (67/72) of the students liked this teaching mode, while 28% (20/72) of the students thought this learning mode was very stressful.Conclusion:This mixed TBL teaching method is effective and feasible in the practical teaching of critical obstetric diseases.

The application of organoid models in diabetes research / 中华内分泌代谢杂志

Organoids are complex tiny organ-like model systems formed by three-dimensional culture in vitro, based on the self-renew and self-organization of stem cells. This article reviewed the recent progress in organoids construction from tissues involved in the regulation of glucose homeostasis and chronic diabetic microvascular complications, and their applications in diabetes mellitus. Organoid technology is expected to further promote the progress of diabetes research in disease modeling, personalized medicine, and regenerative medicine.

Effects of gut microbiota on pharmacokinetics and its consideration in the evaluation of the consistency of quality and efficacy of generic drugs / 中国临床药理学与治疗学

Generic drugs account for more than 95% of the chemicals market in China, and their quality is directly related to the efficacy and safety of the people. The bioequivalence evaluation with pharmacokinetic parameters as the end point is the main content of the consistency evaluation of the quality and efficacy of generic drugs. Gut microbiota is considered to have an important influence on pharmacokinetics. This article reviewed the influence of gut microbiota on pharmacokinetics and analyzed its potential significance in the evaluation of the consistency of quality and efficacy of generic drugs.