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01 December 2023, Volume 35 Issue 179

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  • Jeffrey Okojie, Sarah McCollum, Jared Barrott
    Discovery Medicine. 2023, 35(179): 921-927.
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    The field of oncology is continuously seeking to find effective treatment therapies with limited side effects. Antibody-drug conjugates (ADCs) are a promising class of cancer therapies that have been shown to be effective with limited side effects. Although promising, these therapies experience shortcomings, such as the stability and reproducibility of current conjugation methods. Historically, ADCs have been produced by stochastic conjugation methods; however, new methods of site-specific conjugation have evolved to mitigate current ADC shortcomings. In this article, we highlight the success of ADCs as well as some of their challenges. We also highlight the shortcomings of stochastic conjugation and explore the various site-specific conjugation methods and their advantages over stochastic conjugation.

  • Kush Gupta, Aymen Elfiky, Eshan Patel
    Discovery Medicine. 2023, 35(179): 928-935.
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    Neoadjuvant chemotherapy (NAC) has long been considered technically difficult in locally advanced colon cancer (LACC). However, the introduction of oxaliplatin-based regimens led to a growing interest in NAC for patients with LACC. Several cohort studies showed that NAC was safe and reduced the rate of incomplete resection in patients with LACC. This was followed by the pivotal phase III FOxTROT trials, which showed significant benefits of NAC in this population. However, in patients with deficient mismatch repair (dMMR), the response to a neoadjuvant fluoropyrimidine regimen may be poor, limiting the benefit of NAC in this subset of patients. Neoadjuvant immunotherapy is a potential alternative for NAC in LACC patients with dMMR. In this concise review, we present the published clinical evidence evaluating the efficacy and safety of NAC and/or neoadjuvant immunotherapy in patients with LACC. Overall, the evidence suggests that NAC can be associated with significant downstaging and tumor regression, which facilitate surgical resection. However, the impact of NAC on long-term survival is still under investigation. Despite the promising results of NAC in LACC, several concerns still exist that necessitate further evidence. On the other hand, LACC patients with dMMR can benefit from neoadjuvant immunotherapy; however, further trials are still needed to confirm its effectiveness, as well as biomarkers that can predict response.

  • Article
  • Xia Liu, Xinyun Liu, Chaoshi Zhuo, Jiangfeng Shen, Kaijin Lu, Min Sha, Jun Ye, Junxing Huang, Hexu Han, Hong Yu
    Discovery Medicine. 2023, 35(179): 936-945.
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    Background: NAT10 (N-acetyltransferase 10) is a newly identified novel acetyltransferase. Abnormal expression of NAT10 is associated with several human disorders, including cancer, autoimmune diseases, and cardiovascular disease. This study aimed to investigate the role of NAT10 in promoting lung cancer malignant progression through the NF-κB (nuclear factor κB) signaling pathway.

    Methods: Cells lines BEAS-2B, NCI-H524, A549, PC-9, NCI-H23, and NCI-H258 were cultured for identification. Western blotting and PCR assays determined gene expression within the sample cells. Cellular functionality was assayed using CCK8 (Cell Counting Kit-8), Dual-Luciferase Reporter, and Colony formating.

    Results: The PCR assay and Western blotting showed a significant elevation of NAT10 levels within tumor tissues compared to paraneoplastic tissues (p < 0.05). Specifically, NAT10 only affected the expression and content of RelA/p65 in lung cancer. Analysis from the TCGA (The Cancer Genome Atlas) database indicated that elevated expression levels of NAT10 in tumors can be a good prognostic indicator for lung cancer patients. The CCK8 assay showed that the knockdown of NAT10 significantly suppressed the A549 cells' progression rate (p < 0.05). The colony formation assays further confirmed that the overexpression of NAT10 significantly increased the generation of clones in the NCI-H524 cells (p < 0.05). The proliferation rate influenced by the overexpression of NAT10 was inhibited by blocking the NF-κB signaling pathway (p < 0.05). Dual-luciferase reporter gene assay results revealed NAT10's potential in promoting the NF-κB signaling pathway's activity in lung cancer. Immunohistochemical staining underscored a strong link between NAT10 protein expression and the NF-κB signaling pathway in lung cancer tissues.

    Conclusions: NAT10's expression is significantly upregulated in tumor tissues, supported by PCR results. NAT10 plays a role in the development and proliferation of lung cancer cells and can activate the NF-κB signaling pathway in lung cancer. Hence, NAT10's regulation of the NF-κB signaling pathway is critical in the malignant proliferation of lung cancer.

  • Xingdong Chen, Juan Chen, Yi Ren, Mengmeng Wang, Zhizhou Yang, Wei Zhang, Quan Li, Chao Liu, Zhaorui Sun, Shinan Nie
    Discovery Medicine. 2023, 35(179): 946-955.
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    Background: The dysregulation between pro-inflammatory and anti-inflammatory responses during sepsis is a crucial factor in driving sepsis progression. Acute lung injury (ALI) resulting from excessive production and accumulation of inflammatory mediators in the lungs contributes to impaired lung barrier function. The activation of the NF-κB signaling pathway during inflammation leads to the transcriptional activation of multiple inflammatory genes. Given the plausible impact of NF-κB signaling suppression in mitigating lung injury, substantive evidence demonstrates beta-sitosterol (BS)'s proficient ability to block NF-κB activation. Therefore, the aim of the present investigation was to delve into the impacts of BS in the context of sepsis-induced acute lung injury, employing both a mouse model and a model involving lung epithelial cells.

    Methods: Sepsis-induced lung injury was simulated in mice through cecum ligation and puncture (CLP). To emulate injury in murine lung epithelial (MLE-12) cells, an experiment involving lipopolysaccharide (LPS) was administered. Evaluation of alterations in lung tissue permeability encompassed techniques such as lung wet/dry (W/D) mass ratio, Evans blue staining, and quantification of total protein concentration in bronchoalveolar lavage fluid (BALF). Lung tissue histopathological shifts were ascertained via hematoxylin and eosin (HE) staining. Additionally, the concentrations of inflammatory cytokines IL-6 and TNF-α were quantified in every lung tissue and cell group by implementing enzyme-linked immunosorbent assay (ELISA). Protein quantification for signal biomarkers was carried out using Western blotting and immunofluorescence methodologies. In tandem, the assessment of MLE-12 cell permeability was conducted by evaluating fluorescein isothiocyanate (FITC)-dextran extravasation.

    Results: BS mitigated lung tissue pathologies, reduced inflammatory factors, and lowered tissue and cell permeability. BS inhibited NF-κB signaling and increased claudin-4 and claudin-5 expression, enhancing septic lung epithelial cell permeability.

    Conclusions: Through suppressing the NF-κB signaling cascade, BS effectively curtails the levels of inflammatory mediators. Simultaneously, it orchestrates the modulation of claudin-4 and claudin-5 expression, culminating in the augmentation of lung epithelial cell barrier competence, thus improving sepsis-induced lung injury.

  • Wei Liu, Fang Luo, Hongwei Wu, Huimin Li, Guangchao Bai
    Discovery Medicine. 2023, 35(179): 956-964.
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    Background: Addressing spinal cord injury (SCI) through stem cell therapy is currently at the forefront of medical research despite its complexity. In this study, we investigated the potential of the Noggin protein in promoting the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) into neuronal cells. We transplanted induced cells into a rat model with spinal cord injury. This exploration proposes an innovative perspective on stem cell therapies for spinal cord injuries.

