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

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

ChuanWu (CW), the dried mother root of Aconitum carmichaelii Debx., is a well-known traditional Chinese medicine (TCM) recognized for its potent efficacy but inherent toxicity, primarily due to its alkaloid content. Traditional and modern detoxification methods for CW include proper processing, rational compatibility, and specialized decoction techniques, among which honey-boiled CW is particularly distinctive. However, research on the detoxification mechanism of honey-boiled CW remains limited. This study investigated this mechanism by analyzing alkaloid transformation and supramolecular aggregation. Honey-boiled and water-boiled CW preparations were compared. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to analyze CW alkaloids, specifically diester alkaloids (DDAs), monoester alkaloids (MDAs), and non-esterified diterpenoid alkaloids (NDAs). Transmission electron microscopy was employed to observe and identify supramolecular aggregates in the honey-boiled CW decoction. In vivo absorption of water-boiled, honey-boiled, and NADES-boiled CW was compared. Median lethal dose (LD₅₀) tests assessed toxicity, including hepatotoxicity and nephrotoxicity. In vitro experiments evaluated the safety, anti-inflammatory, and analgesic effects of CW-medicated serum on RAW264.7 cells, with in vivo validation in mice. Results showed that honey promoted the conversion of highly toxic DDAs to less toxic MDAs and prevented MDAs from hydrolyzing into NDAs. Honey-boiled CW formed approximately 250 nm supramolecular aggregates that encapsulated MDAs, inhibiting their conversion to NDAs. These encapsulated MDAs acted as a stable delivery system with higher bioavailability than free benzoylmesaconine. Subsequent mouse experiments confirmed that honey-boiled CW significantly increased the LD₅₀ of CW while reducing hepatotoxicity and nephrotoxicity. Additionally, honey-boiled CW significantly improved cell safety and enhanced anti-inflammatory and analgesic effects. Our findings reveal that honey-boiled CW exhibits a potent detoxification mechanism by influencing alkaloid transformation and facilitating the formation of supramolecular aggregates. This study lays the groundwork for developing detoxification or synergistic strategies within honey-boiled TCM.

The theory of "fire and primordial qi incompatibility" was proposed by LI Gao in Clarifying Doubts about Damage from Internal and External Causes, which has important guiding significance for explaining the pathogenesis, prognosis and treatment of immune-related adverse events (irAEs). "Fire" refers to yin fire, a type of deficient fire transformed from the deficiency of the spleen and stomach, reflecting the pathological state of coexisting deficiency and heat patterns in patients with tumor after immune checkpoint inhibitor (ICI) therapy. "Primordial qi" is the most fundamental essence of human life activities and serves as the source of all bodily qi. Based on the theory of "fire and primordial qi incompatibility" and Western medicine research, we found that excessive use of ICIs can damage the spleen and stomach, leading to excessive yin fire. When yin fire becomes excessive, it consumes and injures the primordial qi; when the primordial qi is depleted, it leads to more excessive yin fire and further deficiency of the spleen and stomach, forming a syndrome in which deficiency and excess coexist. Starting from the theory of "fire and primordial qi incompatibility, "combined with our team′s clinical practice and modern pharmacological research, this study explores the application characteristics of sweet-natured herbs for irAEs during ICIs therapy and interval periods, and summarizes the treatment principles, aiming to provide new perspectives and approaches for the prevention and treatment of tumor-related irAEs with traditional Chinese medicine.

Puerarin is a monomeric isoflavone compound derived from Puerariae Lobatae Radix. It exhibits poor solubility in both water and lipids, resulting in suboptimal oral absorption and low bioavailability. There is therefore an urgent need to develop new methods of applying puerarin to enhance its solubility and bioavailability. Studies have revealed that puerarin possesses distinctive physical and chemical properties, including the ability to self-assemble into supramolecular hydrogels in response to temperature changes. In this review, the research progress of puerarin as a hydrogel system containing loaded drugs, as well as a hydrogel system composed of hydrogel matrix in the field of tissue regeneration was summarized. This is intended to provide a reference for the rational and efficient use of drugs and lay the groundwork for the development and preparation of new drug carrier platforms.

