Discovery medicine最新文献

Since 2020, most of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolution has been focused on the receptor-binding domain (RBD) of the Spike protein. Nevertheless, the N-terminal domain (NTD) of Spike has been shown to represent the target for neutralizing antibodies, and accordingly, NTD mutations are relevant for immune escape. In 2024, after the introduction of the BA.2.86 saltation variant (heavily mutated at the NTD antigenic supersite), its descendant JN.1 has further explored NTD evolution in its progeny, largely focused on positions 22, 31, 59 and 60. In this review, we explore such convergent evolution in detail and hypothesize the underlying mechanisms.

Traditionally viewed as a motor control center, the cerebellum is increasingly recognized as a crucial component of a neural network that enables adaptive behavior across various domains, including cognition, affect, emotion, and social interactions. Recent clinical studies have linked cerebellar dysfunction to impairments in mentalizing and narrative coherence in autism spectrum disorder (ASD). Given that narratives involve the temporal sequencing of causally related events and actions, these findings imply the potential role of the cerebellum in predictive sequence. The aim of this review is to dissect the neural circuitry and computational mechanisms underlying cerebellar predictive cognitive control. We propose that the Kalman filter model, which has been applied successfully to the motor cerebrocerebellum, can be extended to the non-motor (cognitive/affective/social) regions. In sharp contrast, the cerebral cortex employs a recurrent network architecture, as evidenced by intracortical connections, which underlies hierarchical processing in areas such as the visual and motor cortices. Surprisingly, the computational principles of the cerebrocerebellar loop have received relatively little attention in computational and theoretical neuroscience. We stress the need for a comprehensive theory on cerebrocerebellar connectivity that integrates the distinct neural mechanisms of the cerebrum and cerebellum, to help understand the role of this network in cognitive, affective, and social functions. Our theory provides a theoretical framework that explains how the cerebellum deals with motor and non-motor operations. The Kalman filter theory fits with two major requirements: sequencing and predictions. We propose a core operational mechanism for motor, cognitive, affective and social operations handled by the cerebellar circuitry.

Colon cancer accounts for nearly 10% of all cancer diagnoses annually. Microsatellite instability-high (MSI-H) colon cancer is a particularly aggressive subtype of colon cancer that is known to have a significant number of genetic mutations. Microsatellite instability (MSI) refers to genetic hypermutability caused by the dysfunction of the DNA mismatch repair (MMR) system, which leads to errors in repetitive DNA sequences and is a hallmark of certain cancers, including MSI-H colon cancer. MSI-H colon cancer acts on the DNA mismatch repair system causing an accumulation of mutations in microsatellite regions of the DNA. These mutations have been linked with increased tumorigenesis and decreased response to conventional forms of chemotherapy for colon cancer. However, this increased tumor burden results in significant production of neoantigens which makes these tumors immunogenic and therefore perfect candidates for pairing with immunotherapy. As a result, adjuvant immunotherapy in MSI-H colon cancer has become a burgeoning field of research, and synthesizing information regarding the efficacy of these immunotherapies is the goal of this literature review. Pembrolizumab, a monoclonal antibody targeting programmed cell death protein 1 (PD-1), was among the first to receive approval for the treatment of MSI-H colon cancer and was observed to have significant efficacy versus traditional chemotherapy with statistically significant improvements in metrics such as progression-free survival (PFS), overall response (OR), and disease-free survival (DFS). Similarly, Nivolumab, another PD-1 inhibitor, and the combination of nivolumab and ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor) were granted Food and Drug Administration (FDA) approval for the treatment of MSI-H colon cancer and have also shown the ability to outperform traditional chemotherapy with a higher overall response rate (ORR), mean PFS, and overall survival rates. Off-label uses of existing adjuvant immunotherapies such as Atezolizumab (a programmed death-ligand 1 (PD-L1) inhibitor) and Durvalumab (a PD-L1 inhibitor) have shown promise with preliminary results showing higher DFS and recurrence-free survival but need further data collection. Emerging immunotherapy targets such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoreceptor with immunoglobin and Immunoreceptor Tyrosine-based Inhibitory Motif domains (TIGIT) inhibitors show preliminary promise and may one day become a part of the approach to the treatment of MSI-H colon cancer. This review highlights current advancements, challenges, and emerging trends in the application of immunotherapy for MSI-H colon cancer, with a focus on improving patient outcomes.

