Objective: To investigate the protective effects and underlying mechanisms of sodium pyruvate (SP) on RBC storage lesions using an oxidative damage model. Methods: Six units of leukocyte-depleted suspended RBCs (discarded for non-infectious reasons within three days post-collection) were randomly assigned to four groups: negative control (NS), positive control (PS), experimental group 1 (SP1), and experimental group 2 (SP2). Oxidative stress was induced in the PS group by the addition of hydrogen peroxide (H O ), while SP1 and SP2 received SP supplementation at different concentrations (25 mM and 50 mM, respectively) in the presence of H O . After 1 hour of incubation, RBC morphology was assessed microscopically, and biochemical indicators including glutathione (GSH), malondialdehyde (MDA), methemoglobin (MetHb), adenosine triphosphate (ATP), and Na /K -ATPase activity were measured. Results: RBCs in the PS group exhibited pronounced morphological damage, including cell shrinkage and echinocyte formation, whereas both SP-treated groups showed significantly reduced structural injury. SP treatment led to elevated GSH levels and decreased concentrations of MDA and MetHb, suggesting attenuation of oxidative stress. Additionally, SP enhanced intracellular ATP levels and Na /K -ATPase activity, thereby contributing to membrane stability. Notably, the SP2 group (50 mM) demonstrated superior protective effects compared to SP1 (25 mM). Conclusion: Sodium pyruvate effectively attenuates oxidative storage lesions in RBCs, primarily through its antioxidant properties, energy metabolism supporting ability, and celluar membrane stabilizing function. These findings suggest SP as a promising additive for enhancing the quality and safety of stored RBCs.

This study aims to investigate the anti-tumor effect and mechanism of Guiqi Yiyuan Ointment combined with cisplatin on Lewis lung carcinoma-bearing mice via the protein kinase RNA-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2α(eIF2α)/activated transcription factor 4(ATF4)/C/EBP homologous protein(CHOP) signaling pathway. Sixty SPF-grade male C57BL/6 mice were selected and assigned into a blank group and a modeling group by the random number table method. After modeling of the Lewis lung carcinoma, the mice in the modeling group were randomized into model, cisplatin(5 mg·kg~(-1), once a week), and low-, medium-, and high-dose(1.7, 3.5, and 7.05 g·kg~(-1), respectively, once a day) Guiqi Yiyuan Ointment+cisplatin(5 mg·kg~(-1)) groups(n=10). After 14 days of continuous intervention, the spleen, thymus, and tumor samples of the mice were collected, weighed, and recorded, and the spleen index, thymus index, and tumor suppression rate were calculated. Hematoxylin-eosin(HE) staining was employed to observe the pathological changes in the tumor tissue. The morphological changes of the endoplasmic reticulum of tumor cells were observed by transmission electron microscopy. The positive expression of phosphorylated eIF2α(p-eIF2α) and ATF4 in the tumor tissue was detected by immunofluorescence. Western blot was employed to determine the protein levels of phosphorylated PERK(p-PERK), p-eIF2α, ATF4, CHOP, B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), cyclin-dependent kinase inhibitor 1A(p21), and cyclinD1 in the tumor tissue. Real-time fluorescent quantitative PCR was employed to determine the mRNA levels of PERK, eIF2α, ATF4, CHOP, Bax, Bcl-2, p21, and cyclinD1 in the tumor tissue. Compared with the blank group, the model group showed decreases in spleen index and thymus index(P<0.05). Compared with the model group, the cisplatin group showed decreases in spleen index and thymus index(P<0.05), and the medium-and high-dose Guiqi Yiyuan Ointment+cisplatin groups presented increases in spleen index and thymus index(P<0.05). In addition, the treatment groups all showed decreased tumor mass(P<0.05), increased tumor cell lysis and nuclear rupture, widened gap between rough endoplasmic reticulum, enhanced average fluorescence intensity of p-eIF2α and ATF4(P<0.05), up-regulated protein levels of p-PERK/PERK, p-eIF2α/eIF2α, ATF4, CHOP, Bax, and p21(P<0.05), down-regulated protein and mRNA levels of Bcl-2 and cyclinD1(P<0.05), and up-regulated mRNA levels of PERK, eIF2α, ATF4, CHOP, Bax, and p21(P<0.05). Compared with the cisplatin group, the combination groups showed increases in spleen index and thymus index(P<0.05) as well as mean optical density(P<0.05), and the high-dose Guiqi Yiyuan Ointment+cisplatin group showed decreased tumor mass(P<0.05). In addition, the medium-and high-dose Guiqi Yiyuan Ointment+cisplatin groups showcased enhanced average fluorescence intensity of p-eIF2α and ATF4(P<0.05), up-regulated protein levels of p-PERK/PERK, p-eIF2α/eIF2α, ATF4, CHOP, Bax, and p21(P<0.05), down-regulated protein and mRNA levels of Bcl-2 and cyclinD1(P<0.05), and up-regulated mRNA levels of PERK, eIF2α, ATF4, CHOP, Bax, and p21(P<0.05). In conclusion, Guiqi Yiyuan Ointment combined with cisplatin can effectively inhibit the growth of Lewis lung carcinoma in mice by regulating the expression of proteins related to the PERK/eIF2α/ATF4/CHOP signaling pathway and promoting cell cycle arrest and apoptosis.
Animals ; Cisplatin/administration & dosage* ; Activating Transcription Factor 4/genetics* ; Eukaryotic Initiation Factor-2/genetics* ; eIF-2 Kinase/genetics* ; Carcinoma, Lewis Lung/pathology* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Mice ; Signal Transduction/drug effects* ; Mice, Inbred C57BL ; Transcription Factor CHOP/genetics* ; Ointments/administration & dosage* ; Humans ; Cell Proliferation/drug effects* ; Antineoplastic Agents/administration & dosage*

