Dan Zi’s research while affiliated with Guiyang Medical University and other places

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Publications (38)


Intravenous administration of mitochondria improves ovarian function by anti-apoptosis in the premature ovarian insufficiency model
  • Article

January 2025

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12 Reads

Han-Lin Yang

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Yuan-Mei Wang

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Dan Zi

Objective: For patients with contraindications to hormone therapy, the absence of effective treatments for ovarian dysfunction post chemotherapy represents a critical issue requiring resolution. Local administration of mitochondria may enhance ovarian function in premature ovarian insufficiency (POI) by ameliorating diminished mitochondrial activity. Nevertheless, there is a paucity of literature on the efficacy of mitochondrial transplantation through intravenous injection, a less invasive and more convenient method than local injection, for the improvement of ovarian function in POI following chemotherapy. Method: Mitochondria were isolated from mouse livers, their activity and integrity were validated with MitoTracker Red and their localization was examined via confocal microscopy, real-time quantitative PCR and enzyme-linked immunosorbent assay post tail vein injection. An ovarian insufficiency animal model induced by chemotherapy was developed, and ovarian function was assessed through ovarian diameter, vaginal smear, body weight, sex hormone levels and histological analysis. The impact of mitochondrial transplantation on an ovarian cell model was examined through the assessment of mitochondrial function, apoptosis and levels of reactive oxygen species. Conclusion: Tail vein injection of isolated mitochondria has the potential to enhance ovarian functions in an animal model of POI induced by cyclophosphamide, increase mitochondrial activity in impaired ovarian cells and decrease the rate of apoptosis.


Author Correction: STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression
  • Article
  • Full-text available

December 2024

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2 Reads

Communications Biology

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The relationship of age and the cancer specific mortality of CC fit by univariate Cox regression with RCS analyses. The Cox regression indicated a nonlinear relationship between age and the risk of death(p < 0.001), with the lowest risk of mortality at age = 35.58 years. When the age was older than 35.58 years, HR was positively correlated with age, whereas negative correlations between age and HR were identified when age was less than 35.58 years. When age was older than 60 years, the risk of death increased substantial with increasing age. Shaded areas represent 95% CI.
Kaplan-Meier curves of OS (a) and CSS (b) for 3 groups of CC patients.
Forest plots for OS (a) and CSS (b) of young CC patients based on multivariate Cox regression analysis of the training cohort.
Nomograms for predicting OS (a) and CSS (b) of young CC patients.
Calibration plots of the models for predicting 3-, and 5-year OS and CSS of the development cohort (a–d) and 3-, and 5-year OS of external validation cohort (e, f).

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Construction and validation of prognostic models for young cervical cancer patients: age stratification based on restricted cubic splines

November 2024

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3 Reads

Cervical cancer (CC) ranks as the second highest cause of morbidity and mortality among young women; however, there are currently no age-specific definitions for young cervical cancer or prognostic models tailored to this demographic. Data on CC diagnosed between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age stratification is based on the relationship between age and cancer-specific mortality, as demonstrated by restricted cubic spline analyses (RCS). Cox proportional hazards regression analyses were employed to identify independent prognostic factors in the young CC group. Two novel nomograms for this population were developed and validated using an external validation cohort obtained from a local hospital database, evaluated with concordance index (C-index) and calibration plots. Receiver operating characteristic (ROC) curves were utilized to compare the accuracy of the established models against the International Federation of Gynaecology and Obstetrics (FIGO) staging system (2018). A total of 27,658 patients from the SEER database were classified into three age groups (<36 years, 36-60 years, >60 years) based on RCS analyses, with 4,990, 16,922, and 5,746 patients in each group, respectively. The independent prognostic factors identified for young CC included stage, tumour size, grade, histologic type, and surgical intervention. The results of the C-index and calibration in both the training and validation sets confirmed that the two nomograms can accurately predict the occurrence and prognosis of young CC patients. The area under the curve (AUC) values indicated that these models demonstrated higher efficacy in predicting overall survival (OS) compared to the FIGO staging system (2018). These models could potentially serve as effective tools for clinicians to estimate the prognosis of young CC patients. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81644-z.