Chromobox 4 (CBX4) is a polycomb group protein involved in epigenetic regulation via the polycomb repressive complex 1 (PRC1) and its small ubiquitin-like modifier (SUMO) ligase activity. It has been reported that CBX4 plays several oncogenic functions, contributing to tumor growth, metastasis, and therapeutic resistance. Elevated CBX4 expression is also correlated with poor patient prognosis and advanced tumor stages in multiple gastrointestinal cancers. Preclinical studies demonstrate that targeting CBX4 using small-molecule inhibitors, RNA interference, and monoclonal antibodies mitigates tumor progression and enhances treatment efficacy. Additionally, CBX4 exhibits potential as a diagnostic biomarker, with its high expression levels serving as an indicator of early-stage disease. Despite these advances, further research is needed to elucidate molecular mechanisms behind CBX4's involvement in carcinogenesis to accelerate the translation of tools and approaches targeting CBX4 to clinical settings. The aim of this paper is to review the role of CBX4 in gastrointestinal cancers, including gastric, liver, colorectal, and esophageal cancers, offering invaluable insights for developing novel diagnostic tools and targeted therapies to improve patient outcomes.

Myocardial infarction remains a significant worldwide public health issue, primarily owing to its mortality and morbidity rates. This condition is due to myocardial ischemia, appearing once the heart's blood flow is obstructed or significantly reduced, causing the death of heart muscle cells. Reperfusion prevents further death of cardiomyocytes, restoring coronary flow. However, the initial lack of coronary blood flow and the subsequent restoration induce ischemia/reperfusion injury (IRI) due to abrupt metabolic and biochemical changes, such as calcium overload, activation of inflammatory cells, and oxidative stress (OS). OS is associated with damage to cellular biomolecules such as proteins, lipids, DNA, or carbohydrates and with organelles such as mitochondria, activating mitochondrial dynamics. These oxidative conditions may also trigger ferroptosis, cell death linked to cellular oxidation. While ferroptosis induction is desirable in certain diseases like cancer, it is not beneficial in situations such as myocardial IRI. Although considerable research has been conducted on ferroptosis in myocardial IRI, the potential impact of reducing ferroptosis via mitochondrial dynamics in IRI remains to be reviewed. Consequently, this review concentrates on mitochondrial dynamics during myocardial ferroptosis in IRI and explores the potential therapy to inhibit myocardial ferroptosis by targeting mitochondrial dynamics to mitigate IRI.

Background: Glycolytic metabolism has been identified as a facilitator of tumor cell proliferation. Therefore, this study aims to investigate the mechanisms by which the sperm-associated antigen 4 (SPAG4)/cellular myelocytomatosis oncogene (c-Myc)/sulfotransferase 2B1 (SULT2B1) axis regulates glycolytic metabolism and influences the viability of HT29 cells.

Methods: SPAG4, c-Myc, and SULT2B1 levels were assessed in HT29 cells using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot analyses. Moreover, overexpression and knockdown in HT29 cell models were successfully established. Furthermore, cell viability and proliferation were evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays. Various key parameters such as glucose uptake, lactate production, Adenosine Triphosphate (ATP)/Adenosine Diphosphate (ADP) ratio, and the expression levels of Glucose transporter 1 (GLUT1) and Lactate dehydrogenase A (LDHA) were determined to examine glycolytic metabolism. Additionally, the relationship between SPAG4, c-Myc, SULT2B1, and glycolysis was assessed using the immunofluorescence staining approach and 2-Deoxy-D-glucose (2-DG) therapy.