Objective To investigate the effects of icariin on high glucose-induced autophagy and apoptosis of podocytes,and the regulating effects on mammalian target of rapamycin(mTOR)/serine-threonine kinase(Akt)/cyclic adenosine monophosphate response element binding protein(CREB)pathway.Methods The mouse podocytes MPC5 were taken and divided into five groups:normal control group(5.5 mmol·L-1 glucose),high glucose group(30 mmol·L-1 glucose),icariin group(30 mmol·L-1glucose+5 μmol·L-1icariin),GDC-0349 group(30 mmol·L-1glucose+50 μmol·L-1 GDC-0349),icariin+GDC-0349 group(30 mmol·L-1 glucose+5 μmol·L-1 icariin+50 μmol·L-1 GDC-0349).Cultured for 48 hours,the tetramethylazozolium salt method was used to detect the viability of MPC5 cells;acridine orange staining was used to observe the autophagy of MPC5 cells;apoptosis of MPC5 cells was detected by flow cytometry;Western blotting was used to detect the expression of autophagy[microtubule associated protein one light chain 3(LC3)II,LC3Ⅰ,autophagy-related protein(Beclin-1)],apoptosis[Bcl-2 related X protein(Bax),B cell lymphoma-2(Bcl-2)]and mTOR/Akt/CREB pathway-related proteins of MPC5 cells.Results Compared with the normal control group,the cell viability,expression levels of Bcl-2,phosphorylated mTOR(p-mTOR)/mTOR,phosphorylated Akt(p-Akt)/Akt,phosphorylated CREB(p-CREB)/CREB protein of MPC5 cells in the high glucose group were significantly decreased(P＜0.05),the autophagy ability was enhanced,the autophagosome showed orange fluorescence,and the apoptosis rate,LC3Ⅱ/LC3Ⅰ,Beclin-1,Bax protein expression levels were significantly increased(P＜0.05).Compared with the high glucose group,the cell viability,LC3Ⅱ/LC3Ⅰ,Beclin-1,Bcl-2,p-mTOR/mTOR,p-Akt/Akt,p-CREB/CREB protein expression levels of MPC5 cells in icariin group were significantly increased,the autophagy ability was further enhanced,the number of autophagosomes was increased,the autophagosomes showed brick red fluorescence(P＜0.05),the apoptosis rate and Bax protein expression level were significantly decreased(P＜0.05),and the cell viability,LC3Ⅱ/LC3Ⅰ,Beclin-1,Bcl-2,p-mTOR/mTOR,p-Akt/Akt and p-CREB/CREB proteins expression levels of MPC5 cells in GDC-0349 group were significantly decreased,the autophagy ability was weakened,the number of autophagosomes was reduced,the autophagosomes showed orange fluorescence(P＜0.05),and the apoptosis rate and Bax protein expression level were significantly increased(P＜0.05);icariin+GDC-0349 could reverse the effect of icariin on high glucose induced MPC5 cells(P＜0.05).Conclusion Icariin promotes elevated glucose-induced podocyte autophagy and inhibits apoptosis by activating the mTOR/Akt/CREB pathway.

Objective To investigate the relationship between insomnia,gastrointestinal symptoms,and glycosylated hemoglobin(HbA1c)levels in individuals diagnosed with type 2 diabetes mellitus(T2DM),as well as the related influencing factors.Methods A total of 910 T2DM patients treated in our multicenter from January 2022 to December 2022 were enrolled in this study.General information(gender,age,smoking and drinking history,exercise,course of disease,treatment and complications),HbA1c,Athens Insomnia Scale(AIS)scores and Gastrointestinal Symptoms Rating Scale(GSRS)scores of patients were collected.The differences of sleep and gastrointestinal symptoms between groups were analyzed,and the correlation between the differences and HbA1c was analyzed.Furthermore,the risk factors for non-standard HbA1c were analyzed.Results The AIS score and GSRS score in the HbA1c control group were less than those in the non-standard group(P＜0.01).Insomnia was reported by 37.0％of T2DM patients,and the HbA1c level in the insomnia group was significantly higher than that in the non-insomnia group(10.00％±2.38％vs.8.26％±1.73％,P＜0.01).Gastrointestinal symptoms were present in 57.5％of T2DM patients,and the HbA1c levels in the group with gastrointestinal symptoms were significantly higher than those in the group without gastrointestinal symptoms(9.26％±2.23％vs.8.43％±1.98％,P＜0.01).Furthermore,26.3％of T2DM patients experienced both insomnia and gastrointestinal symptoms.Remarkably,the HbA1c levels in the group with both insomnia and gastrointestinal symptoms were significantly higher than those in the group without either condition(10.18％±2.44％vs.8.45％±1.86％,P＜0.01).Correlation analysis demonstrated a significant association between sleep quality,gastrointestinal function,and HbA1c levels(P＜0.01).The logistic regression analysis result revealed that age,GSRS score,AIS score,and the presence of insomnia combined with gastrointestinal symptoms were independent risk factors for predicting HbA1c≥6.5％(P＜0.01).Having both insomnia and gastrointestinal symptoms concurrently was the strongest risk factor for substandard HbA1c control,and the risk of blood sugar control may increase about 5 times when both appear together.Conclusion Insomnia and gastrointestinal symptoms are common comorbidities in T2DM patients,showing a cross-interfering relationship,and they appear together with poor blood sugar control,interact causally,and amplify each other.