The pathogenic APP N-terminal Val225Ala mutation alters tau protein liquid-liquid phase separation and exacerbates synaptic damage

November 2024

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31 Reads

Molecular Psychiatry

Amyloid precursor protein (APP) is predominantly located in synapses of neurons and its mutations have been well recognized as the most important genetic causal factor for the familial Alzheimer’s disease (AD). While most disease-causal mutations of APP occur within the Aβ-coding region or immediately proximal, the pathological impacts of mutations in the N-terminus of APP protein, which remote from the Aβ sequence, on neuron and synapse are still largely unknown. It was recently reported a pathogenic APP N-terminal Val225Ala mutation (APPV225A) with clinically featuring progressive dementia and typical AD pathologies in brain. In our present study, we further found that APPV225A mutation alters the N-terminal structure of APP, which enhances its binding affinity to tau protein and significantly increases APP-mediated endocytosis. Consequently, APPV225A promotes the uptake of extracellular tau into SH-SY5Y cells, further linking the structural change in APP to intracellular tau accumulation. In addition, APPV225A also notably alters the liquid-liquid phase separation (LLPS) of intracellular tau and intensified tau phosphorylation and aggregation in SH-SY5Y cells. Moreover, APPV225A promote AD-like tau pathology and synaptic damages in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells and neurons, as well as in hiPSCs-derived human brain organoids and mouse brain, which can be ameliorated by tau knockdown. Proximity labeling identified several key APPV225A-interacting proteins, including HS3ST3A1, which was shown to directly regulate tau LLPS and phosphorylation. These findings nicely build on our previous work on roles for APP in tau-related pathological phenotypes and further highlight the involvement of N-terminal APP as the key region for both amyloidopathy and tauopathy, two aspects of AD pathogenesis and progression. Our study may also provide a theoretical breakthrough for AD therapy and highlight the important hub roles of APP and making previously neglected N-terminal APP as a potential target for the discovery of novel disease-modifying therapeutic agents against AD, holding significant scientific values and clinical promise.


STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression

November 2024

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10 Reads

Communications Biology

Paclitaxel (PTX) is a first-line drug for ovarian cancer (OC) treatment. However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear. Genes and proteins levels were evaluated by RT-qPCR, western blot and IHC. Cell viability and proliferation were measured by CCK-8 and clone formation. The changes of mitochondrial morphology were observed under a transmission electron microscope (TEM). Reactive oxygen species (ROS), iron, malondialdehyde (MDA) and glutathione (GSH) were measured using suitable kits. The interactions among STUB1, HOXB3 and PARK7 were validated using Co-IP, and dual luciferase reporter assay. Our study found that STUB1 was decreased and PARK7 was increased in tumor tissue, especially from chemotherapy resistant ovarian cancer tissue and resistant OC cells. STUB1 overexpression or PARK7 silencing suppressed cell growth and promoted ferroptosis in PTX-resistant OC cells, which was reversed by HOXB3 overexpression. Mechanistically, STUB1 mediated ubiquitination of HOXB3 to inhibit HOXB3 expression, and HOXB3 promoted the transcription of PARK7 by binding to the promoter region of PARK7. Furthermore, STUB1 overexpression or PARK7 silencing suppressed tumor formation in nude mice. In short, STUB1 promoted ferroptosis through regulating HOXB3/PARK7 axis, thereby suppressing chemotherapy resistance in OC.


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CCR4a promotes metastasis and invasion of ovarian cancer by downregulating LRRC4 via PI3K/AKT Signaling Pathway Activation

October 2024

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5 Reads

Background It has been established that CCR4-NOT transcription complex subunit 6 (CCR4a) can promote the growth of some malignancies. Its role and clinical significance in ovarian cancer, however, have not been documented. This article examined the spread of cancer following CCR4a modulation. Methods Bioinformatics was used to analyze the prognosis of CCR4a using the KM plot dataset. The CCR4a protein was identified by immunohistochemistry investigation in ovarian cancer tissues. Cellular responses were noted following both up-and-down-regulation of CCR4a. The mechanism was validated using Western blotting and RNA sequencing. Results Ovarian cancer metastases were positively correlated with CCR4a expression, and a shorter survival period was linked to higher expression. In contrast, down-regulation of CCR4a inhibits LRRC4 (leucine-rich repeat containing 4), which in turn activates the PI3K/AKT signaling pathway, which in turn promotes cell invasion and migration. In vivo, CCR4a up-regulation increased carcinogenic potential while down-regulation reduced it. Conclusions In ovarian cancer tissues, high CCR4a expression suggested reduced survival. In ovarian cancer cells, CCR4a facilitated migration and invasion by downregulating LRRC4 through the stimulation of PI3K/AKT signaling. It may be a useful target for prognostic and diagnostic purposes.