    Methods: Rat BMSCs were isolated utilizing the bone marrow cell apposition method; The multidirectional differentiation of rat BMSCs was identified by lipid induction and osteogenic induction; Rat BMSCs were induced by different concentrations of Noggin protein and different induction times; Nissel staining was used to identify the induced neuronal-like cells; The expression of synaptic protein Ⅰ (SYN1), glial fibrillary acidic protein (GFAP), and neurofilament protein 200 (NF200) in neuron-like cells was detected by immunofluorescence assay. Rats were randomly divided into a control group and a neuron-like cell group; A rat spinal cord injury model was produced, and neuron-like cells obtained from induction were transplanted into the rat's SCI. The recovery of the rats' hind limbs' motor function was detected by the Basso, Beattie, and Bresnahan (BBB) scores, and the changes in the expression of NF200 mRNA at the spinal cord injury were detected by quantitative real time polymerase chain reaction (qRT-PCR).

    Results: Our cultured rat BMSCs had a long spindle-shaped morphology and stained positively for oil red O after lipogenic induction and modified alizarin red S after osteogenic induction. Nissel staining of cells obtained from rat BMSCs induced by Noggin protein was positive. Immunofluorescence results showed that the induced neuronal-like cells positively expressed NF200 and SYN1, and negatively expressed GFAP. After local transplantation of induced neuronal-like cells in the rat SCI model, the BBB scores in the neuron-like cell group were higher than those in the control group at 1 w, 2 w, and 4 w, with statistically different results (p < 0.05). According to qRT-PCR results, NF200 at the spinal cord injury in the neuron-like cell group was higher than that in the control group at 12 h, 3 d, 1 w, 2 w, and 4 w, with statistically significant differences in results (p < 0.05).

    Conclusions: Our findings indicate that Noggin protein effectively facilitates the differentiation of rat BMSCs into neuronal cells, highlighting its potential as a therapeutic agent for repairing spinal cord injuries. This study elucidates a promising avenue in stem cell research, contributing a novel approach to regenerative strategies for spinal cord injuries.

  • Mengzhe Zhang, Zengtuan Xiao, Chen Chen, Guiyue Wang, Xiaofei Wang, Yunqi Jia, Yiqing Yin, Zhenfa Zhang
    Discovery Medicine. 2023, 35(179): 965-974.
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    Background: Lung isolation and separation is still controversial in thoracic surgery. Preferences of the surgeon can drive the decision to use single- vs. double-lumen endotracheal intubation. We aimed to compare complications and quality of life (QOL) after radical lung cancer resection with a single-lumen tube (ST) and a double-lumen tube (DT) for patients with non-small cell lung cancer (NSCLC).

    Methods: A total of 309 patients who underwent radical lung cancer resection with video-assisted thoracoscopy-lobectomy were subsequently included in the study. Based on the type of endotracheal intubation tube used during surgery, we divided all the patients into a single-lumen tube group (ST-G) and double-lumen tube group (DT-G). Then, we applied propensity score matching (1:1) to balance the baseline characteristics between the two groups. The Analysis of Variance (ANOVA) of two-factor repeated measures data was performed to compare postoperative complications at three and six months after surgery and postsurgical QOL at baseline at one month, three months, six months, and twelve months.

    Results: Within three months after surgery, patients in the ST-G presented less cough symptoms in Lung Cancer Symptom Scale (LCSS), lower cough symptom scores (CSS) (one month and three months, p < 0.05) and better performance of Leicester Cough Questionnaire (LCQ) scores in physical part (one month, three months and six months, p < 0.05) with better overall QOL (one month and three months, p < 0.05) than those in the DT-G.

    Conclusions: Patients with STs displayed less postoperative cough symptoms and higher overall QOL than those with DTs. Although DT is the gold standard for thoracic surgeries, we suggest that postoperative cough symptoms should be given sufficient attention by surgeons.

  • Nana Meng, Leizhou Xia, Yiqing Gong, Chunhe Shi, Zhi Zhao
    Discovery Medicine. 2023, 35(179): 975-981.
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    Background: Idiopathic epiretinal membrane (iERM) is a common disorder of the vitreomacular interface characterized by decreased visual acuity and metamorphopsia. This study aimed to analyze the association between the anatomical change of the retina and functional outcomes in iERM patients so as to derive the prognostic factors of visual acuity (VA) and metamorphopsia.

    Methods: Forty-five patients (one eye per patient; 45 eyes in total) who underwent pars plana vitrectomy and membrane peeling for iERM by a single surgeon were enrolled in this retrospective study. The results on best-corrected visual acuity (BCVA) and metamorphopsia as well as retinal images were obtained before the surgery and 1, 3, 6 months after the surgery. The BCVA and retinal microstructure, including central retinal thickness (CRT), ganglion cell layer (GCL) thickness, inner nuclear layer (INL) and outer nuclear layer + outer plexiform layer (ONL+OPL), and continuity of photoreceptor inner/outer segment (IS/OS) junction before and after iERM surgery were compared using paired samples t-test (continuous variables) or Chi-square test (categorical variables). Multiple regression analysis was carried out to explore the association among BCVA, M-score, and the parameters derived from optical coherence tomography.

    Results: Compared with preoperative data, a significant improvement in BCVA was observed 1, 3, and 6 months postoperatively (t = 5.37, p < 0.0001; t = 7.29, p < 0.0001; t = 6.44, p < 0.0001 for 1, 3, and 6 months postoperatively, respectively), whereas the M-score only decreased significantly 3 and 6 months after the surgery (t = 2.36, p = 0.02; t = 5.00, p < 0.0001, respectively). In comparison with the baseline, the CRT, INL, and ONL+OPL thickness showed a significant decrease at each postoperative follow-up time, and GCL thickness (t = 3.86, p = 0.0002) and IS/OS disruption ratio (χ2 = 4.86, p = 0.027) were markedly reduced only 6 months postoperatively. Six-month postoperative BCVA was considerably associated with preoperative CRT and ONL+OPL thickness, as well as postoperative CRT, ONL+OPL thickness, and severity of IS/OS disruption. Moreover, the M-score after surgery was markedly correlated with both the preoperative and postoperative INL and CRT thickness.

    Conclusions: Both VA and M-score in iERM patients were significantly improved after vitrectomy. Pre- and post-operative CRT was significantly associated with both postoperative BCVA and M-score. Besides, pre- and post-operative INL thickness was correlated to postoperative metamorphopsia, and postoperative BCVA was associated with postoperative ONL+OPL thickness and IS/OS integrity.

  • Ningning You, Yandi Lu, Xiaodan Yan, Zhou Jin, Binbin Gu
    Discovery Medicine. 2023, 35(179): 982-987.
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    Background: The Haptoglobin (Hp) genotypes have been linked to immune diseases and play a significant role in metabolic diseases. This study aimed to analyze the correlation between Hp gene polymorphism and the severity of hepatitis B accompanied by liver steatosis.

    Methods: A total of 182 with Hepatitis B and concurrent hepatic steatosis were included in the study. Clinical biochemical indices for each participant were recorded. DNA was extracted from peripheral blood leukocytes for globin genotyping. Of these participants, 128 underwent biopsy from which histological data were collected.