Diabetic kidney disease (DKD) with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression. Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials. In this study, we integrated large-scale plasma proteomics, genetic-driven causal inference, and experimental validation to identify prioritized targets for DKD using the UK Biobank (UKB) and FinnGen cohorts. Among 2844 diabetic patients (528 with DKD), we identified 37 targets significantly associated with incident DKD, supported by both observational and causal evidence. Of these, 22% (8/37) of the potential targets are currently under investigation for DKD or other diseases. Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4 (IGFBP4), family with sequence similarity 3 member C (FAM3C), and prostaglandin D2 synthase (PTGDS)-were associated with a 4.35, 3.51, and 3.57-fold increased likelihood of developing DKD, respectively. In addition, population-level protein-altering variants (PAVs) analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD, through the classic NLR family pyrin domain containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) apoptotic axis. Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

Objective To understand the willingness of general practitioner(GP) to enhance working competence in community healthcare centers in Shanghai and provide a basis for the competence training of GPs in community healthcare centers. Methods In August 2023,GPs were selected from some community healthcare centers in Shanghai and their willingness to enhance working competence were studied by a questionnaire survey.The survey included 39 secondary indicators in three dimensions:general practice theory,skills,and humanity. Results A total of 1 192 GPs completed the questionnaire,with an effective rate of 100%.The total score of GPs' willingness to enhance their working competence was 258.45±80.93,and the mean score of the three dimensions was 6.63±2.08.The score for the general practice theory was the highest (6.92±1.95),while that for general practice humanity was the lowest (6.44±2.34) among the three dimensions.The score of willingness to enhance working efficiency differed across different age ranges (P<0.001),professional titles (P<0.001),years of work (P<0.001),and educational backgrounds of GPs (P=0.039).Those with the age younger than 30 years old,junior professional titles,less than 5 years of work experience,and a college degree or below had the highest willingness score to enhance their working competence.Among the top three secondary indicators of willingness score in each dimension,the top three methods of working competence enhancement were community general practice and specialized healthcare services combined with outpatient learning,flexible further training,and continuing education courses.Conclusions There is an urgent need for young GPs in community healthcare centers in Shanghai to enhance their working competence.Targeted enhancement plans can be provided to different groups of GPs with different characteristics through community general practice and specialized healthcare services combined with outpatient learning,flexible further training,and continuing education courses,which can further enhance the ability and quality of the GP team.
Humans ; China ; General Practitioners/psychology* ; Surveys and Questionnaires ; Community Health Centers ; Clinical Competence ; Female ; Adult ; Male ; Attitude of Health Personnel ; Middle Aged