Figure 1. IsoLiPro markedly reduces levels of total and phosphorylated tau in cultured cells overexpressing wild-type full-length human tau.
Figure 7. IsoLiPro ameliorates spatial memory impairment in 3xTg-AD mice. (A, B) Schematic representations of the Morris water maze (MWM) training (A) and Y-maze blocked arm assessment (B). (C) Quantification analysis of the time taken to locate the hidden platform during the training, complemented by swim speed (m/s for 1 min) in 3xTg-AD mice. Data were represented as means ± SEM (n = 5 to 8 mice per group). P values were calculated using a two-tailed t-test, with comparisons made against the 3xTg-AD mice/ddH 2 O. (D) Statistical assessment of the time spent and distance traveled in the novel arm of the Y-maze by 3xTg-AD mice. Data were represented as means ± SEM (n = 5 to 8 mice per group). P values were calculated using one-way ANOVA followed by Tukey's HSD test, with comparisons made against the 3xTg-AD mice/ddH 2 O. Source data are available online for this figure.
Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice

October 2024

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14 Reads

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1 Citation

EMBO Molecular Medicine

Alzheimer’s Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients’ cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.




Eukaryotic Initiation Factor 3C Can Affect the Proliferation and Invasion of Ovarian Cancer by Regulating the p53 Signalling Pathway

April 2024

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3 Reads

Recent Patents on Anti-Cancer Drug Discovery

Background Eukaryotic Initiation Factor 3C (EIF3C) represents a pivotal translational initiation factor in eukaryotes and has been shown to facilitate the progression of various neoplasms. However, its mechanistic role in ovarian cancer remains elusive. Methods In this research, the expression of EIF3C in ovarian cancer tissues was investigated using immunohistochemistry. In addition, the assessments were made on changes in cellular proliferation, invasion, and apoptotic abilities by reducing the expression of EIF3C in ovarian cancer cells. By utilizing microarray analysis, a comparison was performed between the downregulated EIF3C group and the control group of ovarian cancer cells, revealing the genes that were expressed differently. Furthermore, the signalling pathways associated with cellular proliferation were validated. The functional role of EIF3C in vivo was investigated using a xenograft tumour model. Results The immunohistochemical analysis showed that elevated levels of EIF3C are linked to a negative prognosis in patients with ovarian cancer. Suppression of EIF3C greatly hindered the growth and spread of SK-OV-3 and HO-8910 cells while enhancing cellular programmed cell death. Following KEGG and GSEA enrichment analyses of differentially expressed genes, the p53 signalling pathway was found to be associated with EIF3C. Suppression of EIF3C resulted in the upregulation of the p53 signalling pathway, leading to the inhibition of cell proliferation and invasion and the promotion of apoptosis. In vivo experiments demonstrated that EIF3C knockdown suppressed the growth of subcutaneous tumours in nude mice. Conclusion There is a correlation between overexpression of EIF3C in tumour tissues of ovarian cancer patients and this is associated with a poorer prognosis. By influencing the p53 signaling pathway, EIF3C facilitates the growth and infiltration of cells in ovarian cancer.


Citations (17)


... Estradiol stimulates USP11 expression, which in turn enhances the transcriptional activity of estrogen receptor alpha, correlating with poorer prognosis in breast cancer [15]. Furthermore, USP11 contributes to an increased risk of Alzheimer's disease in females by stabilizing tau protein, and inhibiting USP11 has been shown to slow disease progression [25,26]. In this study, we identified two potential inhibitors targeting the functional domain of USP11, which effectively promote the ubiquitination and degradation of TPIT, thereby suppressing ACTH secretion. ...

Reference:

X-linked ubiquitin-specific peptidase 11 (USP11) increases susceptibility to Cushing’s disease in women
Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice

EMBO Molecular Medicine

... Following established protocols (Liu et al., 2024), mice in the P_T and P_AT groups underwent intraperitoneal injection of cyclophosphamide (MCE, USA) to induce ovarian dysfunction. Specifically, on the first day of modelling, these mice received an initial dose of 100 mg/kg cyclophosphamide, followed by daily injections of 8 mg/kg for 14 consecutive days. ...

Pyrroloquinoline quinone promotes human mesenchymal stem cell-derived mitochondria to improve premature ovarian insufficiency in mice through the SIRT1/ATM/p53 pathway

Stem Cell Research & Therapy

... For patients with advanced CRC, adjuvant chemotherapy involving fluorouracil-and platinum-based agents is the recommended standard of care according to various treatment guidelines. However, the effectiveness of conventional chemotherapy in advanced CRC is limited, with chemoresistance being a marked factor leading to poor patient outcomes [3][4][5][6]. Chemoresistance often results from a complex combination of factors, including reduced intracellular drug accumulation, increased activity of detoxification systems, enhanced DNA damage repair mechanisms and inhibition of cell death-promoting pathways [7][8][9][10]. Among these, abnormal apoptosis refers to the ability of chemotherapeutic drugs to inhibit tumor growth by inducing apoptosis in tumor cells. ...