    Results: Subjects with hepatitis B and hepatic steatosis carrying the Hp 2-2 genotype exhibited elevated alanine transaminase (ALT), c-glutamyl transferase (GGT), and aspartate amino transferase (AST) levels. In contrast, high-density lipoprotein (HDL) levels and the copy number of Hepatitis B Virus (HBV)-DNA were significantly reduced in those with the Hp 2-2 genotype (p < 0.05). Furthermore, individuals processing the Hp 2-2 genotype demonstrated a heightened hepatitis score and advanced fibrosis stage (p < 0.05). Notably, the Hp 2-2 genotype was independently associated with increased inflammation (odds ratio (OR) = 7.059, p < 0.001) and progressive fibrosis (OR = 3.05, p < 0.022).

    Conclusions: The Hp 2-2 genotype is significantly associated with increased severity in cases of hepatitis B with coexisting hepatic steatosis.

  • Shu Du, Xun Yang, Youyou Zha, Xing Chen, Jing Zhang, Ferenc Kuhn
    Discovery Medicine. 2023, 35(179): 988-994.
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    Background: This study evaluates the clinical effectiveness of employing direct retinal pigment epithelium (RPE) laser photocoagulation as a technique for achieving chorioretinal adhesion to effectively seal retinal breaks.

    Methods: A total of 20 eyes from 20 patients were enrolled in the study; all selected eyes exhibited either rhegmatogenous or combined rhegmatogenous-tractional retinal detachment. During vitrectomy, direct RPE laser photocoagulation was executed, employing a power range of 100–150 mW and a duration of 120–200 ms, targeting the peripheries where the edges of each retinal break were anticipated to settle post-reattachment. This treated area's neuroretina thickness was compared to measurements obtained after conventional transretinal laser photocoagulation.

    Results: Patients were followed for an average duration of 24 months, with a range of 11–46 months. A visible pigmentary reaction in the ophthalmoscopic examination was evident in the treated regions for all but one eye, where the retinal break was situated amidst myelinated nerve fibers. The study encountered no severe complications, and successful retinal reattachment was achieved in all 20 eyes. The mean best-corrected visual acuity (BCVA) at the final follow-up showed a statistically significant improvement compared to preoperative levels (p < 0.0001). A noteworthy difference in neuroretinal thickness was observed one-month post-surgery between areas treated with direct RPE and those treated with transretinal photocoagulation, measuring 217 μm and 104 μm, respectively.

    Conclusions: Our findings suggest that direct RPE laser photocoagulation is an effective therapeutic intervention for sealing retinal breaks.

  • Jiawen Jiang, Wei Dong, Wen Zhang, Qian Wang, Ruyi Wang, Jiaxu Wang, Hao Wu, Hui Dong, Robert Chunhua Zhao, Jiao Wang, Zhe Li
    Discovery Medicine. 2023, 35(179): 995-1014.
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    Background: Hypoxia is a pivotal factor influencing cellular gene expression and contributing to the malignant progression of tumors. Metabolic anomalies under hypoxic conditions are predominantly mediated by mitochondria. Nonetheless, the exploration of hypoxia-induced long noncoding RNAs (lncRNAs) associated with mitochondria remains largely uncharted.

    Methods: We established hypoxia cell models using primary human hepatocytes (PHH) and hepatocellular carcinoma (HCC) cell lines. We isolated mitochondria for high-throughput sequencing to investigate the roles of candidate lncRNAs in HCC progression. We employed in vitro and in vivo assays to evaluate the functions of solute carrier family 1 member 5 antisense lncRNA (SLC1A5-AS). RNA-seq was utilized to scrutinize the comprehensive genome profile regulated by SLC1A5-AS in HCC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were utilized to validate the expression of alanine-serine-cysteine transporter 2 (ASCT2, encoded by the SLC1A5 gene), and a glutamine uptake assay was employed to estimate the glutamine uptake capacity of Huh-7 cells after SLC1A5-AS overexpression. To delve into the mechanisms governing the regulation of SLC1A5 expression by SLC1A5-AS, we employed a biotin-labeled SLC1A5-AS probe in conjunction with a western blot assay to confirm the interactions between SLC1A5-AS and candidate transcription factors. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were utilized to authenticate the effects of the predicted transcription factors on SLC1A5 promoter activity.

    Results: Following the screening, we identified CTB-147N14.6, derived from the antisense strand of the SLC1A5 gene, which we have named SLC1A5-AS. SLC1A5-AS exhibited significantly elevated expression levels in HCC tissue and was associated with poor prognosis in HCC patients. In vitro and in vivo assays revealed that the overexpression of SLC1A5-AS significantly heightened cell invasion and metastasis. RNA-seq data unveiled SLC1A5-AS involvement in glutamine metabolism, left-handed amino (L-amino) acid transmembrane transporter activity, and the nuclear factor kappa-B (NF-κB) signaling pathway. Overexpression of SLC1A5-AS markedly increased ASCT2 mRNA/protein levels, thereby enhancing glutamine uptake and promoting the growth and metastasis of HCC cells. Mechanistically, higher RNA levels of SLC1A5-AS directly bound with myeloid zinc finger 1 (MZF1), acting as a transcriptional repressor, thus diminishing its binding to the SLC1A5 promoter region.

    Conclusions: Our findings unveil a novel role for the lncRNA SLC1A5-AS in glutamine metabolism, suggesting that targeting SLC1A5-AS/MZF1, in conjunction with ASCT2 inhibitor treatment, could be a potential therapeutic strategy for this disease.

  • Xuan Chen, Guixiu Yin, Yuzhen Xi, Jia Wei, Miao Liu, Haibin Wang
    Discovery Medicine. 2023, 35(179): 1015-1025.
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    Background: This study aims to determine how atherosclerotic plaque prevalence and characteristics vary between individuals residing year-round at middle and high altitudes who have intracranial atherosclerotic disease.

    Methods: We conducted a retrospective analysis of patient data from our hospital, focusing on individuals with cerebrovascular symptoms who underwent high-resolution vessel wall imaging (HR-VWI). Patients who had lived at an altitude of <2500 meters for an extended period were classified in group A (n = 91), while those residing at an altitude of ≥2500 meters were placed in group B (n = 75). We examined the differences in plaque prevalence and characteristics between these two groups.

    Results: The detection rate of basilar artery plaque was higher in group A compared to group B (16% vs. 7.6%, p = 0.036). Conversely, the detection rate of anterior cerebral artery plaque was significantly lower in group A than in group B (4% vs. 11.8%, p = 0.016). The eccentricity index (EI) was greater in group B than in group A (0.72 ± 0.11 vs. 0.68 ± 0.12, p = 0.012). The prevalence of intraplaque hemorrhage (IPH) was lower in group B than in group A (39.5% vs. 58.7%, p = 0.002).

    Conclusions: IPH prevalence was lower in patients residing at high altitudes than in those residing at middle altitudes. However, patients living at high altitudes had a higher EI compared to those residing at middle altitudes. These findings underscore the presence of disparities in the prevalence and characteristics of intracranial atherosclerotic plaques between individuals residing at medium and high altitudes. It is essential to account for these distinctions when diagnosing plaques.

  • Shengchang Su, Tingting Pang, Yunfeng Wang, Jie Chen
    Discovery Medicine. 2023, 35(179): 1026-1034.
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    Background: Severe esophageal stricture decreases patient's quality of life after circumferential endoscopic submucosal dissection (ESD). We aimed to evaluate the efficacy of autologous esophageal epithelial cell suspensions in preventing esophageal stricture after circumferential ESD.

