Discovery medicine最新文献

Background: Whether seizure presentation in patients afflicted with primary brain tumors (PBT) is associated with clinical prognosis remains an open question. We explore this association using the Nationwide Readmission Database (NRD).

Methods: A systematic literature review was conducted to summarize prior studies focusing on the association between the presence of seizure and outcomes of PBT/brain metastases (BM). The statistical power of the study was defined as a function of the effect size. We identified 50,380 and 32,789 PBT and BM patients in the NRD (2010-2018), respectively. Multivariable logistic regression models were utilized to assess the risk of mortality and the related factors.

Results: In a multivariable model accounting for known survival pertinent variables (age, gender, insurance status, income, hospital length of stay, discharge disposition, hospital features), the adjusted odds ratio (aOR) of death for PBT patients who presented with seizures and underwent craniotomy was 0.67 [95% Confidence Interval (CI): 0.52-0.86, p = 0.002] relative to those presented without seizures. The aOR of death for PBT patients who presented with seizures and underwent biopsy was 0.55 (95% CI: 0.30-1.00, p = 0.048) relative to those without seizures. This association was not observed for BM patients; the aOR of death for BMs who presented with seizures was 0.91 (p = 0.483) and 0.32 (p = 0.090) relative to those presented without seizures for craniotomy and biopsy patients, respectively. A comprehensive review of the literature showed that the predominance of the available studies supported the reported association.

Conclusions: We report an association between seizure at presentation and decreased mortality risk for PBT patients. The association was robust in both patients who underwent craniotomy as well as stereotactic needle biopsy but was not observed in BM patients.

Osteoarthritis is a multifactorial condition marked by the gradual deterioration of joint cartilage, synovial inflammation, alterations in the subchondral bone and changes in the surrounding soft tissues. Clinical assessments and patient-reported outcome measures can identify pathological tissue alterations in osteoarthritis, in conjunction with radiographic evaluation of osteophytes, bone sclerosis, and joint space reduction. Although available treatments can help manage symptoms, early identification of prognostic factors for osteoarthritis progression is crucial for personalizing interventions and improving long-term outcomes. Therefore, it is essential to identify the key factors that can influence the disease's progression, including biological, mechanical, and clinical aspects. This review synthesizes current findings on the prognostic and diagnostic value of various biomarkers (systemic, intrinsic) and prognostic factors (biochemical, genetic, epigenetic) in knee and hip osteoarthritis. We also discuss the role of machine learning tools in identifying new biomarkers associated with osteoarthritis development and progression, paving the way for translation to clinical studies. In addition, we discuss recent studies aimed at identifying potential biomarkers and molecules that could serve as therapeutic strategies for osteoarthritis treatment.

Background: Premature ovarian insufficiency (POI) is characterized by a reduction in primary follicle count along with abnormal follicle development. This study aims to explore the impact of combined oral contraceptives (COCs) on the apoptosis of ovarian granulosa cells, which are instrumental for follicular development, in POI and the underlying mechanisms, to provide theoretical guidance for the treatment of POI.

Methods: A rat model of POI was established using tripterygium glycoside tablets. After treatment with COCs, the therapeutic effect of the animals was verified by means of hematoxylin-eosin staining, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Flow cytometry, cell counting kit-8 (CCK-8), quantitative polymerase chain reaction, and Western blotting were utilized to investigate the impact of COCs on granulosa cell apoptosis, as well as the function of the interleukin (IL)-11/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Further experiments were also conducted to verify whether COCs could inhibit granulosa cell apoptosis through this pathway.

Results: COCs treatment was effective in improving ovarian granulosa cell status, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and increasing estradiol levels in the POI rats (p < 0.01). IL-11 silencing promoted apoptosis in POI granulosa cells by inhibiting the PI3K/AKT pathway. COCs treatment partially reversed these effects by upregulating IL-11 expression and restoring PI3K/AKT pathway activity. This resulted in increased levels of B-cell lymphoma 2 (Bcl-2) (p < 0.05) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) (p < 0.01), while suppressing the expression of Bax and cleaved-cysteine-aspartic acid protease 3 (cleaved-caspase 3) (p < 0.001).