Hepatocellular carcinoma is a significant disease that seriously threatens the life and health of our people, and chronic hepatitis B virus infection is the most important cause of hepatocellular carcinoma in China. Radical surgery is an essential treatment for hepatocellular carcinoma patients who are expected to achieve long-term survival. However, the high recurrence and metastasis rate after surgery significantly affects the long-term prognosis. Postoperative recurrence of hepatocellular carcinoma is characterized by a bimodal pattern, with early recurrence leading to higher mortality and poorer survival prognosis. Postoperative adjuvant therapy can help to reduce the recurrence rate and improve the overall efficacy, but there is no standardized postoperative adjuvant therapy regimen at home and abroad. Studies have shown that antiviral therapy, interventional therapy, targeted therapy, immunotherapy, radiation therapy, and traditional Chinese medicine may have a specific effect on reducing the recurrence of hepatocellular carcinoma after surgery and prolonging overall survival. Key issues such as how to accurately assess and screen the population with a high risk of postoperative recurrence of hepatocellular carcinoma, select the best postoperative adjuvant treatment modality and timing and determine the duration of postoperative adjuvant treatment still need to be confirmed by high-quality fundamental research breakthroughs and multicenter clinical randomized controlled studies. In this article, the authors will discuss the characteristics of postoperative recurrence of hepatocellular carcinoma, the selection of adjuvant treatment strategies, and the problems faced based on the latest research progress and in light of the reality of hepatocellular carcinoma occurrence in China.

Enhanced recovery after surgery (ERAS) is a concept based on evidence-based medicine, with the reduction of patients' physiological and psychological stress as the core, multiple optimized perioperative paths as specific measures, and the ultimate goal of rapid rehabilitation. In the field of abdominal surgery, perioperative analgesia is a key factor affecting the rapid recovery of patients after surgery and an important link in accelerating the rehabilitation of ERAS program. With the development of modern medical technology and clinical research, breakthroughs have been made in the development of new analgesic drugs, and analgesic techniques and programs have been improved day by day. Preventive, multimodal and individualized analgesic regiments are currently recommended. We reviewed the current application status of analgesics and pain management techniques in the field of abdominal surgery. Combined with the pain management experience of our center, the research progress and existing problems in preventive, multi-modal and individualized analgesia are discussed.

Objective To investigate whether VHD prefabricated foot orthoses can reduce the incidence of lower limb overuse injury (LLOI) in naval recruits. Methods Totally 400 recruits who underwent enlistment training were enrolled and randomly assigned to the intervention group (n=200) and control group (n=200). During the enlistment training,the recruits in the intervention group wore VHD prefabricated foot orthoses,while those in the control group did not wear foot orthoses. Questionnaire survey was conducted 1 week later,and the foot orthoses of those recruits with adverse events were remoulded. The health data of recruits were collected again by questionnaire survey and physical examination 12 weeks later.The primary outcome was the incidence of LLOI. The secondary outcomes included the type of LLOI,the lost training time due to LLOI,the comfort score of the foot orthoses,and the adverse events. Results There were no significant differences in the baseline characteristics between the 2 groups (P>0.05). A total of 76 cases of LLOI was recorded,including 24 cases (12％) in the intervention group and 52 cases (26％) in the control group. Plantar fasciitis was the most common type of LLOI. The lost training time of the intervention group and the control group were 51 d (2.12 d for each one) and 123 d (2.37 d for each one),respectively. The comfort scores of the foot orthoses at 1 week and 12 weeks were 3.76±1.87 and 2.03±1.74,respectively. The incidences of adverse events in 1 week and 3 months were 18％ (36/200) and 5％ (10/200),respectively. The most common adverse event was arch pain. Conclusion VHD prefabricated foot orthoses can reduce the incidence of LLOI and lost training time due to LLOI in recruits,with good wearing comfort and less adverse events.