Publications by authors named "Xinghan Wu"

11 Publications

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NAMPT reduction-induced NAD insufficiency contributes to the compromised oocyte quality from obese mice.

Aging Cell 2021 11 18;20(11):e13496. Epub 2021 Oct 18.

College of Animal Science & Technology, Nanjing Agricultural University, Nanjing, China.

Maternal obesity is associated with multiple adverse reproductive outcomes, whereas the underlying molecular mechanisms are still not fully understood. Here, we found the reduced nicotinamide phosphoribosyl transferase (NAMPT) expression and lowered nicotinamide adenine dinucleotide (NAD ) content in oocytes from obese mice. Next, by performing morpholino knockdown assay and pharmacological inhibition, we revealed that NAMPT deficiency not only severely disrupts maturational progression and meiotic apparatus, but also induces the metabolic dysfunction in oocytes. Furthermore, overexpression analysis demonstrated that NAMPT insufficiency induced NAD loss contributes to the compromised developmental potential of oocytes and early embryos from obese mice. Importantly, in vitro supplement and in vivo administration of nicotinic acid (NA) was able to ameliorate the obesity-associated meiotic defects and oxidative stress in oocytes. Our results indicate a role of NAMPT in modulating oocyte meiosis and metabolism, and uncover the beneficial effects of NA treatment on oocyte quality from obese mice.
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http://dx.doi.org/10.1111/acel.13496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590097PMC
November 2021

Selective thermotherapy of tumor by self-regulating photothermal conversion system.

J Colloid Interface Sci 2022 Jan 30;605:752-765. Epub 2021 Jul 30.

College of Pharmacy, Weifang Medical University, Weifang 261053, China; Collaborative Innovation Center for Target Drug Delivery System, Weifang Medical University, Weifang 261053, China; Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang 261053, China. Electronic address:

One major challenge of photothermal therapy (PTT) is achieving thermal ablation of the tumor without damaging the normal cells and tissues. Here, we designed a self-regulating photothermal conversion system for selective thermotherapy based on self-assembling gold nanoparticles (S-AuNPs) and investigated the selectivity effect using a novel home-made in vitro selective photothermal transformation model and an in vivo skin damaging assessment model. In the in vitro selective photothermal transformation model, laser irradiation selectively increased the temperature of the internal microenvironment (pH 5.5) and resulted in an obvious temperature difference (ΔT ≥ 5 °C) with that of the external environment (pH 7.4). More importantly, in the in vivo skin damaging assessment model, S-AuNPs achieved good tumor inhibition without damaging the normal skin tissue compared with the conventional photothermal material. This work provides not only a novel validation protocol for tumor thermotherapy to achieve the biosafety of specifically killing tumor cells and normal tissue but also an evaluation methodology for other precise therapy for cancers.
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http://dx.doi.org/10.1016/j.jcis.2021.07.134DOI Listing
January 2022

Dual Modal Imaging-Guided Drug Delivery System for Combined Chemo-Photothermal Melanoma Therapy.

Int J Nanomedicine 2021 18;16:3457-3472. Epub 2021 May 18.

Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang, 261053, People's Republic of China.

Purpose: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate. Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease. In this study, we fabricated a multifunctional drug delivery system that incorporates dacarbazine (DTIC) and indocyanine green (ICG) into manganese-doped mesoporous silica nanoparticles (MSN(Mn)) coupled with magnetic resonance imaging (MRI) and photothermal imaging (PI), for achieving the superior antitumor effect of combined chemo-photothermal therapy.

Materials And Methods: MSN(Mn) were characterized in terms of size and structural properties, and drug loading and release efficiency MSN(Mn)-ICG/DTIC were analyzed by UV spectra. Photothermal imaging effect and MR imaging effect of MSN(Mn)-ICG/DTIC were detected by thermal imaging system and 3.0 T MRI scanner, respectively. Then, the combined chemo-phototherapy was verified in vitro and in vivo by morphological evaluation, ultrasonic and pathological evaluation.

Results: The as-synthesized MSN(Mn) were characterized as mesoporous spherical nanoparticles with 125.57±5.96 nm. MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25±2.20% and 50.00±3.24%, and 32.68±2.10% of DTIC was released, respectively. Manganese doping content could reach up to 65.09±2.55 wt%, providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 mMs. And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells. Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro.

Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.
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http://dx.doi.org/10.2147/IJN.S306269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144848PMC
June 2021

Fe(II) and Tannic Acid-Cloaked MOF as Carrier of Artemisinin for Supply of Ferrous Ions to Enhance Treatment of Triple-Negative Breast Cancer.

Nanoscale Res Lett 2021 Feb 23;16(1):37. Epub 2021 Feb 23.

