Background: Cervical cancer (CC) is one of the major types of gynecological cancer, with a high global incidence and mortality rate. Methyltransferase-like 3 (METTL3), a key constituent of methyltransferase, plays a crucial role in various biological processes. Still, only a rare report has been made on its involvement in the progression of CC. Therefore, this study aims to investigate the impact of METTL3 in CC and its molecular mechanisms.
Methods: Gene expression datasets about CC were obtained from the Gene Expression Omnibus (GEO) database, and the expression of METTL3 and Myc was analyzed. Cell viability was detected after METTL3 knockdown in HeLa and SiHa cells, followed by cell counting Kit-8 (CCK-8) assays. The relative expression of METTL3 and Myc was detected via real-time quantitative PCR (qPCR) assays, and the protein expression was determined using Western blot. Meanwhile, cell invasion and migration capabilities were assessed utilizing transwell assays, and cell proliferation was detected using the EdU experiment. Furthermore, RNA methylation immunoprecipitation-qPCR detection was performed to determine the expression of Myc after N6-methyladenosine (m6A) modification.
Results: Analysis of the GEO database indicated elevated expression of METTL3 and Myc in CC tissues. Patients with high METTL3 expression had shorter disease-free survival, and patients with high Myc expression had shorter overall survival. Following the knockdown of METTL3, there was a significant reduction in the viability, proliferation, invasion, and migration abilities of HeLa and SiHa cells. Besides, the expression of METTL3 and Myc mRNAs and proteins was greatly reduced. The level of m6A Myc decreased significantly after METTL3 knockdown.
Conclusions: METTL3 plays an important role in regulating cervical cancer cells. METTL3 promotes CC development through m6A modification to regulate the expression of the oncogene Myc.
Background: The connection between viral infection and the onset of demyelination has garnered considerable attention. Omicron, the most recent prevalent strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised concerns. Optic neuritis (ON) associated with Omicron infection and spontaneous demyelinating ON may manifest distinct disease progressions. This study aims to contrast the features of these two distinct etiologies of ON.
Methods: This case-control study comprised fifteen patients (21 eyes) diagnosed with Omicron infection-related ON and fifteen patients (24 eyes) with demyelinating ON serving as the control group. Clinical characteristics, cerebrospinal fluid (CSF) analysis, treatment protocols, and outcomes were compared between the two groups.
Results: The Omicron-infected group exhibited a higher incidence of pain upon ocular movement (p = 0.023) and peripapillary hemorrhages (p = 0.046). In CSF analysis, there was an elevation in white cell counts (WCCs) (p = 0.004), with lymphocytes being the predominant cell type in the Omicron-related ON group. However, oligoclonal bands (OCBs), indicative of intrathecal synthesis, were significantly lower and lagged behind those of the demyelinating ON group (p = 0.021). SARS-CoV-2 RNA was not directly detected in the CSF of the Omicron-related ON group, and the degree of WCC elevation was closely linked with peripapillary hemorrhages (odds ratio = 0.029, p = 0.02). Additionally, the Omicron-related ON group displayed more pronounced ganglion cell loss following 3-month treatment (p = 0.02).
Conclusion: Omicron-related ON is distinguished by more pronounced clinical symptoms and distinct CSF characteristics compared to spontaneous demyelinating ON. The absence of viral RNA sequence in the CSF of Omicron-associated ON supports the use of steroid monotherapy; however, varying treatment options and prognoses should be considered for these two types of ON.
Background: Susceptibility-weighted imaging (SWI) is a common imaging technique used to identify cerebral microbleeds. Given that spinal cord injury (SCI) often creates an environment that favors ferroptosis, a type of cell death driven by iron, this study aimed to explore the relationship between microbleeds on SWI and ferroptosis, and explore the effect of deferoxamine on SCI.
Methods: Thirty-six rabbits were divided into three groups: sham, SCI, and SCI with deferoxamine (DFO, a ferroptosis inhibitor) treatment (SCI+DFO). Following 48 hours of SCI modeling, the rabbits underwent magnetic resonance imaging (MRI) and SWI examinations. Ferroptosis markers and spinal cord tissue morphology were examined, and the modified Tarlov's score was used to assess neurological function.
Results: SWI analysis revealed that rabbits in the SCI group exhibited lower signal intensities and larger microbleed areas compared to the those in the SCI+DFO group (p < 0.05). The SCI+DFO group demonstrated significantly decreased iron and malondialdehyde (MDA) levels, coupled with increased glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with attenuated ferroptosis (p < 0.05). This group also displayed greater Neuronal Nuclei (NeuN) expression, Tarlov's scores, and neurological recovery rates (all p < 0.05). A significant positive correlation was found between the microbleed area and iron content (r = 0.59, p = 0.04), MDA (r = 0.75, p = 0.01), and mitochondrial damage (r = 0.90, p < 0.01). Conversely, a negative correlation was established between the microbleed area and GPX4 levels (r = -0.87, p < 0.01), as well as neurological function recovery (r = -0.62, p = 0.03).