    Methods: Twelve male mini-pigs underwent circumferential ESD and were randomized into four groups: G1 (control), G2 (esophageal stent), G3 (autologous esophageal epithelial cell suspension), and G4 (autologous esophageal epithelial cell suspension combined with esophageal stent). Post-ESD status was observed in each group, and endoscopy was performed weekly. Esophageal stents were removed 3 weeks after ESD. The esophageal stricture rates and histologic characteristics were assessed 4 weeks after ESD.

    Results: G1 showed the greatest weight loss (p < 0.05). Dysphagia scores were not significantly different among the groups. The esophageal mucosal stricture rates were 77.7 ± 2.9%, 74.2 ± 1.9%, 69.2 ± 3.8% and 65.9 ± 1.9% in G1-4, respectively; with the highest in G1 (G1 vs. G3, p = 0.005; G1 vs. G4, p = 0.001). The regenerated epithelium lengths were 4.408 ± 1.980 mm, 8.319 ± 0.857 mm, 11.801 ± 2.455 mm and 12.353 ± 1.111 mm in G1-4, respectively. The lowest degree of re-epithelialization was observed in G1, followed by G2, with the highest degrees in G3 and G4 (G1 vs. G3, p = 0.001; G1 vs. G4, p = 0.000). The maximum wound fibrosis thicknesses were 2.546 ± 0.389 mm, 2.136 ± 0.231 mm, 1.126 ± 0.211 mm and 1.131 ± 0.438 mm in G1-4, respectively, with higher degrees in G1 and G2 than in G3 and G4 (G1 vs. G3, p = 0.001; G1 vs. G4, p = 0.001).

    Conclusions: Autologous esophageal epithelial cell suspensions can promote re-epithelialization and reduce fibrosis, thus decreasing esophageal stricture severity after ESD.

  • Yaping Liu, Xu Liu, Miaosha Luo, Yarui Li, Hongxia Li
    Discovery Medicine. 2023, 35(179): 1035-1042.
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    Background: Approximately 50% of hepatocellular carcinoma (HCC) arises due to the infection by hepatitis B virus X protein (HBx). Sorafenib, a unique targeted oral kinase inhibitor, is the therapeutic agent of choice for advanced HCC. The mechanism of HBx in drug resistance of sorafenib-resistant HCC cells was evaluated in this study.

    Methods: Employing a stepwise increase of the sorafenib content, Hep3B and HepG2 cells were iteratively induced to establish drug-resistant cell lines (Hep3B/R and HepG2/R). The survival rate of Hep3B, Hep3B/R, HepG2, and HepG2/R cells was estimated using the cell counting kit-8 (CCK-8) assay. The IC50 values of sorafenib were calculated, exploring its effects under varying concentrations. The HBx content was quantified via quantitative reverse transcription PCR (RT-qPCR) and Western Blot. HBx overexpression and interfering virus vectors were constructed and transfected into Hep3B/R and HepG2/R cells. Cell viability and metastasis were assessed by colony formation, wound healing, and transwell assays. E-cadherin, N-cadherin, Vimentin, Slug, and Snail content was evaluated via Western Blot.

    Results: HBx content was significantly elevated in Hep3B/R and HepG2/R subgroups compared to Hep3B and HepG2 subgroups. The proliferation, clonogenicity, invasiveness, and migratory abilities of Hep3B/R and HepG2/R cells in the HBx subgroup were markedly enhanced; E-cadherin content was significantly reduced, whereas the content of N-cadherin, Vimentin, Slug, and Snail was significantly elevated in the HBx subgroup. Conversely, in the sh-HBx subgroup, the proliferation, clonogenicity, invasion, and migration of Hep3B/R and HepG2/R cells were significantly reduced, E-cadherin content was markedly increased, and N-cadherin, Vimentin, Slug, and Snail content was significantly reduced, compared to the sh-negative control (NC) subgroup.

    Conclusions: HBx knockout may affect the development of HCC by reducing the proliferation, invasion, and migration of Hep3B/R and HepG2/R cells through the inhibition of Epithelial-Mesenchymal Transition (EMT).

  • Pusong Xie, Shaobo Zhu, Huowang Zhou, Runtao Fang, Jinling Zhuang, Jiefang Wen, Miaoxiong Yang, Jinshui He
    Discovery Medicine. 2023, 35(179): 1043-1051.
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    Background: Rapamycin (RAP), as a Mammalian Target of Rapamycin (mTOR) inhibitor, has a certain antiepileptic effect. The blood-brain barrier (BBB), neuroinflammation, lymphocyte immune cells, and neuronal apoptosis play an obligatory role in the course of a seizure. The aim of this study is to probe whether the antiepileptic mechanism of RAP involves the blood-brain barrier, neuroinflammation, lymphocytes, and neuronal apoptosis.

    Methods: First, we established a rat epilepsy model by injecting lithium chloride and pilocarpine into the rats (intraperitoneal injection). Then the epileptic rats were treated with different doses of RAP (1 mg/kg.d, 2 mg/kg.d, 4 mg/kg.d). Peripheral blood, brain tissue, and temporal lobe tissue were collected. The levels of blood-brain barrier-related proteins and inflammatory cytokines in the peripheral blood of rats were measured by enzyme-linked immunosorbent assay (ELISA). The effect of RAP on T cell subsets in epileptic rats was analyzed by flow cytometry. The apoptosis of neurons and glial cells in the temporal lobe of rats was analyzed by immunohistochemistry.

    Results: This study found that RAP reduces the levels of BBB-interrelated proteins (matrix metallopeptidase 9 (MMP-9), MMP-2, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2) and inflammatory cytokines (interleukin-2 (IL-2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α)) in epileptic rats compared to the model group (p < 0.05). RAP increases the level of total T cells (CD3+CD45+) and T helper cells (CD3+CD4+), decreases the level of cytotoxic T lymphocytes (CD3+CD8+), and inhibits the apoptosis of neurons and glial cells in the temporal lobe compared to the model group (p < 0.05).

    Conclusions: The antiepileptic mechanism of RAP may be to restore BBB dysfunction, reduce the inflammatory response, balance T cell subsets, and inhibit neuronal and glial cell apoptosis in temporal lobe epilepsy lesions.

  • Bijun Wu, Yaolin Yang, Ping Zhao
    Discovery Medicine. 2023, 35(179): 1052-1063.
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    Background: In China, endomyocardial fibrosis (EMF) is a type of restrictive cardiomyopathy that is rare and easy to be misdiagnosed. Our aim was to examine the value of routine echocardiography (RE) combined with contrast-enhanced echocardiography (CEE) in EMF diagnosis.

    Methods: We studied 16 EMF patients retrospectively, from 2012 to 2022. All patients underwent RE, from which 11 underwent CEE. We divided the patients into three groups: biventricular EMF (Bi-EMF), right ventricular EMF (RV-EMF), and left ventricular EMF (LV-EMF) based on different lesion locations. We also analyzed the clinical and conventional ultrasound characteristics of the three groups of patients and examined the ventricle opacification (VO) and myocardial contrast echocardiography (MCE) characteristics of patients who underwent CEE.