Conclusion: Our findings demonstrated that COCs protect ovarian granulosa cells from apoptosis in rats with POI, an effect mediated through the IL-11/PI3K/AKT signaling cascade.

Leukemia, a group of malignant blood disorders, arises from the uncontrolled proliferation of abnormal white blood cells. Genetic mutations play a critical role in the initiation and progression of leukemia. This review aims to provide an overview of the genetic landscape of leukemia, focusing on the most common genetic alterations and their clinical implications. A literature search was conducted to identify relevant studies on genetic mutations in leukemia. The identified studies were critically appraised to assess their methodological quality. The present review highlights the key genetic alterations associated with different types of leukemia, including chromosomal translocations, point mutations, and gene copy number variations. These genetic abnormalities can impact disease prognosis, treatment response, and overall patient survival. A comprehensive understanding of the genetic basis of leukemia is essential for accurate diagnosis, prognostication, and the development of targeted therapies. Future research should focus on identifying novel genetic markers, elucidating the underlying mechanisms of leukemogenesis, and developing innovative therapeutic strategies.

Background: Asthma is a common respiratory system disease characterized by airway inflammation and airway remodeling. Amygdalin, an active component of the traditional Chinese medicine Bitter Almonds, has been shown to inhibit liver fibrosis via the inactivation of the transforming growth factor-beta 1 (TGF-β1)/Smads pathway. This study aims to investigate the effects of Amygdalin on airway inflammation and remodeling in asthma, as well as its regulatory mechanisms.

Methods: An asthma mouse model was constructed using ovalbumin (OVA) induction. Mouse bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for in vivo experiments, and airway smooth muscle cells (ASMCs) were isolated from BALB/c mice for in vitro experiments. The mechanism of Amygdalin and the TGF-β1/Smads signaling pathway in the mouse model was analyzed pathologically and molecularly using hematoxylin-eosin (HE) staining, Masson trichrome staining, Western blot, and enzyme-linked immunosorbent assay (ELISA).

Results: Amygdalin ameliorated the pathological abnormalities of lung tissues in the OVA-induced mouse model, reducing inflammation by downregulating OVA-specific immunoglobulin E (IgE) and inflammatory factors interleukin (IL)-4, IL-5, and IL-13 (p < 0.001). It also reduced lung tissue fibrosis (p < 0.01). Additionally, Amygdalin inhibited the levels of TGF-β1, p-Smad2, and p-Smad3 proteins (p < 0.05), and downregulated the fibrosis markers alpha-smooth muscle actin (α-SMA), Collagen I, and Collagen III expression in the OVA-induced asthma mouse model (p < 0.01).

Conclusion: Amygdalin can regulate the TGF-β1/Smads signaling pathway and alleviate airway inflammation and remodeling in an asthma model in mice.

Objective: Pancreatic cancer (PC) is a type of highly malignant tumor associated with poor prognosis, whose progression is driven by hypoxia in the tumor microenvironment. This study aims to explore the effects of hypoxia-induced upregulation of acetyl-CoA synthetase 2 (ACSS2) on the proliferation and stemness of PC cells and its potential molecular mechanism, so as to provide new targets and therapy strategies for the PC.

Materials and methods: PC cells (PANC-1) were cultured under separate conditions: hypoxic and normoxic. Cell models of ACSS2 overexpression, ACSS2 knockdown and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) knockdown were constructed using transfection technique. Cell counting kit 8 (CCK-8) and clonal formation assay were used to assess cell viability, and cell stemness was analyzed by means of sphere-formation assay and detection of stem-related markers. A mouse tumor model was established by axilla injection of tumor cells, and tumor growth was evaluated by measuring the volume and weight of the isolated tumors. Relative mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry.

Results: Hypoxic condition upregulated the expression of ACSS2 in PC cells. CCK-8 and clonal formation assays showed that upregulation of ACSS2 promoted cell proliferation (p < 0.001), while knockdown of ACSS2 inhibited cell proliferation (p < 0.001). Sphere formation assay and stemness marker detection showed that ACSS2 upregulation could maintain cell stemness (p < 0.001), while knockdown could inhibit it (p < 0.01). Through mechanistic studies, we found that ACSS2 activated phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway through HMGCS1. Interference with HMGCS1 inhibited pathway activation caused by ACSS2 upregulation and hindered cell proliferation and stemness. In vivo experiments further demonstrated that ACSS2 accelerated PC xenograft tumor growth and promoted tumor stemness.