Conclusion: The extent of microbleeds on SWI following SCI is closely correlated with ferroptosis, and the inhibition of ferroptosis could improve neurologic function. These findings suggest that the area of microbleeds on SWI could potentially serve as a predictive marker for ferroptosis in spinal cord injury.
Background: In China, the environmental concern of Dibutyl Phthalate (DBP) exposure significantly endangers human health by inducing insulin resistance (IR). Skeletal muscle tissue plays a critical role in this process. However, the precise molecular mechanisms through which DBP interferes with the insulin signaling pathway remain to be fully elucidated. This study aims to explore the molecular mechanisms by which DBP induces IR in skeletal muscle, focusing on the phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (AKT)-glucose transporter 4 (GLUT4) signaling pathway.
Methods: To investigate the molecular mechanisms underlying DBP-induced IR, an experimental study was established on a human skeletal muscle cell line (HSkMC). Expression levels of mRNA and proteins associated with key signaling genes within the insulin receptor (INSR)-insulin receptor substrate (IRS)-PI3K-AKT-GLUT4 pathway were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot techniques. Additionally, this study explored the effects of DBP alone and in combination with a PI3K inhibitor (BKM120) or phosphatase and tensin homolog (PTEN) overexpression lentivirus on these signaling components.
Results: Results from this study demonstrated that DBP exposure significantly decreased mRNA levels of INSR, IRS1, PI3K, AKT2, and GLUT4 in HSkMC cells compared to untreated control cells. This reduction was exacerbated when DBP was combined with BKM120 or PTEN overexpression lentivirus, suggesting a synergistic effect. Furthermore, DBP treatment reduced the expression and phosphorylation of AKT2, indicating a disruption in the insulin signaling pathway.
Conclusions: This study elucidates a molecular mechanism by which DBP induces IR in skeletal muscle cells, primarily through the deregulation of the PI3K-dependent insulin signaling pathway. These insights enhance comprehension of the pathophysiological changes associated with IR caused by environmental pollutants like DBP, potentially guiding future strategies for prevention and intervention.
Background: Dental caries is a multifactorial chronic bacterial infectious disease. Variations in the predisposition of the general population to dental cavities suggest that genetic and immunological factors play significant roles in its pathogenesis. This study aims to explore the impact of the Beta-Defensin 1 (DEFB1) rs11362 polymorphism on caries susceptibility in permanent dentition among the Bai Kuyao and Zhuang ethnic groups in China.
Methods: A sample of 754 adolescents aged 12-15 was randomly selected from primary and junior high schools in Nandan County, Guangxi, China. All adolescents underwent clinical examinations, and DNA samples were collected. The genotype of DEFB1 rs11362 was determined using single nucleotide polymorphism (SNP) typing. The concentration of human β Defensin 1 (hBD-1) protein in saliva was measured using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA).
Results: The distribution of the DEFB1 rs11362 T allele was lower in the Bai Kuyao group compared to the Zhuang group. The disparity in the rs11362 genotype was statistically significant in the superficial dentin caries subgroup of the Bai Kuyao population (p = 0.017). Following adjustment for all potential confounding variables, the analysis revealed a heightened risk of superficial dental caries among CT genotype carriers in the Bai Kuyao population under a co-dominant model (odds ratios (OR) = 2.70; 95% confidence intervals (CI) [1.35-5.44]; p = 0.005), and an increased risk among CC genotype carriers in the Bai Kuyao population under a dominant model (OR = 2.35; 95% CI [1.18-4.67]; p = 0.015). A significant difference (p < 0.05) was noted in the distribution of rs11362 genotypes and salivary hBD-1 levels among the Bai Kuyao group. Salivary hBD-1 levels were notably higher in the CC genotype group (4.12 ± 2.07 ng/mL) compared to both the CT (2.77 ± 1.62 ng/mL) and TT genotype groups (2.32 ± 0.98 ng/mL).
Conclusion: The DEFB1 rs11362 polymorphism showed an association with caries susceptibility in permanent teeth and influenced hBD-1 protein expression in saliva. Consequently, the DEFB1 polymorphism likely represents a concealed risk factor for caries.
Background: Colon cancer (CC) is a highly prevalent malignancy that contributes significantly to global morbidity and mortality. The polycomb group ring finger 2 (PCGF2) has been identified as a relevant factor influencing the outcomes of CC. At the same time, the centromere-associated protein E (CENPE) is implicated in promoting carcinogenesis and adversely affecting the survival of tumor patients. The primary objective of this study was to elucidate the precise impact of PCGF2 on CC and unravel the underlying mechanisms associated with CENPE.
