Objective To explore the mechanism of Yiqi Tongbi Capsules in the treatment of ischemic heart failure(IHF)using network pharmacological method and molecular docking technique;To verify through in vivo experiments.Methods The effective components and corresponding target of Yiqi Tongbi Capsules were screened using TCMSP and BATMAN-TCM databases.The targets related to IHF disease were searched using GeneCards,OMIM and TTD databases.The common targets between the drug active components and IHF disease-related targets were obtained.A Chinese materia medica-active component-common target network was constructed to select the key targets.The common targets were input into the STRING database to obtain PPI network relationships,and the core targets were selected.The GO function and KEGG pathway enrichment analyses were performed on the common targets using the Metascape platform.The key active components and core targets were verified by molecular docking using the AutoDock 4.2.6 software.A mouse IHF model was established by ligating the left anterior descending branch of the coronary artery surgically,and the mice were divided into sham-operation group,model group,captopil group(3.25 mg/kg),Yiqi Tongbi Capsules low-,medium-,and high-dosage groups(2.34,4.68,9.36 g/kg).The heart function of mice was detected by Doppler ultrasound imaging system for 6 weeks after continuous administration;the mRNA expressions of LC3B,Beclin1,p62,EGFR and STAT3 were detected by RT-qPCR in mouse myocardial tissue.Results A total of 186 potential target genes for the therapeutic effects of Yiqi Tongbi Capsules on IHF were screened out;the top 5 key active components were quercetin,β-sitosterol,lutein,stigmasterol and baicalein;the core targets included AKT1,STAT3,HIF1A,BCL2 and EGFR,etc.The GO function and KEGG enrichment analysis showed that the core targets mainly participated in the processes of active oxygen metabolism,cytokine receptor binding,and involving the pathways of lipid and atherosclerosis,AGE-RAGE signaling pathway and IL-17 signaling pathway.The key active components and core target genes had good binding affinity.Yiqi Tongbi Capsules significantly improved the heart function of IHF mice;the RT-qPCR results showed that the EGFR/STAT3 signaling pathway and autophagy process were activated in the myocardial tissue of the model group mice,but the degree was not enough to improve IHF.However,Yiqi Tongbi Capsules could significantly up-regulate the expression levels of LC3B,Beclin1 mRNA in the myocardial tissue of mice,and significantly down-regulate the expression of p62,EGFR and STAT3 mRNA.Conclusion Yiqi Tongbi Capsules may playing a role in the treatment of IHF by regulating quercetin,β-sitosterol and stigmasterol,among other active compounds,down-regulating the EGFR/STAT3 signaling pathway,enhancing autophagy in cardiomyocytes of IHF mice,and improving left ventricular remodeling.

G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Objective:To analyze the clinical features of pachydermoperiostosis (PDP) and improve its diagnostic level.Methods:A retrospective analysis was conducted on the clinical data of four patients with PDP treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University from 2015 to 2023, including clinical manifestations, laboratory tests, imaging examinations, and genetic testing results.Results:All four patients were male with an average onset age of 15 years old (ranging from 9 to 18 years old). One patient′s uncle had PDP, and another patient′s parents were consanguineous, though neither parent showed signs of PDP. All four patients exhibited clubbing, skin thickening, and acne; three had frontal bossing and deepened nasolabial folds; two showed scalp sulci changes on head MRI, and all had periosteal thickening of the phalanges visible on X-ray. One patient accompanied with hypokalemic nephropathy, and another had gastric ulcer. One patient underwent whole exome sequencing test which revealed a homozygous mutation, SLCO2A1 gene c.1406C>T, leading to a protein change p.Pro469Leu. Computational tools REVEL, SIFT, and Polyphen2 predicted this variant as deleterious.Conclusion:In addition to skin thickening, frontal bossing, scalp sulci changes, clubbing, and periosteal proliferation, patients with PDP may also present with hypokalemic nephropathy and gastric ulcer. The SLCO2A1 gene c.1406C>T mutation may be pathogenic.

Diabetic cardiomyopathy(DCM)is one of the complications of diabetes.The onset of DCM is hidden and easy to be ignored.Myocardial injury is serious in the later stage and the prognosis is poor.At present,symptomatic treatment is the main clinical treatment.Cuproptosis is a novel cell death mode caused by imbalanced copper ion concentration in the body,leading to mitochondrial metabolic abnormalities,which is one of the important mechanisms of DCM.Targeted cuproptosis pathway therapy for DCM is currently a focus and hotspot of research.The"Qi Luo Theory"is one of the disciplinary branches of the theory of collateral diseases,which mainly operates the meridian Qi system.The syndrome and treatment system of collateral diseases cardiovascular diseases have important guiding significance for the treatment of DCM.Traditional Chinese medicine believes that deficiency and stagnation of Qi that in the collaterals are the root causes of DCM,with stasis and toxin obstructing collaterals and damage to the heart collaterals being the core of the disease.The ultimate outcome is the deficiency and decline of Qi,Blood,Yin,and Yang in the heart.The"Qi Luo Theory"and cuproptosis have similarities in physiological functions and pathological processes,and cuproptosis can be said to be one of the microscopic manifestations of the"Qi Luo theory".Based on this,the staged treatment principle of tonifying deficiency and promoting stagnation as the norm,attacking and supplementing simultaneously as the principle,and strengthening the body and consolidating the core has been proposed,in order to provide theoretical reference for the clinical treatment of DCM.