Objective:To explore the mechanism of noise-induced hidden hearing loss by proteomics.Methods:In October 2022, 64 SPF male C57BL/6J mice were divided into control group and noise exposure group with 32 mice in each group according to random sampling method. The noise exposure group was exposed to 100 dB sound pressure level, 2000-16000 Hz broadband noise for 2 h, and the mouse hidden hearing loss model was established. Auditory brainstem response (ABR) was used to test the change of hearing threshold of mice on the 7th day after noise exposure, the damage of basal membrane hair cells was observed by immunofluorescence, and the differentially expressed proteins in the inner ear of mice in each group were identified and analyzed by 4D-Label-free quantitative proteomics, and verified by Western blotting. The results were statistically analyzed by ANOVA and t test. Results:On the 7th day after noise exposure, there was no significant difference in hearing threshold between the control group and the noise exposure group at click and 8000 Hz acoustic stimulation ( P>0.05) . The hearing threshold in the noise exposure group was significantly higher than that in the control group under 16000 Hz acoustic stimulation ( P<0.05) . Confocal immunofluorescence showed that the basal membrane hair cells of cochlear tissue in noise exposure group were arranged neatly, but the relative expression of C-terminal binding protein 2 antibody of presynaptic membrane in middle gyrus and basal gyrus was significantly lower than that in control group ( P<0.05) . GO enrichment analysis showed that the functions of differentially expressed proteins were mainly concentrated in membrane potential regulation, ligand-gated channel activity, and ligand-gated ion channel activity. KEGG pathway enrichment analysis showed that differentially expressed proteins were significantly enriched in phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, etc. Western blotting showed that the expression of inositol 1, 4, 5-trisphosphate receptor 3 (Itpr3) was increased and the expression of solute carrier family 38 member 2 (Slc38a2) was decreased in the noise exposure group ( P<0.05) . Conclusion:Through proteomic analysis, screening and verification of the differential expression proteins Itpr3 and Slc38a2 in the constructed mouse noise-induced hidden hearing loss model, the glutaminergic synaptic related pathways represented by Itpr3 and Slc38a2 may be involved in the occurrence of hidden hearing loss.

Targeted regulation of hypoxia inducible factor(HIF)pathway can provide therapeutic basis for inflammatory anemia,hypoxic nephropathy,cardiovascular diseases related to chronic kidney disease and other hypoxic diseases.At present,the first drug to act on the HIF pathway,roxadustat,has been used for the treatment of renal anemia,and other prolyl hydroxylase(PHD)inhibitors are also in clinical research.This article mainly reviews the various pathways and mechanisms of the protective effect of PHD inhibitors on the kidneys.

Objective:To explore the mechanism of noise-induced hidden hearing loss by proteomics.Methods:In October 2022, 64 SPF male C57BL/6J mice were divided into control group and noise exposure group with 32 mice in each group according to random sampling method. The noise exposure group was exposed to 100 dB sound pressure level, 2000-16000 Hz broadband noise for 2 h, and the mouse hidden hearing loss model was established. Auditory brainstem response (ABR) was used to test the change of hearing threshold of mice on the 7th day after noise exposure, the damage of basal membrane hair cells was observed by immunofluorescence, and the differentially expressed proteins in the inner ear of mice in each group were identified and analyzed by 4D-Label-free quantitative proteomics, and verified by Western blotting. The results were statistically analyzed by ANOVA and t test. Results:On the 7th day after noise exposure, there was no significant difference in hearing threshold between the control group and the noise exposure group at click and 8000 Hz acoustic stimulation ( P>0.05) . The hearing threshold in the noise exposure group was significantly higher than that in the control group under 16000 Hz acoustic stimulation ( P<0.05) . Confocal immunofluorescence showed that the basal membrane hair cells of cochlear tissue in noise exposure group were arranged neatly, but the relative expression of C-terminal binding protein 2 antibody of presynaptic membrane in middle gyrus and basal gyrus was significantly lower than that in control group ( P<0.05) . GO enrichment analysis showed that the functions of differentially expressed proteins were mainly concentrated in membrane potential regulation, ligand-gated channel activity, and ligand-gated ion channel activity. KEGG pathway enrichment analysis showed that differentially expressed proteins were significantly enriched in phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, etc. Western blotting showed that the expression of inositol 1, 4, 5-trisphosphate receptor 3 (Itpr3) was increased and the expression of solute carrier family 38 member 2 (Slc38a2) was decreased in the noise exposure group ( P<0.05) . Conclusion:Through proteomic analysis, screening and verification of the differential expression proteins Itpr3 and Slc38a2 in the constructed mouse noise-induced hidden hearing loss model, the glutaminergic synaptic related pathways represented by Itpr3 and Slc38a2 may be involved in the occurrence of hidden hearing loss.