    Results: All patients with EMF subtypes had the following ultrasound findings: apical occlusion on one or both sides, corresponding atrial dilatation, atrioventricular valve regurgitation in varying degrees, and cardiac diastolic dysfunction. Of the subjects, 69% had apical thrombus calcification and 81% had mild pericardial effusion. RV-EMF patients had statistically significant right atrial enlargement compared with the other two groups (p < 0.05), moderate or severe tricuspid regurgitation, and inferior vena cava (IVC) dilation. LV-EMF patients had statistically significant left atrial enlargement compared with the other two groups (p < 0.05), elevated pulmonary artery systolic pressure (PASP), and 60% of LV-EMF patients had moderate or severe mitral regurgitation. Bi-EMF patients had bilateral atrial enlargement, an IVC collapsibility index <50%, and elevated PASP. CEE was performed in 11 patients, whose ventricle opacification showed no contrast filling in the apical occluded area and the heart chambers presented the “mushroom sign” during diastole. Their myocardial contrast echocardiography (MCE) showed delayed perfusion in the thickened fibrotic endomyocardium (TFE) of the apical and subvalvular regions and perfusion defect in the apical thrombus. The number and location of thrombus determined by the MCE combined with RE were the same as those detected by cardiac magnetic resonance imaging (CMR). MCE shows that the position and range of TFE are similar to CMR.

    Conclusions: EMF has characteristic RE presentation, and different EMF subtypes have unique characteristics. CEE can better display heart structure, ventricular wall motion, and tissue perfusion compared to RE. A combination of RE and CEE can make the EMF diagnosis more accurate, thereby allowing early treatment for EMF patients.

  • Boshu Cui, Zaifeng Wu, Bing Yu, Yuting Li, Hongyu Liu
    Discovery Medicine. 2023, 35(179): 1064-1070.
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    Background: The thyroid cancer incidence has been experimenting an accelerated growth all over the world. The serine/threonine-protein kinase (BRAF) V600E gene detection or the DNA ploidy analysis has been employed in the identification of thyroid cancer type. This study aimed to evaluate the diagnostic value of the BRAF V600E gene integrated with DNA ploidy analysis in thyroid cancer.

    Methods: From August 2022 to May 2023, 400 individuals from the thyroid surgery outpatient department of our hospital were enrolled in this study. The participants were divided into low-risk groups (Ⅰ+Ⅱ+Ⅲ group; n = 200) and high-risk groups (Ⅳ+Ⅴ group; n = 200) based on the Thyroid Imaging Reporting and Data System (TI-RADS). A total of the patients were subjected to the DNA ploidy analysis, the BRAF V600E gene detection, or the combination of both techniques. We evaluated the diagnostic value of the above techniques and considered the postoperative pathology results as gold standard for cancer diagnosis. The negative predictive value (NPV), accuracy, specificity, sensitivity, and positive predictive value (PPV) of TI-RADS, BRAF V600E gene detection, DNA ploidy analysis, and BRAF V600E gene detection joined with DNA ploidy analysis were calculated.

    Results: Among 400 subjects, 238 presented thyroid cancer and 162 had benign lesions, according to the postoperative pathology results. The obtained sensitivity, specificity, accuracy, PPV, and NPV values of TI-RADS were 55.88%, 58.64%, 57.00%, 66.50%, 47.50%, respectively; of BRAF V600E gene detection were 81.93%, 69.75%, 77.00%, 79.92%, 72.44%, respectively; of DNA ploidy analysis were 83.19%, 72.84%, 79.00%, 81.82%, 74.68%, respectively; of BRAF V600E gene combined with DNA ploidy analysis were 90.34%, 76.54%, 84.75%, 84.98%, 84.35%, respectively. Compared with TI-RADS, the sensitivity, specificity, accuracy, PPV, and NPV values of DNA ploidy analysis, BRAF V600E gene detection, and the conjunction of these last two methods were increased (p < 0.05). The combination of DNA ploidy analysis and BRAF V600E gene detection had the highest values among them all.

    Conclusions: BRAF V600E gene detection in conjunction with DNA ploidy analysis showed a better diagnostic value than both methods separately or TI-RADS.

  • Sun Fu, Bing Cai, Gong Yao, Pengyi Zhang
    Discovery Medicine. 2023, 35(179): 1071-1076.
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    Background: Arthroscopic bipolar radiofrequency energy (bRFE) is a common method for minimally invasive treatment of cartilage injuries. The benefits of bRFE are still controversial, and its safety has become the focus of attention.

    Objective: This study aimed to reveal the effects of energy setting and recovery period on the efficacy and safety of bRFE.

    Methods: The New Zealand white rabbit knee cartilage injury model was established, and bRFE was used to treat the cartilage with different energy settings, including 20 W and 40 W, and recovery periods of 0 and 1 month. By observing the immediate and late results on damaged cartilage, along with chondrocyte apoptosis, the effects of energy setting and recovery period on the efficacy and safety of bRFE were accessed.

    Results: The pathological conditions, surface profile and chondrocyte viability in the bRFE treatment group produced greater late effects and were significantly better than those in the model group. Nevertheless, bRFE produced a timely injury that resulted in an increased rate of apoptosis (p < 0.05), which was alleviated in subsequent recovery (p < 0.05).

    Conclusions: bRFE can effectively trim and improve the cartilage lesion area, and reduce cracks. Although bRFE produced timely chondrocyte damage, this was alleviated on subsequent recovery. Therefore, bRFE with appropriate energy is beneficial to the recovery of cartilage damage, proper attention should be paid to the recovery period.

  • Jirong Zhang, Jimei Zhang, Xicheng Jiang, Juan Jin, He Wang, Qiao Zhang
    Discovery Medicine. 2023, 35(179): 1077-1085.
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    Background: Extracellular vehicles (EVs) secreted from adipose-derived stem cells (ASCs) (ASCs-EVs) have the potential to treat myocardial infarction (MI), although the underlying mechanism remains unclear. The current study explored the ability of ASCs-EVs to inhibit apoptosis and promote myocardial function in the infarcted heart via microRNAs (miRNAs)-221.

    Methods: In hypoxia-induced H9C2 cells, a cardiac cell strain derived from the SD Rat left ventricle, we measured the cell viability and apoptosis-related protein expression after transfection with the ASCs-EVs-NC (negative control for EVs-miR-221) or ASCs-EVs-miR-221 mimics. We then verified the cardioprotective effects of miR-221-overexpressing ASCs-EVs by investigating myocardial cell apoptosis and cardiac function in a MI rat model treated with ASCs-EVs from miR-221-overexpressing ASCs by comparing control with ASC treatment.

    Results: The in vitro experiment results showed that the proliferation of H9C2 cells and the anti-apoptotic protein expression were significantly enhanced by the ASCs-EVs-miR-221 mimic. The in vivo experiment results found that ASCs-EVs from miR-221-overexpressing ASCs have cardioprotective effects, as demonstrated by lower serum troponin levels and left ventricular end-systolic volume, and a lower number of apoptotic myocardial cells than those in control and ASC-treated rats.

    Conclusions: ASCs-EVs have therapeutic effects on MI by inhibiting cardiomyocyte apoptosis via miR-221.

  • Xuan Zhou, Wenting Wang, Li Liu
    Discovery Medicine. 2023, 35(179): 1086-1092.
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    Background: Pancreatic cancer (PC), a commonly recognized malignancy, arises within the digestive tract. Somatostatin (SOM) is a regulatory peptide that acts on secretion in vivo. Several studies have shown that SOM has inhibitory effects on various cancers. This work aims to probe the inhibitory effect, and mechanism of SOM action, on the epithelial–mesenchymal transition (EMT) of PC cells.