Objective To explore the mechanism of Yiqi Tongbi Capsules in the treatment of ischemic heart failure(IHF)using network pharmacological method and molecular docking technique;To verify through in vivo experiments.Methods The effective components and corresponding target of Yiqi Tongbi Capsules were screened using TCMSP and BATMAN-TCM databases.The targets related to IHF disease were searched using GeneCards,OMIM and TTD databases.The common targets between the drug active components and IHF disease-related targets were obtained.A Chinese materia medica-active component-common target network was constructed to select the key targets.The common targets were input into the STRING database to obtain PPI network relationships,and the core targets were selected.The GO function and KEGG pathway enrichment analyses were performed on the common targets using the Metascape platform.The key active components and core targets were verified by molecular docking using the AutoDock 4.2.6 software.A mouse IHF model was established by ligating the left anterior descending branch of the coronary artery surgically,and the mice were divided into sham-operation group,model group,captopil group(3.25 mg/kg),Yiqi Tongbi Capsules low-,medium-,and high-dosage groups(2.34,4.68,9.36 g/kg).The heart function of mice was detected by Doppler ultrasound imaging system for 6 weeks after continuous administration;the mRNA expressions of LC3B,Beclin1,p62,EGFR and STAT3 were detected by RT-qPCR in mouse myocardial tissue.Results A total of 186 potential target genes for the therapeutic effects of Yiqi Tongbi Capsules on IHF were screened out;the top 5 key active components were quercetin,β-sitosterol,lutein,stigmasterol and baicalein;the core targets included AKT1,STAT3,HIF1A,BCL2 and EGFR,etc.The GO function and KEGG enrichment analysis showed that the core targets mainly participated in the processes of active oxygen metabolism,cytokine receptor binding,and involving the pathways of lipid and atherosclerosis,AGE-RAGE signaling pathway and IL-17 signaling pathway.The key active components and core target genes had good binding affinity.Yiqi Tongbi Capsules significantly improved the heart function of IHF mice;the RT-qPCR results showed that the EGFR/STAT3 signaling pathway and autophagy process were activated in the myocardial tissue of the model group mice,but the degree was not enough to improve IHF.However,Yiqi Tongbi Capsules could significantly up-regulate the expression levels of LC3B,Beclin1 mRNA in the myocardial tissue of mice,and significantly down-regulate the expression of p62,EGFR and STAT3 mRNA.Conclusion Yiqi Tongbi Capsules may playing a role in the treatment of IHF by regulating quercetin,β-sitosterol and stigmasterol,among other active compounds,down-regulating the EGFR/STAT3 signaling pathway,enhancing autophagy in cardiomyocytes of IHF mice,and improving left ventricular remodeling.

Diabetic cardiomyopathy(DCM)is one of the complications of diabetes.The onset of DCM is hidden and easy to be ignored.Myocardial injury is serious in the later stage and the prognosis is poor.At present,symptomatic treatment is the main clinical treatment.Cuproptosis is a novel cell death mode caused by imbalanced copper ion concentration in the body,leading to mitochondrial metabolic abnormalities,which is one of the important mechanisms of DCM.Targeted cuproptosis pathway therapy for DCM is currently a focus and hotspot of research.The"Qi Luo Theory"is one of the disciplinary branches of the theory of collateral diseases,which mainly operates the meridian Qi system.The syndrome and treatment system of collateral diseases cardiovascular diseases have important guiding significance for the treatment of DCM.Traditional Chinese medicine believes that deficiency and stagnation of Qi that in the collaterals are the root causes of DCM,with stasis and toxin obstructing collaterals and damage to the heart collaterals being the core of the disease.The ultimate outcome is the deficiency and decline of Qi,Blood,Yin,and Yang in the heart.The"Qi Luo Theory"and cuproptosis have similarities in physiological functions and pathological processes,and cuproptosis can be said to be one of the microscopic manifestations of the"Qi Luo theory".Based on this,the staged treatment principle of tonifying deficiency and promoting stagnation as the norm,attacking and supplementing simultaneously as the principle,and strengthening the body and consolidating the core has been proposed,in order to provide theoretical reference for the clinical treatment of DCM.

