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.

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 clinical characteristics and prognosis of primary renal dedifferentiated liposarcoma.Methods:A retrospective analysis was conducted on the clinical data of 10 patients diagnosed with renal dedifferentiated liposarcoma in the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2023. The cohort consisted of 8 males and 2 females, with a mean age of (59.0±6.8) years. Tumors were located in the left kidney in 8 cases and in the right kidney in 2 cases. Presentations included flank or abdominal masses in 4 patients, back pain in 3 patients, and asymptomatic in 3 patients. Imaging studies revealed solitary lesions in 9 cases and multiple lesions in 1 case. The maximum tumor diameter ranged from 95 to 178 mm, with a median of 119.5 mm. CT showed tumors within the renal parenchyma with unclear boundaries and displayed a "slow in, slow out" pattern of gradual enhancement. Clinical staging revealed T 2N 0M 0 in 3 cases, T 3N 0M 0 in 4 cases, T 4N 0M 0 in 3 cases, and T 2N 1M 0 in 1 case. Nine patients underwent radical nephrectomy, including 4 laparoscopic surgeries, 4 open surgeries, and 1 robotic-assisted with thrombectomy. One patient, presenting with multiple lymph node metastases confirmed by PET-CT, underwent a diagnostic biopsy. Postoperative pathological features, follow-up and prognosis were analyzed. Results:Pathological specimens appeared grayish-red, grayish-yellow or grayish-white cut surfaces with soft to moderate texture. Microscopically, tumor cells were ovoid or short spindle-shaped with significant atypia and cytoplasmic vacuoles, with visible pathological mitoses. Six cases showed only dedifferentiated components with tumor giant cells and multinucleated giant cells resembling pleomorphic undifferentiated sarcoma, with focal tumor necrosis. Fluorescence in situ hybridization showed MDM2 gene amplification in all cases. All cases were diagnosed as primary renal dedifferentiated liposarcoma. Pathological staging showed 4 cases as pT 2N 0M 0, 3 cases as pT 3N 0M 0, 2 cases as pT 4N 0M 0, and 1 case lacked pathological staging due to biopsy only. Five patients received postoperative adjuvant therapy, including two pT 2N 0M 0 cases who received immunotherapy and apatinib treatment respectively, with no recurrence. One pT 3N 0M 0 case received anlotinib treatment, with local recurrence after 12 months, followed by radiofrequency ablation combined with chemotherapy. Two pT 4N 0M 0 cases received ifosfamide combined with epirubicin and pirarubicin combined with lobaplatin respectively, with one case showing no progression at 11 months follow-up, and another case developing splenic metastasis 3 months post-surgery, followed by chemotherapy combined with targeted therapy, surviving for 20 months. Among the 4 cases without adjuvant therapy, two pT 2N 0M 0 cases developed multiple metastases within 1 month post-surgery and received immunotherapy combined with targeted therapy and/or chemotherapy, surviving 4-5 months.One of the two pT 3N 0M 0 cases developed local recurrence 2 months post-surgery and received chemotherapy, surviving 6 months, and another pT 3N 0M 0 case developed gluteal subcutaneous metastasis 1 month post-surgery and received immunotherapy combined with targeted therapy, surviving 8 months.One non-surgical pT 2N 1M 0 patient received chemotherapy and survived for 15 months. All patients were followed up for 4-52 months, with a median follow-up time of 11 months. At the last follow-up, 6 patients died and 4 survived. Conclusions:Primary renal dedifferentiated liposarcoma is clinically rare, with atypical symptoms and difficult preoperative diagnosis, relying on pathology for confirmation. Radical nephrectomy is the main treatment method, but surgery alone has poor prognosis with high recurrence and metastasis rates. Adjuvant therapy based on surgery may improve patient prognosis.Larger sample studies are needed for confirmation.

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.

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 explore the clinical characteristics and prognosis of primary renal dedifferentiated liposarcoma.Methods:A retrospective analysis was conducted on the clinical data of 10 patients diagnosed with renal dedifferentiated liposarcoma in the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2023. The cohort consisted of 8 males and 2 females, with a mean age of (59.0±6.8) years. Tumors were located in the left kidney in 8 cases and in the right kidney in 2 cases. Presentations included flank or abdominal masses in 4 patients, back pain in 3 patients, and asymptomatic in 3 patients. Imaging studies revealed solitary lesions in 9 cases and multiple lesions in 1 case. The maximum tumor diameter ranged from 95 to 178 mm, with a median of 119.5 mm. CT showed tumors within the renal parenchyma with unclear boundaries and displayed a "slow in, slow out" pattern of gradual enhancement. Clinical staging revealed T 2N 0M 0 in 3 cases, T 3N 0M 0 in 4 cases, T 4N 0M 0 in 3 cases, and T 2N 1M 0 in 1 case. Nine patients underwent radical nephrectomy, including 4 laparoscopic surgeries, 4 open surgeries, and 1 robotic-assisted with thrombectomy. One patient, presenting with multiple lymph node metastases confirmed by PET-CT, underwent a diagnostic biopsy. Postoperative pathological features, follow-up and prognosis were analyzed. Results:Pathological specimens appeared grayish-red, grayish-yellow or grayish-white cut surfaces with soft to moderate texture. Microscopically, tumor cells were ovoid or short spindle-shaped with significant atypia and cytoplasmic vacuoles, with visible pathological mitoses. Six cases showed only dedifferentiated components with tumor giant cells and multinucleated giant cells resembling pleomorphic undifferentiated sarcoma, with focal tumor necrosis. Fluorescence in situ hybridization showed MDM2 gene amplification in all cases. All cases were diagnosed as primary renal dedifferentiated liposarcoma. Pathological staging showed 4 cases as pT 2N 0M 0, 3 cases as pT 3N 0M 0, 2 cases as pT 4N 0M 0, and 1 case lacked pathological staging due to biopsy only. Five patients received postoperative adjuvant therapy, including two pT 2N 0M 0 cases who received immunotherapy and apatinib treatment respectively, with no recurrence. One pT 3N 0M 0 case received anlotinib treatment, with local recurrence after 12 months, followed by radiofrequency ablation combined with chemotherapy. Two pT 4N 0M 0 cases received ifosfamide combined with epirubicin and pirarubicin combined with lobaplatin respectively, with one case showing no progression at 11 months follow-up, and another case developing splenic metastasis 3 months post-surgery, followed by chemotherapy combined with targeted therapy, surviving for 20 months. Among the 4 cases without adjuvant therapy, two pT 2N 0M 0 cases developed multiple metastases within 1 month post-surgery and received immunotherapy combined with targeted therapy and/or chemotherapy, surviving 4-5 months.One of the two pT 3N 0M 0 cases developed local recurrence 2 months post-surgery and received chemotherapy, surviving 6 months, and another pT 3N 0M 0 case developed gluteal subcutaneous metastasis 1 month post-surgery and received immunotherapy combined with targeted therapy, surviving 8 months.One non-surgical pT 2N 1M 0 patient received chemotherapy and survived for 15 months. All patients were followed up for 4-52 months, with a median follow-up time of 11 months. At the last follow-up, 6 patients died and 4 survived. Conclusions:Primary renal dedifferentiated liposarcoma is clinically rare, with atypical symptoms and difficult preoperative diagnosis, relying on pathology for confirmation. Radical nephrectomy is the main treatment method, but surgery alone has poor prognosis with high recurrence and metastasis rates. Adjuvant therapy based on surgery may improve patient prognosis.Larger sample studies are needed for confirmation.