Objective To investigate the association between triglyceride glucose index(TyG)combined with waist circumference(WC)and the risk of new-onset coronary heart disease(CHD)in the middle-aged and elderly people in 10 years of non-interventional follow-up in Luzhou area.Methods A total of 8 647 eligible individu-als participated in epidemiological survey in Luzhou area were selected.The subjects were divided into different groups according to the quartiles of the TyG-WC and followed for ten years.The correlation between different TyG-WC quartile group and 10-year new CHD in middle-aged and elderly population was analyzed by using univariate analy-sis and Cox regression analysis.Results Of the 8 647 participants in the study,484 had new CHD,accounting for 5.5%.The comparison of the number of newly diagnosed CHD subjects grouped by TyG-WC quartiles indicated the 4th quartile group>the 3rd quartile group>the 2nd quartile group>the 1st quartile group,showing statistical significance(P<0.001).Cox regression analysis showed that without adjusting for any variables,the risk of new CHD in 10 years increased with the increase of TyG-WC quartile group,and the differences between the second,third and fourth quartile array and the first quartile array were statistically significant(P<0.05).After adjusting for age and sex and further adjusting for the influence of various influencing factors,the risk of new CHD in 10 years increased with the increase of TyG-WC quartile group.The difference between the third and fourth quartile array and the first quartile array was statistically significant(P<0.05).Conclusion TyG-WC is a risk factor for new-onset CHD in the middle-aged and elderly population in Luzhou area in 10 years of non-interventional follow-up,and TyG-WC may be a predictor of the risk of CHD in the middle-aged and elderly population.

Objective:To test the feasibility, efficacy and safety of percutaneous patent foramen ovale(PFO) closure utilizing the Pansy biodegradable occluder(PBO) at 1-, 3-, 6-, 12-, 24-, and 36-month follow-up.Methods:In this single-center prospective clinical study, we enrolled 15 patients with PFO eligible for closure, all treated with the PBO, with device sizes ranging 24-34 mm. All clinical data were recorded in a 36-month follow-up period. Patients were summoned to the hospital in the 1, 3, 6, 12, 24, and 36 months after closure for transthoracic echocardiography(TTE), or transesophageal echocardiography(TEE), contrast transcranial doppler(cTCD) or contrast transthoracic echocardiography(cTTE), and a routine fasting blood sample.Results:The mean age was 27-68(44.0±16.4) years old. Indications for closure were cryptogenic stroke in 6 patients and migraine in 9 patients. Procedures were technically successful in 100%(15/15), in which course TTE showed that the position and shape of occluders were satisfactory. Small residual shunt was found by TTE in 2 patients with ASA in 1 month and 6 months after closure, respectively. 1 patient with cryptogenic stroke had another recurrent stroke 8 months after closure. At 12-month follow-up, 11 cases were closure. At 36-month follow-up, 13 cases were closure. 12 patients without atrial septal aneurysm(ASA) were closure. 1 patients with ASA was complete closure. No device-related complications occurred during the follow-up.Conclusion:PBO has good biocompatibility and suitable degradation time. A high technical success rate and closure rate can be achieved in those patients without ASA. Percutaneous closure of PFO using PBO is feasible, effective, and safe.

Objective:Referring to the Code of Medical Research Integrity and Related Conduct, to investigate the current status of scientific research integrity management of tertiary medical institutions, and to understand the current status and possible problems of scientific research integrity construction in working mechanism, institutional specifications, education guidance, supervision and punishment of various institutions.Methods:An electronic questionnaire was distributed to 72 researchers covering 46 tertiary medical institutions. The research content included basic information about the institution, the construction of the management mechanism, and the current status of research integrity management.Results:All of the surveyed medical institutions established scientific research integrity systems, publicized the policy of scientific research integrity regularly, carried out self-inspection, and conveyed the cases of notifications and alerts.84.29% of units had ″related courses for academic norms/scientific research integrity″, training were set up in ″student enrollment″ for 82.86% of the units, in ″employee recruitment″ for 94.29% of the units, in "project application" for 84.29% of the units, etc. The incidence of research misconduct in medical institutions, in descending order, is improper authorship, duplicate application, split publication, failure to obtain ethical approval, and multiple submissions. The contributing factors came from the pressure of title promotion(72.86%), the lack of scientific research integrity knowledge (71.43%), and interest motivation(70%). The analysis showed that there was a correlation between the ″convenient and open channels for research misconduct complaints and reports″ and the occurrence of ″scientific research misconduct″.Conclusions:The tertiary medical institutions have well-established scientific research integrity management systems, have taken scientific research integrity as a regular management feature, and have used diversified publicity, education, and training methods to promote academic norms and knowledge of research integrity.