    Methods: First, the effects of SOM and transforming growth factor-β (TGF-β) on the proliferation of PC cells was determined by Cell Counting Kit-8 (CCK-8) assay. Next, we assessed the impact of SOM and TGF-β on the metastasis and apoptosis of PC cells using transwell assays and flow cytometry. Finally, we evaluated the effects of SOM and TGF-β on the expression of EMT-related proteins, apoptosis-related proteins, and proteins related to the TGF-β/Smad signaling pathway in PC cells using western blot analysis.

    Results: SOM suppressed the growth and metastasis of PC cells, and facilitated their apoptosis (p < 0.05). Moreover, SOM reversed pro-apoptotic effects of TGF-β (p < 0.05). Specifically, SOM increased the expression of Cysteine-aspartic acid protease 3 (Caspase-3) and Bcl-2-associated X protein (Bax) proteins while reducing the expression of B-cell lymphoma 2 (Bcl-2) protein (p < 0.05). SOM also reversed the TGF-β-induced EMT process. The TGF-β1, Smad2, and Smad3 proteins in PC cells treated with SOM were significantly down-regulated (p < 0.05).

    Conclusions: SOM suppressed the EMT progression in PC cells through its regulation of the TGF-β/Smad signaling pathway.

  • Min Xu, Yanyan Zhou
    Discovery Medicine. 2023, 35(179): 1093-1103.
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    Background: Autophagy plays critical adaptive and nonadaptive roles in the pathogenesis of Sepsis-associated acute kidney injury (Sepsis-AKI). However, it remains unknown whether myocardial infarction associated transcript (MIAT) is involved in the process of autophagy in Sepsis-AKI. This study aimed to explore the exact association between MIAT1 and Beclin 1 (BECN1)-mediated autophagy in Sepsis-AKI in vitro.

    Methods: HK-2 (human renal tubular epithelial cell line) cells were stimulated by lipopolysaccharide (LPS) to construct a septic kidney injury cell model in vitro. The relative expression changes of genes or proteins in clinical samples and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell survival was detected by cell counting kit-8 (CCK-8) and flow cytometry analysis. The production of inflammatory mediators was determined using Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR assays. The interlinked relationship between polypyrimidine tract-binding protein 1 (PTBP1) and MIAT or BECN1 was validated by RNA immunoprecipitation (RIP) and RNA pull-down detections.

    Results: The expression of MIAT was up-regulated in Sepsis-AKI patients and LPS-stimulated HK-2 cells. Down-regulation of MIAT strikingly lightened LPS-induced cell apoptosis and inflammation, but enhanced cell viability. Evidenced by mechanistic experiments, MIAT silencing was confirmed to activate BECN1-mediated cell autophagy by interacting with PTBP1. Furthermore, the elimination of BECN1 remarkably reversed the antiapoptotic and anti-inflammatory roles mediated by MIAT silencing.

    Conclusions: In summary, the experimental data reinforced that MIAT downregulation attenuated LPS-stimulated renal cell inflammatory injury by promoting BECN1-mediated autophagy activation through binding to PTBP1, providing some new insights into the function and mechanism of MIAT in Sepsis-associated acute kidney injury (Sepsis-AKI).

  • He-peng Nie, Qiong Wu, Jin Wu, Kun-zhan Cai, Yue Shen, Chun-bo Tang
    Discovery Medicine. 2023, 35(179): 1104-1113.
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    Background: Endosseous implants are widely used as a treatment for tooth loss, but gaps in the implant-abutment interface, and the cavity inside the implant, can cause inflammation of the tissue surrounding the implant. Currently available filling materials, however, cannot solve these problems. Therefore, the development of new antibacterial materials is key. In this study, we synthesized Ag nanoparticle-coated polytetrafluoroethylene (PTFE), analyzed the effect of Ag ion concentration, and estimated the antibacterial effects against oral pathogens in vitro.

    Method: The Ag nanoparticles (AgNPs)-modified PTFE was achieved using self-polymerized dopamine in an alkaline solution (2 mg/mL) and reduction reaction of Ag ions (0.01 mol/L and 0.05 mol/L). The surface features, chemical components, and wettability were characterized by scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and contact angle measurement. The antibacterial effect against Streptococcus mutans and Porphyromonas gingivalis was evaluated by counting colony-forming units on agar media and the visualization of bacteria present on the specimens by SEM and confocal laser scanning microscope (CLSM).

    Results: The surface characterization results indicated that a polydopamine film was successfully formed on the PTFE membrane, and spherical AgNPs were successfully reduced. With increasing concentration of the Ag precursor, the contents of the AgNPs increased (p < 0.05). The antibacterial ratio of AgNP-coated PTFE against Streptococcus mutans and Porphyromonas gingivalis reached 94.2% and 80.6%, respectively. The results of antibacterial testing analyzed via SEM and CLSM also demonstrated the robust antibacterial ability of AgNPs-modified PTFE (p < 0.05).

    Conclusions: AgNPs-modified PTFE has great potential to function as an implant filling material with enhanced antibacterial properties, and has the potential to be a novel antimicrobial material for the prevention of peri-implantitis in the clinic.

  • Huiwen Sun, Chen Men, Hui Deng, Chun Wang, Ruiyao Li, Yale Sun, Hao Yang, Mingyang Wu, Wen Zheng, Yiyang Zhan
    Discovery Medicine. 2023, 35(179): 1114-1122.
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    Background: Approximately 50.0% of patients with type 2 diabetes mellitus (T2DM) experience macrovascular diseases, and nearly 80.0% of them succumb to macrovascular complications. Atherosclerotic cardiovascular disease (ASCVD) ranks among the most prevalent macrovascular complications in T2DM. In this study, we aim to develop a nomogram model for the early detection of ASCVD in T2DM patients, enabling us to provide valuable recommendations for the clinical prevention and management of macrovascular complications in this patient population.

    Methods: This retrospective analysis encompassed 2620 T2DM patients admitted between June 2015 and June 2021. The cohort comprised 1270 T2DM patients with coexisting ASCVD (referred to as the “ASCVD group") and 1350 individuals who did not experience ASCVD (the “non-ASCVD group"). We conducted a comparative assessment of their baseline characteristics and clinical data. A nomogram model for the identification of ASCVD in T2DM patients was constructed utilizing Logistic regression analysis and the R package. The model's performance was evaluated through receiver operating characteristic (ROC) curve analysis and calibration curves.

    Results: We developed a nomogram model for the identification of ASCVD in T2DM patients, incorporating ten variables: sex, age, hypertension, smoking history, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio, alanine transaminase (ALT), adenosine deaminase (ADA), postprandial 2-hour C-peptide, monocyte count (MONO), and eosinophil count (EOS). ROC curves demonstrated that the area under the curve (AUC) of the nomogram model for identifying ASCVD in T2DM patients was 0.673 for the training dataset (with a cut-off value of 0.473, specificity of 0.629, and sensitivity of 0.637) and 0.655 for the validation dataset (with a cut-off value of 0.460, specificity of 0.605, and sensitivity of 0.675). The calibration curve indicated a substantial agreement between the predicted and observed cases of ASCVD in the training dataset and an acceptable level of agreement in the validation dataset.