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.

ObjectiveTo evaluate the predictive value of the sperm quality to fertilization outcomes after short-time insemination.MethodsA total of 558 cycles of short-time insemination in the Reproductive Medical Center of Henan Provincial People's Hospital during January 2009 to June 2010 excluding patients aged ＞ 38 years and M Ⅱ oocyte number ＜ 3 were analyzed retrospectively.According to whether undergo rescue intracytoplasmic sperm injection( Re-ICSI),all cycles were divided into in vitro fertilization (IVF)group (472 cycles) and rescue intracytoplasmic sperm injection (Re-ICSI) group (86 cycles).Both IVFgroup and Re-ICSI group were subdivided into primary infertility and secondary infertility according to previous history of pregnancy.269 primary infertility cycles and 203 secondary infertility cycles were characterized in IVF group; and 64 primary infertility cycles and 22 secondary infertility cycles were characterized in Re-ICSI group.x2 test was applied for comparison of embryo plant rate,clinical pregnancy rate,early miscarriage rate between IVF and Re-ICSI groups,while Fisher test was used for comparison of live birth rate.and Mann-Whitney U test was utilized for comparison of duration of infertility,forward moving sperm counts,abnormal sperm rate,sperm acrosin activity between IVF and Re-ICSI groups.ResultsThe embryo plant rate,clinical pregnancy rate,early miscarriage rate,live birth rate of IVF group were:29.4％,44.9％,13.4％,37.0％ respectively; the above indicators in Re-ICSI group were:25.7％,34.6％,10.7％,29.6％ respectively,the differences of the indicators between the two groups had no statisticalsigmficance (x2 =0.869,2.963,0.010,P =0.351,0.085,0.922,0.098).Median of duration of infertility,forward moving sperm counts,abnormal sperm rate,sperm acrosin activity of primary infertility cycles in IVF group were:4.00(3.00 -6.00) years,58.37(33.64 - 102.27) × 106,81.09％ (79.41％ -88.69％ ),76.30 (48.50 - 92.46 ) μIU/106 sperm respectively ; in Re-ICSI group were:5.00 ( 3.25 -8.00) years,36.33 (20.59 -64.43 ) × 106,85.5％ (81.28％ - 89.02％ ),47.14( 31.61 -90.24) μIU/106 sperm respectively,the differences of them between the two groups had statistical significance (Z =-2.617, -3.505, -3.553, -3.530,P =0.009,0.000,0.000,0.000).Median of duration of infertility,forward moving sperm counts,abnormal sperm rate,sperm acrosin activity of secondary infertility cycles in IVF group were:5.00 (3.00 -7.00) years,63.00 (34.20 - 107.73 ) × 106,81.29％ (79.90 -86.09) ％,78.34 ( 53.87 - 98.00) μIU/106 sperm respectively,in Re-ICSI group were:5.00 ( 3.75 -7.00) years,28.80 ( 18.57 - 48.56 ) × 106,88.79％ ( 84.04 - 95.64 ) ％,54.70 ( 39.73 - 76.77 ) μIU/106 sperm respectively,the differences of them between the two groups showed statistical significance except duration of infertility (Z =- 0.338,- 3.505,- 3.553,- 3.530,P =0.735,0.000,0.000,0.006).ConclusionThe duration of infertility,forward moving sperm counts,abnormal sperm rate,sperm acrosin activity have predictive value of fertilization outcomes after short-time insemination.

Natural product is an important source of new drug research and development (R&D). Traditional Chinese medicine (TCM) innovation is the key step for its modernization and internationalization. However, due to the complexity of TCM, there are many difficulties and confusions in this process. Target-based drug discovery is the mainstream model and method of R&D. TTD, short for therapeutic target database, is developed by National University of Singapore. Besides a large amount of information on drug targets, the database also contains considerable information related to natural products. This paper briefly introduces the TTD, analyzes the natural products derived drugs/compounds recorded in TTD, which we think might provide some inspiration for the innovation of TCM.