College of Pharmacology, Weifang Medical University, Weifang, 261053, China.

Suppression of tumor development by inducing ferroptosis may provide a potential remedy for triple-negative breast cancer, which is sensitive to intracellular oxidative imbalance. Recently, artemisinin (ART) and its derivatives have been investigated as potential anticancer agents for the treatment of highly aggressive cancers via the induction of ferroptosis by iron-mediated cleavage of the endoperoxide bridge. Owing to its poor water solubility and limited intracellular iron content, it is challenging for further application in antitumor therapy. Herein, we developed ferrous-supply nano-carrier for ART based on tannic acid (TA) and ferrous ion (Fe(II)) coated on the zeolitic imidazolate framework-8 (ZIF) with ART encapsulated (TA-Fe/[email protected]) via coordination-driven self-assembly. Drug release experiments showed that ART was not nearly released in pH 7.4, while 59% ART was released in pH 5.0 after 10 h, demonstrating the excellent pH-triggered release. Meanwhile, a high level of intracellular ROS and MDA, accompanied with decreasing GSH and GPX4, displayed a newly developed nano-drug system displayed markedly enhanced ferroptosis. Compared with monotherapy, in vitro and vivo tumor inhibition experiments demonstrated higher efficiency of tumor suppression of TA-Fe/[email protected] This work provides a novel approach to enhance the potency of ferroptotic nano-medicine and new directions for TBNC therapy.
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http://dx.doi.org/10.1186/s11671-021-03497-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902752PMC
February 2021

MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells.

Cell Death Dis 2020 09 14;11(9):751. Epub 2020 Sep 14.

Department of Pathology, Weifang Medical University, Weifang, Shandong Province, 261014, China.

Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/[email protected] (E/[email protected]) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/[email protected] had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.
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http://dx.doi.org/10.1038/s41419-020-02939-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490417PMC
September 2020

Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer.

Mol Cell Biochem 2020 Oct 8;473(1-2):217-228. Epub 2020 Jul 8.

Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China.

Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.
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http://dx.doi.org/10.1007/s11010-020-03821-8DOI Listing
October 2020

Melatonin ameliorates the advanced maternal age-associated meiotic defects in oocytes through the SIRT2-dependent H4K16 deacetylation pathway.

Aging (Albany NY) 2020 01 24;12(2):1610-1623. Epub 2020 Jan 24.

State Key Laboratory of Reproductive Medicine, Suzhou Municipal Hospital, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.

It has been widely reported that advanced maternal age impairs oocyte quality. To date, various molecules have been discovered to be involved in this process. However, prevention of fertility issues associated with maternal age is still a challenge. In the present study, we find that both supplement and administration of melatonin are capable of alleviating the meiotic phenotypes of aged oocytes, specifically the spindle/chromosome disorganization and aneuploidy generation. Furthermore, we identify SIRT2 as a critical effector mediating the effects of melatonin on meiotic structure in old oocytes. Candidate screening shows that SIRT2-controlled deacetylation of histone H4K16 is essential for maintaining the meiotic apparatus in oocytes. Importantly, non-acetylatable-mimetic mutant H4K16R partially rescues the meiotic deficits in oocytes from reproductive aged mice. In contrast, overexpression of acetylation-mimetic mutant H4K16Q abolishes the beneficial effects of melatonin on the meiotic phenotypes in aged oocytes. To sum up, our data uncover that melatonin alleviates advanced maternal aged-associated meiotic defects in oocytes through the SIRT2-depenendet H4K16 deacetylation pathway.
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http://dx.doi.org/10.18632/aging.102703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053624PMC
January 2020

The impact mechanism of the controlling system in hospitals on quality of care: A study on clinical practice in China.

Technol Health Care 2020 ;28(2):155-163

Background: Quality control system is one of the hospital information systems. The adoption of quality control system increases the work efficiency; however, to some extent, it also increases the workload for physicians.

Objective: The purpose of this study is to investigate the impacts of the quality control system on quality of care (e.g., process and outcome performance).

Methods: Our study collected physicians' behavior information from a large urban hospital in China. We constructed the fixed-effect model to examine the relationship between the quality control system adoption and quality of care.

Results: Using the quality control system has a significant (p< 0.001) and negative effect on patients' stay length in the hospital (process performance). Furthermore, using the quality control system has a significant (p< 0.001) and positive effect on the trends of cure rate in the hospital (outcome performance). The coefficient of the dependent variable from the patients' stay length (process performance) is lower than the trends of cure rate (outcome performance).

Conclusions: The controlling system can improve medical quality even though it limits physician behavior to some extent. The controlling system improves both the process performance and outcome performance, and it brings more benefits to outcome performance rather than process performance which means the reflection of the new technology may have more evident on outcome variables.
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http://dx.doi.org/10.3233/THC-191596DOI Listing
January 2021

NMNAT2-mediated NAD generation is essential for quality control of aged oocytes.

