Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Objective: To research the prevalence and influencing factors of asymptomatic arrhythmia among college students, and provide scientific basis for heart rate control and health management of asymptomatic arrhythmia among college students. Methods: Using cluster sampling method, 3 012 college students who studied in the First Clinical Medical College of Henan University of Traditional Chinese Medicine and the Second Clinical Medical College of Henan University of Traditional Chinese Medicine were selected as the research objects from September to November 2022. After entering school in autumn (September in 2022), all college students were investigated by questionnaire, and the general data and living habits of asymptomatic arrhythmia college students and normal college students were compared. Logistic regression was used to analyze the influencing factors of asymptomatic arrhythmia among college students. Results: A total of 62 patients with asymptomatic arrhythmia were found. The detection rates of the patients with body mass index(BMI)≥24.0 kg/m 2 , systolic blood pressure(SBP)≥120 mmHg, diastolic blood pressure(DBP)≥80 mmHg, family history of cardiovascular disease, smoking, drinking, exercising less than three times a week, heavy study pressure, irregular work and rest, depression tendency and anxiety tendency were 5.58%, 4.49%, 5.63%, 6.18%, 4.26%, 4.50%, 3.72%, 4.29%, 4.28%, 9.15%,9.03%, which were significantly higher than those of patients with BMI<24.0 kg/m 2, SBP＜120 mmHg, DBP<80 mmHg, no family history of cardiovascular disease, no smoking, no drinking, exercise more than three times a week, little study pressure, regular work and rest, no depression tendency and no anxiety tendency (1.20%, 1.37%, 1.35%, 1.53%, 1.55 %, 1.59%, 1.27%, 1.52%, 1.38%, 1.71%,1.71%), and the differences were statistically significant ( χ 2=45.33, 25.20, 37.74, 32.24, 16.69, 17.25, 19.57, 17.83, 22.36, 37.23,39.42, P <0.01). Logistic regression analysis showed that the higher of BMI,SBP and DBP, family history of cardiovascular disease, smoking, drinking, times of exercise, heavy study pressure, irregular work and rest, depression tendency and anxiety tendency were positively correlated with asymptomatic arrhythmia of college students ( P <0.05). Conclusions The higher of BMI and blood pressure, family history of cardiovascular diseases, bad living habits and psychological status are related to asymptomatic arrhythmia in college students. It is of great significance to control weight and blood pressure reasonably and maintain good living habits and mental state for preventing and improving asymptomatic arrhythmia.

Objective To investigate the effect of nicotine on coagulation in intestinal ischemia-reperfusion injury rats.Methods 32 male Sprague-dawley rats,weighing 250-300g,were randomly divided into 4 groups(n=8):sham operation group(S),intestinal ischemia-reperfusion(IR)group,nicotine(NIC)group,α7 nicotinic acetylcholine receptor(α7nAchR)antagonist group α-bungarotoxin(α-BGT)group.Intestinal IR was induced by clamping superior mesenteric artery for 45min and 120min of reperfusion.In group NIC nicotine 400μg/kg was injected intraperitoneally at 30min before superior mesenteric artery occlusion.In group α-BGT 1μg/kg was injected intraperitoneally at 15min before superior mesenteric artery occlusion.Plasma tumor necrosis factor-α(TNF-α),tissue factor(TF),antithrombin(AT),tissue plasminogen activator(tPA),fiber plasminogen activator inhibitor-1(PAI-1),D-dimer levels and platelet count(PLT)were measured after 120min reperfusion.Chiu's count was used to assess the changes in intestinal mucosal pathlolgical morphology.Results Compared with group S and group NIC,the plasma TNF-α,TF,tPA,PAI-1 and D-dimer levels were significantly increased,and plasma AT level and platelet count were significantly decreased,in group IR and group α-BGT(P<0.05),Chiu's scores were significantly increased(P<0.05).Conclusion Nicotine can inhibit the excessive activation of coagulation function in intestinal ischemia-reperfusion injury rats.Its mechanism may be related to activation of cholinergic antiinflammatory pathway,reducing the release of pro-inflammatory cytokines thereby reducing endothelial cell injury.