Results: The expression levels of SPAG4, c-Myc, and SULT2B1 were significantly elevated in HT29 cells (p < 0.05). Moreover, silencing SPAG4 and c-Myc substantially reduced glycolytic metabolism and suppressed HT29 cell viability and colony formation capability (p < 0.05). Additionally, elevated SULT2B1 expression effectively counteracted the glycolytic reduction induced by silencing SPAG4 and c-Myc, enhancing cellular viability and colony formation capability (p < 0.05).

Conclusions: In summary, SPAG4 knockdown effectively suppresses HT29 cell proliferation and colony formation ability by decreasing SULT2B1 expression through the downregulation of c-Myc, leading to the reduction of glycolytic metabolism.

Background: The incidence of atrial fibrillation (AF) presents a markedly increasing trend with advancing age. Thus, with the growing population of elderly individuals, AF has emerged as a significant medical and socioeconomic problem. The objective of this study was to investigate the correlation of mitogen-activated protein kinase 10P (MAPK10P) gene polymorphism with P-wave peak time (Pwd) and P-wave dispersion (Pmax) among elderly individuals with paroxysmal AF.

Methods: From January 2021 to October 2022, 125 elderly patients with essential hypertension were recruited for research in our Cardiology Department. According to the European Society of Cardiology (ESC) Atrial Fibrillation Management Guidelines, 53 patients with ≥2 documented paroxysmal AF episodes in the previous year were classified as the observation group, while 72 patients without AF formed the control group. Patient data were collected, and a 12-lead electrocardiogram was used to measure Pwd and Pmax. MAPK10P genotype was identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association between MAPK10P genotype and AF risk, as well as the impact of different genotypes on Pwd and Pmax parameters, were evaluated.

Results: The baseline characteristics did not show any significant difference between the two groups (p > 0.05). The values of Pwd and Pmax in the observation group were significantly greater than those in the control group (p < 0.05). The occurrence rate of the CC genotype was lower in the observation group than in the control group (p < 0.05), while the occurrence rates of the CG and GG genotypes were higher in the observation group than in the control group (p < 0.05). Additionally, the frequency of the G allele was higher in the observation group than in the control group (p < 0.05). AF patients with the CG+GG genotype exhibited higher Pwd and Pmax values compared to those with the CC genotype (p < 0.05). Patients without AF who had the CG+GG genotype had higher Pwd and Pmax values compared to those with the CC genotype (p < 0.05).

Conclusion: In elderly patients, the presence of the G allele in the MAPK10P gene polymorphism is linked to an increased risk of AF, as well as Pwd and Pmax. This study provides valuable insights into the potential role of MAPK10P gene variations in influencing P-wave characteristics during the development of paroxysmal AF in elderly patients.

Background: Glioblastoma is a common primary malignant tumor posing a serious threat to human life and health. Protocatechuic acid (PCA) is a natural phenolic compound with good anti-tumor activity. The study aimed to investigate whether pyroptosis can be activated by PCA in glioma cell.

Methods: Different concentrations of PCA were used to treat glioma cell lines U87 and U251 for varying durations. Cell proliferation was quantified using the Cell Counting Kit-8 (CCK-8) assay. The Transwell chamber assay was employed to evaluate cell invasion, while cell migration was assessed via the scratch assay. Pyroptosis levels were determined through immunofluorescence staining. Additionally, the protein and mRNA expression levels of nucleotide-binding and oligomerization domain-like receptor thermal protein domain-associated protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase-1), and gasdermin D (GSDMD) were analyzed using Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR).

Results: Intervention with PCA resulted in a significant suppression of viability, invasion and migration of glioma cells in a dose-dependent manner (p < 0.05). Additionally, the GSDMD positivity rate, as well as the protein and mRNA expression levels of NLRP3, caspase-1, and GSDMD showed significant increases in glioma cells (p < 0.05). Further intervention with NLRP3-specific inhibitor MCC950 reversed the effects of PCA and resulted in a significant increase in cell viability and number of invading cells (p < 0.01), a significant decrease in GSDMD positivity (p < 0.01), and a significant decrease in the protein and mRNA expression levels of NLRP3, caspase-1, and GSDMD in glioma cells (p < 0.01).