Methods: Human normal colon epithelial cells and CC cells were utilized to investigate the differential expression of PCGF2 and CENPE. CC cell line LOVO was exploited and transfected for PCGF2 regulation. Subsequently, cell viability and proliferation were assessed using the cell counting kit 8 (CCK-8) and colony forming assay. Cell viability and proliferation were assessed using the terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, while cell migration and invasion capabilities were determined using the transwell assay, and mRNA levels of cell cycle-related genes were measured for evaluating cell cycle activation. In addition, mice were used for in vivo experiments to investigate the progression of CC cells with different levels of PCGF2. Moreover, GSK-923295 was used to inhibit CENPE, followed by the evaluation of cell progression.
Results: PCGF2 and CENPE were upregulated in CC cell lines (p < 0.001), and upregulation/downregulation of PCGF2 led to the upregulation and downregulation of CENPE (p < 0.001). The upregulation/downregulation of PCGF2 led to an increase/decrease in viability, proliferation, migration, and invasion while suppressing/enhancing apoptosis in LOVO cells (p < 0.001), promoting cell progression. The tumor progression of LOVO cells with PCGF2 knockdown was slower (p < 0.001). The PCGF2-promoting LOVO cell progression was disrupted when CENPE was inhibited, presented by the reversely decreased viability, proliferation, migration, invasion, and cell cycle activation, and increased apoptosis (p < 0.001).
Conclusion: PCGF2 promotes CC cell progression by upregulating CENPE, providing PCGF2 inhibition and CENPE inhibition as potential therapeutic targets for treating CC.
Systemic light-chain (AL) amyloidosis is a rare and complex clonal plasma cell neoplasm characterized by the production of misfolded and unstable immunoglobulin light-chains leading to multisystem amyloid deposition, which progresses to organ dysfunction and eventual failure. The importance and urgency of AL amyloidosis depends on its potential to induce significant organ impairment, progressive course, risk of life-threatening complications, and the limited treatment options available. Treatment options and prognosis depend on the number and severity of organ involvement at the time of diagnosis with cardiac involvement carrying the worst outcomes. The treatments aim to target eliminating the underlying clonal plasma cell neoplasm and prevent the production and deposition of amyloid precursor immunoglobulin light-chain protein in the affected vital organs. Strategies for treating systemic AL amyloidosis have incorporated anti-plasma cell therapies approved in the management of multiple myeloma due to their shared cellular derivation. Quadruplet therapy of cyclophosphamide, bortezomib, dexamethasone and daratumumab (DaraCyborD) is the currently approved first-line induction therapy for systemic AL amyloidosis. Some patients need upfront autologous hematopoietic stem cell transplantation (HSCT) after high-dose melphalan conditioning particularly if DaraCyborD is not able to achieve complete hematologic response (CHR). Additionally, a promising treatment option involves disassembling amyloid deposits from the vital organs using monoclonal antibodies such as CAEL 101 or Birtamimab with the expectation of restoring damaged tissues of the vital organs affected thereby improving or reversing patients' symptoms. Both CAEL 101 and Birtamimab are currently being tested in phase 3 clinical trials for systemic AL amyloidosis patients with advanced cardiac involvement. This comprehensive review provides an up-to-date overview of AL amyloidosis therapy, with a particular focus on recent advances and future directions of immunotherapeutic strategies.
Background: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid, and its invasiveness and metastatic ability are closely related to patient prognosis. Chaperonin containing TCP1 subunit 2 (CCT2) is an important component of the molecular chaperone protein complex and has been shown to regulate cell proliferation and migration in various tumors. Epithelial-mesenchymal transition (EMT) is a critical process in tumor metastasis, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1) is a core transcription factor that regulates EMT. This study aims to explore how CCT2 induces EMT gene transcription through ZEB1, thereby promoting the metastasis and tumorigenesis of PTC.
Methods: CCT2 in PTC tissues was analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. siRNA and overexpression vectors were used to silence and overexpress CCT2, respectively, and the effects on PTC cell migration, invasion, proliferation, and apoptosis were observed. Rescue experiments were used to investigate the effect of CCT2 on ZEB1 and EMT-related genes. Cell apoptosis was detected by Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay. Silencing ZEB1 was used to verify its effect on the oncogenic activity of CCT2.
Results: CCT2 was found to be highly expressed in PTC tissues (p < 0.01). In in vitro and in vivo experiments, silencing CCT2 inhibited the migration and invasion of PTC cells and their metastasis, while overexpression of CCT2 produced the opposite effect. Additionally, CCT2 promoted PTC cell proliferation and inhibited apoptosis (p < 0.01). Mechanistic studies revealed that CCT2 upregulated ZEB1 expression (p < 0.01), thereby inducing EMT gene transcription (p < 0.01). Silencing ZEB1 reduced the oncogenic effect of CCT2.
Conclusion: This study first revealed the high expression of CCT2 in PTC and its essential role in the migration, invasion, proliferation, and anti-apoptosis of tumor cells. CCT2 promotes the metastasis and tumorigenesis of PTC by regulating ZEB1 and EMT-related genes. These findings provide new potential targets for molecular targeted therapy of PTC and explore new directions for future clinical treatment strategies.
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