Objective:To compare the changes in pelvic floor electrophysiology and imaging in female patients with myofascial pelvic pain (MFPP), and to explore the characteristics and significance of these changes.Methods:A total of 49 MFPP patients who were admitted to the of Dalian Women′s and Children′s Medical Center (Group) from January 2019 to October 2021 were randomly selected as the research group, and 41 healthy women during the same period were selected as the control group. Both groups filled in the center′s medical history and general condition survey form. French PHENIX series pelvic floor muscle potential detection instrument was used to detect the resting vaginal muscle potential and maximum muscle potential of the two groups. The static tension, dynamic tension and pelvic floor muscle contraction force of the two groups were measured by French PHENIX series electronic tensioning apparatus with 5° and 10° opening respectively. Two dimensional transperineal ultrasound and three dimensional transvaginal ultrasound produced by B-K Company in Denmark were used to measure the length between the lower margin of the bladder neck from the symphysis pubis and the bladder neck and the bladder bottom (BND, BSD), the diameter of the genital tract hiatus and the angle of the anus and rectum. The area, anterior-posterior diameter, transverse diameter and different damage degrees of levator ani levator were measured.Results:The resting muscle potential of the study group was higher than that of the control group: 2 μV vs. 1 μV ( P<0.05); the maximum vaginal myopotential was higher than that of the control group: 7 μV vs. 6 μV ( P<0.05). The static tension, dynamic tension and contractile force: 204 g/m 2 vs. 175 g/m 2, 450 g/m 2 vs. 410 g/m 2 and 237 g/m 2 vs. 51 g/m 2 of pelvic floor muscle in the study group were higher than those in the control group when the tensioner was opened for 5° ( P<0.05). In resting state, BND, BSD and reproductive tract hiatus diameter in the study group were smaller than those in the control group: 14.0 mm vs. 16.7 mm, 15.3 mm vs. 19.7 mm, 46.7 mm vs. 49.5 mm ( P<0.05). The anal angle was greater than that of the control group: 129° vs. 112° ( P<0.05). The anal right angle in the study group was greater than that in the control group: 113° vs. 109° ( P<0.05). In the resting state, the area of levator ANI hiatus: 10.1 cm 2 vs. 11.6 cm 2, anterior and posterior diameters: 44.2 mm vs. 47.4 mm, transverse diameters and the defect scores of levator ani in the study group were all smaller than those in the control group ( P<0.05). Conclusions:MFPP presents with persistent pelvic floor muscle spasm and loss of coordination. MFPP can be treated by spasmolysis of pelvic floor muscle and fascia, which provides reference value for clinical treatment.

【Objective】 To analyze the basic characteristics of whole blood donors from blood stations before and after the outbreak of COVID-19. 【Methods】 After excluding invalid data, data related to the basic characteristics of whole blood donors collected from 26 blood stations in China during 2018 to 2021 were statistically analyzed, including the trend of total whole blood donors, the number of repeated blood donors, the frequency of blood donation, the average age of donors and the recruitment of first-time blood donors. 【Results】 Affected by the epidemic, 8 out of 14 indicators were with large variations, accounting for 57%. The overall growth rate of total whole blood donors during the epidemic was higher than before the epidemic (P<0.05).The number of repeated blood donors has shown an increased trend, with a higher number during the epidemic than before (P<0.05). The frequency of blood donation was lower during the epidemic than before(P<0.05).Average ages of blood donors and female blood donors fluctuated widely during the epidemic, both higher than those before the epidemic(P<0.05).The donation rate of first-time blood donors <25 years old and ≥25 years old varied widely and irregularly during the epidemic (both P<0.05). The percentage of first-time blood donors fluctuated irregularly during the epidemic, with overall percentage lower than that before the epidemic(P<0.05). 【Conclusion】 Whole blood donors from 26 blood stations increased after the outbreak of COVID-19, and some indicators in certain areas showed significant fluctuations during the epidemic.

Traumatic cerebrospinal fluid leakage commonly presents in traumatic brain injury patients, and it may lead to complications such as meningitis, ventriculitis, brain abscess, subdural hematoma or tension pneumocephalus. When misdiagnosed or inappropriately treated, traumatic cerebrospinal fluid leakage may result in severe complications and may be life-threatening. Some traumatic cerebrospinal fluid leakage has concealed manifestations and is prone to misdiagnosis. Due to different sites and mechanisms of trauma and degree of cerebrospinal fluid leak, treatments for traumatic cerebrospinal fluid leakage varies greatly. Hence, the Craniocerebral Trauma Professional Group of Neurosurgery Branch of Chinese Medical Association and the Neurological Injury Professional Group of Trauma Branch of Chinese Medical Association organized relevant experts to formulate the " Chinese expert consensus on the diagnosis and treatment of traumatic cerebrospinal fluid leakage in adults ( version 2023)" based on existing clinical evidence and experience. The consensus consisted of 16 recommendations, covering the leakage diagnosis, localization, treatments, and intracranial infection prevention, so as to standardize the diagnosis and treatment of traumatic cerebrospinal fluid leakage and improve the overall prognosis of the patients.

Humans ; Aripiprazole/therapeutic use* ; Schizophrenia/drug therapy* ; Antipsychotic Agents/therapeutic use* ; Risperidone ; China ; Treatment Outcome

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.

ObjectiveTo systematically evaluate the safety of interferon β-1a for treatment of corona virus disease 2019 （COVID-19）， and to provide references for interferon β-1a's clinical application. MethodsThis study was conducted with the database from US Food and Drug Administration adverse event reporting system （FAERS） from January 1， 2015 to March 31， 2021. Information component （IC） and reporting odds ratio （ROR） methods were applied for signal mining. ResultsA total of 463 700 records of COVID-19 were selected for analysis， and 45 positive drug adverse event signals were detected. Headache （IC₀₂₅=1.09， ROR₀₂₅=2.28）， pyrexia （IC₀₂₅=0.51， ROR₀₂₅=1.51） and multiple sclerosis relapse （IC₀₂₅=3.67， ROR₀₂₅=14.71） were positive adverse events with higher frequency. Autoimmune disorder （IC₀₂₅=4.42， ROR₀₂₅=24.03）， streptococcal infection （IC₀₂₅=4.12， ROR₀₂₅=19.82）， and multiple sclerosis relapse （IC₀₂₅=3.67， ROR₀₂₅=14.71） were positive adverse events. Acute lung injury， cardio-respiratory arrest and metabolic acidosis were associated with a higher proportion and frequency of death. ConclusionThere are certain safety issues with interferon β-1a in the treatment of COVID-19， and some adverse events with high frequency and high death rate deserve further attention by medical staffs.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*