Conclusion: PCA mediates pyroptosis in glioma cells by regulating the NLRP3/caspase-1/GSDMD signaling pathway.

Objective: This study aimed to investigate the effects of curcumin (Cur) on programmed cell death 1 ligand 1 (PD-L1) expression in neutrophils from septic rats and its regulatory influence on T-lymphocyte apoptosis and lung injury in a rat sepsis model.

Methods: Cecum ligation and puncture (CLP) experiments were conducted to establish a rat sepsis model, with the subsequent grouping of rats based on curcumin administration. Rats were monitored for 7 days to assess the 7-day survival rate. Serum, lung tissues, and thymus tissues were collected. Flow cytometry and immunohistochemistry were utilized to assess the number of PD-L1-positive neutrophils and PD-L1 positivity in both blood and lung tissues. Hematoxylin and eosin (HE) staining and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) histochemistry were employed to examine pathological changes and cell apoptosis in lung and thymus tissues. Furthermore, a kit was employed to measure the activity of myeloperoxidase (MPO), a marker of neutrophil activation, in lung tissues. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine plasma levels of inflammatory factors. Neutrophils were extracted and co-cultured with normal T lymphocytes. TUNEL assays were used to evaluate T-lymphocyte apoptosis, and Western blotting was performed to analyze the expression of PD-L1 and programmed cell death 1 (PD-1).

Results: In in vivo experiments, septic rats exhibited a markedly low 7-day survival rate of 12.5%, significantly elevated PD-L1 expression and positivity in blood and lung tissues, severe lung and thymus tissue damage, and significant cell apoptosis. Additionally, they had increased plasma concentrations of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and decreased plasma concentration of interleukin 10 (IL-10) compared to normal and sham-operated rats (p < 0.05). Curcumin-treated septic rats demonstrated significantly improved 7-day survival, reduced PD-L1 expression and positivity in blood and lung tissues, mitigated lung and thymus tissue injury and cell apoptosis, lower plasma concentrations of TNF-α and IL-6, and higher plasma concentrations of IL-10 (p < 0.05). In vitro experiments showed that co-culture of T lymphocytes with neutrophils from septic rats resulted in a significantly higher rate of T cell apoptosis and increased expression of PD-L1 and PD-1 compared to co-culture with neutrophils from sham-operated rats (p < 0.05). Neutrophils from curcumin-treated rats exhibited a significantly lower rate of apoptosis in co-cultured T lymphocytes and decreased expression of PD-L1 and PD-1 (p < 0.05). The addition of PD-L1 antibodies to co-cultured neutrophils and T lymphocytes in septic rats significantly reduced T lymphocyte mortality (p < 0.05).

Conclusion: Curcumin effectively mitigates lung and thymus inju

Interleukins (ILs) are a group of cytokines that regulate immune responses and inflammation, playing important roles in the pathogenesis, diagnosis, and treatment of urological diseases. This review provides an analysis of the involvement of interleukins in bladder cancer, benign prostatic hyperplasia (BPH), renal cell carcinoma (RCC), urinary tract infections (UTIs), interstitial cystitis/bladder pain syndrome (IC/BPS), and urolithiasis. ILs regulate immune cell activity and mediate tumor progression, immune evasion, and inflammation, making them valuable biomarkers and therapeutic targets. Elevated levels of IL-6, IL-8, and IL-18 are associated with disease severity and prognosis in bladder cancer, RCC, and BPH. Additionally, IL-10 is anti-inflammatory, offering therapeutic potential in chronic inflammatory conditions such as BPH and IC/BPS. Emerging therapies targeting IL pathways, including IL-2 and IL-17 inhibitors, have shown promise in modulating immune responses and improving clinical outcomes. The diagnostic utility of urinary IL biomarkers, particularly IL-6 and IL-8, has been demonstrated in UTIs and urolithiasis. This review highlights not only the therapeutic potential of interleukins but also their integral role in the immunopathology of urological diseases, distinguishing it from previous analyses by emphasizing IL-targeted therapies to improve diagnostic and therapeutic outcomes.