Circ_0078607 increases platinum drug sensitivity via miR-196b-5p/GAS7 axis in ovarian cancer

... Alzheimer's disease (AD) is a degenerative disease of the central nervous system that seriously endangers the physical and mental health of the elderly. The main pathological changes of AD include senile plaques formed by amyloid β-protein deposition, over phosphorylation of Tau protein, neurofibrillary tangles, neuronal apoptosis, and inflammatory response [1,2]. Age-related macular degeneration (AMD) is one of the important age-related blindness eye diseases. ...

APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology

Cellular and Molecular Life Sciences

... Снижение уровня экспрессии hsa_circ_0084927 уменьшало рост опухоли in vivo и вызывало остановку клеточного цикла, апоптоз, подавляло образование колоний, пролиферацию, инвазию и опухолевых миграцию клеток in vitro. В другой работе было продемонстрировано, что hsa_circ_0002762 был высоко экспрессирован в тканях и клетках РШМ [23]. Инактивация hsa_circ_0002762 уменьшала пролиферацию, миграцию и инвазию опухолевых клеток. ...

The circCDK17/miR-122-5p/ASF1B axis regulates the progression of cervical cancer
  • Citing Article
  • September 2022

Histology and Histopathology

... Adding to this complexity, renal cell carcinoma demonstrates a negative correlation between ANGPTL3 levels and patient survival, suggesting a tumor-suppressive role where its overexpression impedes cancer cell proliferation and spread [13,14]. This contradictory behavior underscores the multifaceted nature of ANGPTL3 in cancer biology and its potential influences on the PI3K-AKT-mTOR pathway, a pivotal modulator of cell growth and a contributor to chemoresistance [15,16]. Intriguingly, recent findings by Wu et al. [17] hint at ANGPTL3 functioning as a tumor suppressor in OC, with elevated levels enhancing vulnerability to immune-mediated destruction. ...

CXCR4 knockdown enhances sensitivity of paclitaxel via the PI3K/Akt/mTOR pathway in ovarian carcinoma

Aging

... In exceptional cases, a myomectomy can be performed during pregnancy (25). Considering leiomyoma refractive to conservative management, the laparoscopic approach has been associated with favorable outcomes and reduced complication rates (26). ...

Title: Critical Steps to Performing a Successful Single Site Laparoscopic Myomectomy during Pregnancy

Journal of Minimally Invasive Gynecology

... SARS-CoV-2 pseudovirus has been extensively used to assess the binding affinity of the spike protein for various types of cells expressing SARS-CoV-2related receptors, especially ACE2. 48,49 To assess whether SARS-CoV-2 binds to islets via ACE2 and whether FGF7 influences the binding rate, SARS-CoV-2 pseudo-virus was incubated with purified β cells. It is not surprising that the majority of cells permissive to pseudo-virus (green) infection were also co-stained with ACE2 (red, Fig. 4k). ...

Inhibition of SARS-CoV-2 pseudovirus invasion by ACE2 protecting and Spike neutralizing peptides: An alternative approach to COVID19 prevention and therapy

International Journal of Biological Sciences

... 60 Involved in skeletal development regulation, ZEB1, a zinc finger homeodomain-containing transcriptional repressor, suppresses E-cadherin transcriptional activity in various cancers. [61][62][63][64][65] An in vitro investigation demonstrated that PC3 cell subpopulations that had acquired the ability for transendothelial migration showed elevated ZEB1 alongside diminished E-cadherin levels ( Figure 2), contrasting with their parental cell lines. Research indicates that as prostate cancer progresses, ZEB1 plays a crucial role in governing the vascular extravasation of cancer cells and is a key mediator of EMT. ...

Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT

Journal of Experimental & Clinical Cancer Research

... B. Highly recommended, and C. Optional) before, during, and after surgery ( (Table S1), it can be concluded that careful preoperative history collection and strict gynecologic examination can provide important clues for screening for surgical contraindications. [43][44][45] In addition, preoperative transvaginal ultrasound assessment of the "sliding sign" is consistent with the auxiliary examination recommended by Zhang et al. 27 The last line of defense is to pull the vaginal wall back and forth at the posterior fornix before the incision. ...

Vaginal hysterectomy combined with transvaginal natural orifice transluminal endoscopic surgery bilateral adnexectomy: a case report