Aging Cell 2019 06 25;18(3):e12955. Epub 2019 Mar 25.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Advanced maternal age has been reported to impair oocyte quality; however, the underlying mechanisms remain to be explored. In the present study, we identified the lowered NAD content and decreased expression of NMNAT2 protein in oocytes from old mice. Specific depletion of NMNAT2 in mouse oocytes disturbs the meiotic apparatus assembly and metabolic activity. Of note, nicotinic acid supplementation during in vitro culture or forced expression of NMNAT2 in aged oocytes was capable of reducing the reactive oxygen species (ROS) production and incidence of spindle/chromosome defects. Moreover, we revealed that activation or overexpression of SIRT1 not only partly prevents the deficient phenotypes of aged oocytes but also ameliorates the meiotic anomalies and oxidative stress in NMNAT2-depleted oocytes. To sum up, our data indicate a role for NMNAT2 in controlling redox homeostasis during oocyte maturation and uncover that NMNAT2- NAD -SIRT1 is an important pathway mediating the effects of maternal age on oocyte developmental competence.
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http://dx.doi.org/10.1111/acel.12955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516161PMC
June 2019

The Efficacy of Mobile Phone Apps for Lifestyle Modification in Diabetes: Systematic Review and Meta-Analysis.

JMIR Mhealth Uhealth 2019 01 15;7(1):e12297. Epub 2019 Jan 15.

Department of Statistics, University of California at Riverside, Riverside, CA, United States.

Background: Diabetes and related complications are estimated to cost US $727 billion worldwide annually. Type 1 diabetes, type 2 diabetes, and gestational diabetes are three subtypes of diabetes that share the same behavioral risk factors. Efforts in lifestyle modification, such as daily physical activity and healthy diets, can reduce the risk of prediabetes, improve the health levels of people with diabetes, and prevent complications. Lifestyle modification is commonly performed in a face-to-face interaction, which can prove costly. Mobile phone apps provide a more accessible platform for lifestyle modification in diabetes.

Objective: This review aimed to summarize and synthesize the clinical evidence of the efficacy of mobile phone apps for lifestyle modification in different subtypes of diabetes.

Methods: In June 2018, we conducted a literature search in 5 databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and PsycINFO). We evaluated the studies that passed screening using The Cochrane Collaboration's risk of bias tool. We conducted a meta-analysis for each subtype on the mean difference (between intervention and control groups) at the posttreatment glycated hemoglobin (HbA) level. Where possible, we analyzed subgroups for short-term (3-6 months) and long-term (9-12 months) studies. Heterogeneity was assessed using the I statistic.

Results: We identified total of 2669 articles through database searching. After the screening, we included 26 articles (23 studies) in the systematic review, of which 18 studies (5 type 1 diabetes, 11 type 2 diabetes, and 2 prediabetes studies) were eligible for meta-analysis. For type 1 diabetes, the overall effect on HbA was statistically insignificant (P=.46) with acceptable heterogeneity (I=39%) in the short-term subgroup (4 studies) and significant heterogeneity between the short-term and long-term subgroups (I=64%). Regarding type 2 diabetes, the overall effect on HbA was statistically significant (P<.01) in both subgroups, and when the 2 subgroups were combined, there was virtually no heterogeneity within and between the subgroups (I range 0%-2%). The effect remained statistically significant (P<.01) after adjusting for publication bias using the trim and fill method. For the prediabetes condition, the overall effect on HbA was statistically insignificant (P=.67) with a large heterogeneity (I=65%) between the 2 studies.

Conclusions: There is strong evidence for the efficacy of mobile phone apps for lifestyle modification in type 2 diabetes. The evidence is inconclusive for the other diabetes subtypes.
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http://dx.doi.org/10.2196/12297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350094PMC
January 2019

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation.

Aging Cell 2018 08 29;17(4):e12789. Epub 2018 May 29.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

SIRT4 modulates energy homeostasis in multiple cell types and tissues. However, its role in meiotic oocytes remains unknown. Here, we report that mouse oocytes overexpressing SIRT4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization. Moreover, we find that phosphorylation of Ser293-PDHE1α mediates the effects of SIRT4 overexpression on metabolic activity and meiotic events in oocytes by performing functional rescue experiments. By chance, we discover the SIRT4 upregulation in oocytes from aged mice; and importantly, the maternal age-associated deficient phenotypes in oocytes can be partly rescued through the knockdown of SIRT4. These findings reveal the critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and indicate that SIRT4 is an essential factor determining oocyte quality.
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http://dx.doi.org/10.1111/acel.12789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052465PMC
August 2018
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