Conclusion: Hypoxia induces upregulation of ACSS2 and activates PI3K/AKT/mTOR pathway through HMGCS1, thereby enhancing the proliferation and stemness of PC cells. This finding offers a novel perspective for understanding the development mechanism of PC and highlights a potential molecular target for developing targeted therapeutic strategies.

Background: Ovarian cancer (OC) is one of the most lethal forms of gynecological malignancies. Previous studies indicate that S100 calcium-binding protein A8 (S100A8) regulation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway has been implicated in the development and progression of a variety of cancers, but its effects and mechanisms in OC cells remain unclear. This study aims to explore the effect of S100A8 on autophagy and apoptosis in OC cells and the regulatory effects of the PI3K/Akt signaling pathway.

Methods: Viability of OC cells was assessed by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration was determined using the Transwell assay. The effect of S100A8 on autophagy in OC cells was assessed using immunofluorescence and transmission electron microscopy. Flow cytometry analysis was conducted to assess apoptosis. To study the expression of genes associated with cell viability, migration, autophagy, apoptosis, and the PI3K/Akt signaling pathway, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were performed.

Results: High concentrations of S100A8 protein significantly inhibited the activity of OC cells, with the most pronounced effect observed at 72 hours (p < 0.05). S100A8 protein inhibited the proliferation of OC cells and decreased the expression level of migration-driving factors (p < 0.05). S100A8 protein promoted apoptosis and inhibited the protein levels of Beclin 1 and microtubule-associated protein 1 light chain 3-II (LC3-II) in OC cells (p < 0.05). However, the PI3K/Akt activator blocked the inhibitory effects of S100A8 on OC cell activity, autophagy, and migration, and hindered it from promoting apoptosis.

Conclusions: With its ability to inhibit proliferation, migration, and autophagy, and promote apoptosis in OC cells by inhibiting the PI3K/Akt pathway, S100A8 holds promise as a potential target for the prevention and treatment of OC, providing an effective therapeutic strategy for the clinic.

Background: Chlorogenic acid (CGA) exerts immunomodulatory effects by regulating the proportion of regulatory T cells (Tregs), and T-cell dysregulation is a known feature of post-traumatic osteomyelitis (PTO). This study explored the mechanism of CGA in the treatment of PTO from the perspective of T-cell immunity.

Methods: Lymphocytes isolated from rat spleens were stimulated with interleukin (IL)-2. A PTO model was established by injecting Staphylococcus aureus into the tibial marrow cavity of New Zealand white rabbits. PTO rabbits were treated with either CGA by gavage or lentiviral IL-2 injection. The Treg proportion was evaluated by flow cytometry. The expression of forkhead box protein 3 (Foxp3), cytotoxic T lymphocyte antigen-4 (Ctla-4), and IL-2 was quantified by quantitative real-time polymerase chain reaction. The concentrations of tumor necrosis factor-α (TNF-α), IL-10, and IL-2 were measured using enzyme-linked immunosorbent assays. Micro-computed tomography and hematoxylin and eosin staining were performed to characterize bone destruction. The proliferation of CD4⁺ T/CD8⁺ T cells was evaluated by flow cytometry.

Results: IL-2 stimulation elevated the proportion of Tregs in rat splenic lymphocytes, upregulated Foxp3, Ctla-4, and IL-10 expression, and decreased TNF-α expression (p < 0.05). PTO rabbits exhibited significant bone destruction and inflammatory cell infiltration in bone tissue. In the peripheral blood of PTO rabbits, the Treg proportion was elevated, with increased expressions of Foxp3, Ctla-4, IL-10, and IL-2, reduced TNF-α expression, and increased proliferation of CD4⁺ T/CD8⁺ T cells. These changes were significantly reversed by CGA administration (p < 0.001). However, the reversal effects of CGA were offset by exogenous IL-2 (p < 0.001).

Conclusion: CGA alleviates PTO by inhibiting IL-2-mediated upregulation of Tregs.