    Conclusions: The nomogram model effectively identifies ASCVD in T2DM patients, which can be instrumental in pinpointing the high-risk population for ASCVD among T2DM patients and facilitating timely clinical management.

  • Chunli Ma, Qing Gao, Li Zhang, Chao Li, Geng Wu, Lei Yang
    Discovery Medicine. 2023, 35(179): 1123-1133.
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    Background: Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to patients and society, making the exploration of new therapeutic targets for preventing and treating ischemic stroke urgent. This study aimed to explore the effect of phosphoglycerate mutase family member 5 (PGAM5) on oxidative stress and mitochondrial dysfunction in ischemic stroke.

    Methods: The model of ischemic neuronal brain injury was established through culturing purchased human neuroblastoma cells (SH-SY5Y) by oxygen-glucose deprivation/reoxygenation (OGD/R). There were six experimental groups, including the OGD/R model group (SH-cells of OGD/R model), OE-NC group (cells of OGD/R model transfected with scramble cDNA), OE-PGAM5 group (cells of OGD/R model transfected with full-length sequence of PGAM5), si-NC group (cells of OGD/R model transfected with negative control small interference (si)RNA), si-PGAM5 group (cells of OGD/R model transfected with siRNA for PGAM5 knockdown), and a control group (cells cultured normally). Cell counting kit-8 (CCK-8) and flow cytometry were used to determine the activity and apoptosis of cells. Subsequently, the effects of PGAM5 expression on oxidative stress and mitochondrial dysfunction were analyzed. Mitochondrial morphology was observed by transmission electron microscopy (TEM), and mitochondrial membrane potential (MMP) was determined by JC-1 fluorescent probe. The levels of reactive oxygen species (ROS) were measured by flow cytometry, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) assay. The expression of light chain (LC)3-II/I and autophagy-related gene 5 (ATG5) proteins were measured, and the regulation of PGAM5 expression on PTEN-induced putative protein kinase 1 (PINK1)/Parkin pathway was also explored.

    Results: PGAM5 overexpression in OGD/R cells decreased the cell viability (p < 0.001) while increasing cell apoptosis (p < 0.01) compared to the OGD/R group. Inhibition of PGAM5 expression reversed the decreased cell viability (p < 0.001) and the increased cell apoptosis (p < 0.01). The JC-1 fluorescence showed that OGD/R treatment reduced mitochondrial membrane potential (p < 0.001) and TEM showed an obvious increase in phagosomes. In addition, OGD/R treatment enhanced oxidative stress (increased ROS, p < 0.01; increased MDA, p < 0.001; decreased SOD, p < 0.001), which could be further enhanced by overexpression of PGAM5 (ROS, p < 0.001; MDA, p < 0.001; SOD, p < 0.001) while reversed by the inhibition of PGAM5 (ROS, p < 0.01; MDA, p < 0.001; SOD, p < 0.001). The OGD/R-activated PINK1/Parkin pathway was inhibited by the knockdown of PGAM5 (p < 0.01) but promoted by the overexpression of PGAM5 (p < 0.05).

    Conclusions: PGAM5 stimulates oxidative stress and impairs mitochondrial function in ischemic stroke, and regulates the PINK1/Parkin signaling pathway. Therefore, PGAM5 is likely to be a target for the therapy of ischemic stroke.

  • Liuqing Sheng, Xiaolong Yao, Jianfeng Ye, Zhizhong Wang, Yinchun Chen, Jun Li, Mingchang Li
    Discovery Medicine. 2023, 35(179): 1134-1146.
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    Background: Inflammation and oxidative stress (OS) are major causes of aneurysmal subarachnoid hemorrhage (aSAH)-induced early brain injury (EBI). Eriocitrin (EC), a flavonoid compound, has anti-inflammatory and antioxidant actions. However, there is still no relevant studies on the role of EC in SAH. Accordingly, this research aims to clarify the anti-OS and anti-inflammatory efficacy of EC in SAH.

    Method: Rat SAH model was established in vivo and administered with Eriocitrin (25 mg/kg). In vitro, BV2 cells were exposed to oxyhemoglobin (OxyHb) for 24 hours and pretreated with Eriocitrin (1 uM/mL, 2 uM/mL, 4 uM/mL) for 30 minutes. Water maze experiments and neurological function scores were conducted to assess cognitive and motor function. TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was used to detect cortical cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) were used to detect the inflammatory factors and malondialdehyde (MDA), as well as the expression of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Western blots were used to semi quantify nuclear factor erythroid-2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), dual specificity phosphatase 14 (DUSP14) expression.

    Results: The findings suggest that EC (25 mg/kg) reduced SAH-induced central nervous system (CNS) damage, neuronal apoptosis, inflammatory reactions and OS. Regarding a mechanistic study, EC enhanced Nrf2 and NF-κB by increasing DUSP14 activation, thereby reducing the inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6. In addition, EC decreased MDA while markedly elevating SOD and enhancing GSH-px. Furthermore, specifically inhibiting DUSP14 expression via using protein-tyrosine-phosphatase (PTP) inhibitor IV, neutralized the protective action of EC and aggravated inflammation and OS. In vitro experiments of OxyHb-induced BV2 cells revealed that EC promoted Nrf2 while markedly suppressing NF-κB by increasing DUSP14 activation, thereby reducing the concentrations of the above inflammatory cytokines. Moreover, EC decreased MDA while evidently increasing SOD and GSH-px.

    Conclusion: In summary, this paper lays a theoretical grounding for EC treatment of SAH-induced inflammatory reactions and OS by regulating DUSP14.

  • Shanfeng Li, Haichuan Shen, Qingzhi Wan, Pinjing Chen, Chenggan Shu, Hongmei Wang, Weipei Zhu
    Discovery Medicine. 2023, 35(179): 1147-1159.
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    Background: Emerging evidence indicates the importance of heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) in a number of developmental processes. Little is known regarding its biological function in regulating cervical cancer (CC) progression. In this study, we aim to explore the role of HS6ST2 in CC progression.

    Methods: The transcriptome sequencing data of CC tissues from three databases, GSE64217, GSE138080, and GSE63514, was examined for genes with significant changes. The expression profile for HS6ST2 within CC tissue was then assessed through fluorescence quantitative PCR and immunohistochemistry and compared to data from patients with clinicopathological features. A multivariate survival analysis was performed using the COX regression. The real-time quantitative PCR assessed the HS6ST2 expression profile within CC cellular cultures. The results of knocking down HS6ST2, considering the proliferative activity and invasiveness of CC cultures in vitro, were detected through cell viability assay, clonogenic assessment, tumorsphere formation analysis, 3D invasion experiment and transwell assay. The impact of HS6ST2 knockdown in CC proliferation was also evaluated in vivo using a nude mice model.

    Results: HS6ST2 was severely upregulated within CC tissues across the three explored databases (GSE64217, GSE138080, and GSE63514). Fluorescent quantitative PCR and immunohistochemistry experiments identified HS6ST2 as highly upregulated within patients CC tissues. Survival analysis taking into account the parameters of lymph node metastasis, Federation of Gynecology and Obstetrics (FIGO) stage, depth of invasion, pathological grade, and HS6ST2 expression level demonstrated that individuals with downregulated HS6ST2 exhibited considerably extended progression-free survival (PFS) and overall survival (OS) in comparison to upregulated HS6ST2 cases. According to the findings of COX univariate analysis, the parameters lymph node metastasis, FIGO stage, depth of invasion, pathological grade, and HS6ST2 expression level, all showed a statistically significant correlation with effect upon prognosis of CC patients. The FIGO stage, depth of invasion and expression level of HS6ST2 were identified as independent risk variables influencing CC case prognosis within subsequent COX multivariate analysis. Cell function experiments proved that HS6ST2 knockdown can considerably diminish the proliferative potential, stemness and invasive traits of CC cells. Tumor formation experiments in nude mice in vivo demonstrated that knocking down HS6ST2 can significantly thwart CC cellular proliferative properties within animal models.