Objective:To analyze the clinical features of pachydermoperiostosis (PDP) and improve its diagnostic level.Methods:A retrospective analysis was conducted on the clinical data of four patients with PDP treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University from 2015 to 2023, including clinical manifestations, laboratory tests, imaging examinations, and genetic testing results.Results:All four patients were male with an average onset age of 15 years old (ranging from 9 to 18 years old). One patient′s uncle had PDP, and another patient′s parents were consanguineous, though neither parent showed signs of PDP. All four patients exhibited clubbing, skin thickening, and acne; three had frontal bossing and deepened nasolabial folds; two showed scalp sulci changes on head MRI, and all had periosteal thickening of the phalanges visible on X-ray. One patient accompanied with hypokalemic nephropathy, and another had gastric ulcer. One patient underwent whole exome sequencing test which revealed a homozygous mutation, SLCO2A1 gene c.1406C>T, leading to a protein change p.Pro469Leu. Computational tools REVEL, SIFT, and Polyphen2 predicted this variant as deleterious.Conclusion:In addition to skin thickening, frontal bossing, scalp sulci changes, clubbing, and periosteal proliferation, patients with PDP may also present with hypokalemic nephropathy and gastric ulcer. The SLCO2A1 gene c.1406C>T mutation may be pathogenic.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Objective To study the effects of the intelligent hearing-assistive system incorporated in Nuro-tron cochlear implants(CI),including the autonomic acoustic scene recognition(ASR),intelligent strategy config-uration as well as the objective and subjective hearing improvements on recipients.Methods ① To evaluate the per-formance of the ASR matule,in a sound-proof room,the preset five kinds of test audios,including speech,noise,speech in noise,pure music(without human voice)and non-pure Music(with human voice)were played.Each type of scenes included 6 to 9 5 min test files.The prediction accuracy and scene switching times were calculated.② In order to evaluate the noise-reduction performance of the ABeam technology in the speech enhancement module,13 Nurotron? CI recipients were recruited and their speech recognition rate when ABeam was"ON"and"OFF"with noise coming from 90°,180°or 270°were tested,individually.Also,their subjective hearing feedback was evaluated through visual analogue scale(VAS)evaluation.Results The ASR module achieved high prediction performance,with prediction accuracy 99％±4％,96％±9％,94％±12％,94％±15％,92％±13％for speech,noise,noisy speech,pure music and non-pure music,respectively.The scene transation times for each individual scene were 1.1 ±0.3,1.4±0.7,1.3±0.5,1.4±0.8 and 1.3±0.5,indicating that the prediction was also stable.When noise came from the sides and behind of recipients and speech signal from the front,the adaptive dual microphone noise re-duction algorithm ABeam significantly increased the speech recognition score(SRS)in 5 dB signal-to-noise(SNR)environment(P＜0.001),with an average increase of 15.92％.Especially when the noise came from 180 degree backward,the SRS increased 28.68％when ABeam was"0N",which was significantly higher than when ABeam was"OFF"(P＜0.01).Conclusion The intelligent hearing-assistive system can help CI recipients automatically configure appropriate SPSs under different environments,improving the speech intelligibility and hearing comfort.

Objective:To establish an active monitoring model for adverse reactions/events of sodium-glucose cotransporter 2 inhibitor (SGLT2i) for application and promotion in medical institutions.Methods:The subjects were type 2 diabetes patients who were discharged from the First Affiliated Hospital of Guangdong Pharmaceutical University (our hospital) from March 1, 2021 to October 1, 2022 and treated with SGLT2i. The patients were divided into 2 parts and assigned to the pre-trial phase and clinical application validation phase, respectively. SGLT2i-related adverse reactions/events from domestic and foreign databases and drug labels were retrieved, and triggering items were developed preliminarily. After soliciting opinions from experts in our hospital, referring to relevant medical orders, disease course records, and laboratory indicator reference values, the triggering items were modified, and a questionnaire survey was conducted using the Delphi method. According to expert opinions, the items were sorted, analyzed, discussed, and modified to form preliminary triggering items. A monitoring model was established based on the Chinese hospital drug surveillance system, the triggering items were improved during the pre-trial phase, and validated during the clinical application phase.Results:A total of 218 and 858 patients were obtained in the pre-trial phase and clinical application validation phase, respectively. Based on literature and drug labels, 44 triggering items were preliminarily formed. A total of 16 survey questionnaires from experts were collected. After being modified based on expert opinions, and further improved during the pre-trial phase, 24 triggering items were determined finally, including 8 laboratory indicators (A), 4 rescue agents (B), 11 clinical symptoms (C), and 1 intervention measure (D). The number of positive cases monitored by the model during the pre-trial phase and clinical application validation phase was 56 and 189, respectively. The actual number of positive cases under manual review was 12 and 57, respectively. The positive predictive value (PPV) of the triggering items in the pre-trial phase and clinical application phase were 25.0% (18/72) and 30.9% (77/249), respectively, with adverse reaction/event detection rates of 5.5% (12/218) and 6.6% (57/858), sensitivity of 92.3% (12/13) and 100% (57/57), and specificity of 78.5% (161/205) and 83.5% (669/801). Among the 12 positive cases in the pre-trial phase and 57 positive cases in the clinical application validation phase, the association evaluation was probable and possible (4, 8 cases and 16, 41 cases, respectively). The severity of adverse reactions/events was mainly grade 2 (11 cases and 55 cases, respectively). The main adverse reactions/events of SGLT2i were hypoglycemia, urinary tract infections, rashes, etc. Pancreatitis, weight loss, etc., which were not stated in the drug labels, were evaluated as probable.Conclusion:Through pre-trial and internal clinical validation phase, the adverse reaction/event active monitoring model established for SGLT2i in this study has high sensitivity and specificity, and can be applied practically in medical institutions.