    Conclusions: The clinicopathological features and the survival time of the patients significantly correlate with the level of HS6ST2 expression in CC tissue samples.

  • Yuling Li, Siyu Ye, Zaiting Ye, Zhangyong Yin, Xiaoping Cai, Jiongwei Pan
    Discovery Medicine. 2023, 35(179): 1160-1166.
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    Background: Automatic recognition of cough sounds shows promise in the diagnosis of respiratory conditions. This study investigated the diagnostic value of cough sounds in elderly patients with lower respiratory tract infection (LRTI).

    Methods: We selected 83 elderly patients with suspected LRTI who sought medical advice at our hospital from January 2022 to September 2022, and grouped them into the infected and uninfected categories, according to their clinical traits. The cough sound of each subject was recorded and features were extracted using the Mel Frequency Cepstrum Coefficient. Four cough sound indexes, including the length of light or heavy cough time (T1), frequency of sound, decibels full scale (dBFs) and total length of cough time (T0) were compared between the two groups. The diagnostic efficacy of each index was analyzed using the receiver operating characteristic (ROC) curve.

    Results: 22 patients were diagnosed with LRTI in the infected group including 15 males and 7 females, 13 were in the LRTI-free uninfected group, including 7 males and 6 females. Cough sound indexes were higher in the infected group compared with the uninfected group at T1 (p = 0.127), frequency of sound (p = 0.894), dBFs (p = 0.532) and T0 (p = 0.854). ROC curve analysis showed that the area under the curve (AUC) values of the above four indexes and the combined indexes for LRTI diagnosis were 0.680, 0.503, 0.577, 0.486 and 0.696, respectively.

    Conclusions: Cough sounds are correlated with LRTI. However, due to the small sample size of this study, the current results do not find that automatic recognition of cough has obvious diagnostic value, but its diagnostic potential in elderly patients with LRTI cannot be denied.

  • Jinsong Yang, Xue Jiang, Ying Chen, Lisong Teng
    Discovery Medicine. 2023, 35(179): 1167-1176.
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    Background: Doxorubicin (DOX) is a commonly used chemotherapeutic agent, but bladder cancer (BC) patients often develop resistance that limits therapeutic efficacy. Recent research has demonstrated a link between medication resistance and the expression of eukaryotic translation initiation factor 5A2 (EIF5A2) in tumors. This study aimed to investigate whether EIF5A2 affects the resistance of BC cells to doxorubicin through the transforming growth factor (TGF)-β signaling pathway.

    Methods: Doxorubicin-resistant cells in BC (T24/DOX and 5637/DOX) were constructed, then cell viability was detected by cell counting kit-8 (CCK-8); EIF5A2 mRNA expression was detected using quantitative real-time PCR (qRT-PCR); cell proliferation was detected using clone formation; apoptosis was detected by flow cytometry; and finally, proteins related to the TGF-β signaling pathway (EIF5A2, TGF-β1, p-small mothers against decapentaplegic 2 (Smad2)/Smad2, p-Smad3/Smad3) were detected using western blot.

    Results: EIF5A2 was up-regulated in DOX-resistant BC cells, and DOX intervention promoted proliferation and inhibited apoptosis in DOX-resistant BC cells. si-EIF5A2 reversed the above effects. EIF5A2 resulted in DOX resistance by activating the TGF-β pathway, and the TGF-β activator SRI-011381 reversed the inhibitory effect of si-EIF5A2 on DOX resistance.

    Conclusions: EIF5A2 promotes DOX resistance in BC cells through the TGF-β signaling pathway, and EIF5A2 may be a potential counter-resistance therapeutic strategy in BC chemotherapy.

  • Daojun Hu, Li Zhang, Bing Qin, Ning Wang, Xingjun Li, Wenjie Shi
    Discovery Medicine. 2023, 35(179): 1177-1189.
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    Background: Previous studies have explored the relationship between serum lead levels and the risk of female breast cancer (FBC). However, it is still uncertain whether urinary lead levels are associated with FBC. This study aimed to investigate the potential association between urinary lead and FBC.

    Methods: A cross-sectional case-control study was conducted using the National Health and Nutrition Examination Survey (NHANES), which is a series of cross-sectional, nationally representative surveys of the United States population consisting of 10 survey waves from 1999 to 2018. This study analyzed a total of 2795 female participants (≥20 years), consisting of 210 participants with FBC and 2585 healthy controls. Urinary lead was detected using Inductively Coupled Plasma-Mass Spectrometry, which was divided into four levels by using quartiles-defining cut points. Multivariate logistic regression was used to analyze the association between urinary lead and FBC.

    Results: Multivariate logistic regression revealed that urinary lead was positively correlated with FBC (Odds ratio [OR], 2.16; 95% confidence interval [CI]: [1.18, 3.95], p < 0.05) in a fully adjusted model. There were significantly increased ORs of FBC in quartile 4 (Q4) and quartile 3 (Q3), compared with the lowest quartile 1 (Q1) (Q4, OR = 1.48, 95% CI [0.89, 2.48]; Q3: OR = 1.01, 95% CI [0.59, 1.73], p for trend = 0.021). No significant interaction effects were observed between urinary lead levels and FBC between the subgroups (age, race, educational status, body mass index (BMI), marital status, family income to poverty ratio, hypertension status, diabetes status, renal function status, smoking history, ever been pregnant, oral contraceptive use, occupation classification, etc.) (All interaction p-value > 0.05).

    Conclusions: Urinary lead is likely positively associated with FBC in the US population.

  • Zhi Zhao, Qingli Fang, Longqin Wei, Jinquan Lin, Ruping Su, Ni Li
    Discovery Medicine. 2023, 35(179): 1190-1201.
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    Background: Autophagy is involved in the survival, differentiation, and activation of immune cell subsets. In this study, we determined the prognostic value and biological functions of autophagy genes in gastric cancer (GC).

    Methods: The RNA sequencing dataset for gastric cancer was obtained. Differences in prognosis and enrichment pathways in non-negative matrix factorization (NMF) subclasses were analyzed. Next, we analyzed CXC chemokine receptor 4 (CXCR4) by differential expression, clinical value, immune effects, tumor mutation burden (TMB) values, somatic variants, and biological functions.

    Results: NMF identified three subclasses. Among the three subclasses, there were differences in prognosis, immune cell infiltration, immune checkpoint genes, and enrichment pathways. Moreover, CXCR4 level was elevated in most tumors, and high CXCR4 level was related to poor prognosis in GC patients. CXCR4 expression was significantly correlated with B cells, eosinophils, macrophages, and plasma cells. In in vitro experiment, CXCR4 promoted GC cell proliferation.

    Conclusions: Our results showed that CXCR4 is a promising biomarker for predicting prognosis and response to immunotherapy in GC.