Discovery medicine最新文献

Cardiogenic shock (CS) is a critical condition marked by end-organ hypoperfusion and sustained hypotension, necessitating the use of inotropic or vasoactive agents for hemodynamic support. It is the leading cause of mortality in patients with acute myocardial infarction (AMI), exhibiting in-hospital mortality rates of 40% to 50% despite advances in treatment. Treatment strategies aim to restore hemodynamic stability and address the underlying cause through pharmacological agents and mechanical circulatory support devices. However, the persistently high mortality rates underline the challenges of a timely diagnosis, the limitations of current treatments, and the lack of a standardized multidisciplinary network of care. This review critically examines the existing literature on CS management, focusing on the efficacy, safety, and practical application of pharmacological interventions. By synthesizing evidence from recent studies, clinical guidelines, and expert consensus, our objective is to provide a useful, comprehensive, evidence-based framework to guide clinicians in the use of pharmacologic therapies tailored to the diverse presentations and stages of CS.

Background: Recurrent spontaneous abortion (RSA), also known as repeated miscarriage, refers to the consecutive loss of pregnancy three times or more before the fetus reaches viability. In this study, we aimed to investigate the impact of transforming growth factor β3 (TGF-β3), which plays a crucial role in immune dysregulation, on the imbalance of regulatory T cell (Treg) and T helper 17 (Th17) cells.

Methods: First, we isolated T cells from an RSA mouse model we established in-house. Tregs and Th17 cells were labeled by targeting forkhead box protein P3 (Foxp3) and retinoic-acid-receptor-γt (RORγt), respectively, and the levels of Tregs and Th17 were determined by flow cytometry. The expression levels of Foxp3, RORγt, TGF-β3, interleukin (IL)-10, and IL-17 in T cells were measured by means of reverse-transcription quantitative polymerase chain reaction (qRT-PCR) and Western blotting. The levels of interferon-γ (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4 in mouse serum were quantified using enzyme-linked immunosorbent assay (ELISA). si-TGF-β3 was transfected into RSA mice, and the expression levels of IL-17 and CD25 were determined by flow cytometry, during which T cells were labeled with antibodies against IL-17 and CD25, respectively. Additionally, si-TGF-β3 or TGF-β3 interference therapy was administered to RSA mice, and the expression levels of IL-1β, tumor necrosis factor-α (TNF-α), IL-6, IFN-γ, GM-CSF, and IL-4 in mouse serum were measured using ELISA.

Results: In the RSA model, there was a significant decrease in the percentage of Treg cells, alongside an elevation of TGF-β3 mRNA (p < 0.05). The percentage of Th17 cells in RSA mice significantly increased and correlated positively with TGF-β3 levels. In RSA, the levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, IFN-γ, and GM-CSF increased, while those of anti-inflammatory cytokine IL-4 decreased (p < 0.05). Transfection of si-TGF-β3 into RSA mice reduced the percentage of Th17 cells and increased the percentage of Tregs and Treg/Th17 (p < 0.05). Increased levels of Th17-related markers and reduced levels of Tregs-related markers occurred following the administration of TGF-β3 to RSA mice (p < 0.05). Transfection of si-TGF-β3 into RSA mice also resulted in a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines (p < 0.05), while TGF-β3 administration reversed these changes in RSA mice, indicating the role of TGF-β3 in modulating the inflammatory response during RSA.

Conclusions: Knockdown of TGF-β3 enhanced Treg/Th17 balance in RSA, suggesting TGF-β3 as a potential therapeutic target for RSA.

Conjugation of substrate proteins with ubiquitin (Ub), a 76 amino acid protein, was discovered as the first major translational modification responsible for protein degradation. Ubiquitination occurs as a cascade among ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligases (E3) enzymes that transfer and covalently conjugate Ub to the lysine (Lys) residue and α-amino group in methionine (Met) residues of substrates. Following the initial conjugation, Ub itself then undergoes ubiquitination via its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and N-terminal methionine (M1). These possible sites of Ub polymerization/assembly result in a significantly diverse and numerous set of linkage types and lengths, including homotypic, mixed and/or branched chains, which provoke distinct cellular responses via their proteolytic and non-proteolytic functions. We overview here the multiplicity of ubiquitin code with a particular focus on linkage-specific roles in biological processes, especially in the pathogenesis and progression of diseases such as cancer, neurodegeneration, and immune disorders. We will also discuss the possibility and ongoing efforts of modulating the ubiquitin code as a therapeutic strategy in drug development, including targeted protein degradation (TPD).

Background: Glioblastoma is an incurable and aggressive oncological disease of the brain. Recent studies have shown that transcranial non-invasive photobiomodulation is a promising new alternative method for suppression of glioblastoma growth. The lymphatic endothelium of the meningeal lymphatic vessels is an important target for the therapeutic effects of photobiomodulation. However, the functions of the meningeal lymphatic vessels decline with age. Therefore, it remains unknown whether photobiomodulation can be effective in adults and the elderly. To answer this question, this study examined the role of the meningeal lymphatic vessels and brain drainage in age-related differences in resistance to glioblastoma.

Methods: The studies were performed on 6- and 24-month-old rats using a model of fluorescent glioblastoma. Tumor progression was assessed using magnetic resonance imaging and the Fluor I in vivo fluorescence imaging system. Photobiomodulation was performed for 14 days for phototherapy of glioblastoma or once to study photoeffects on the brain's drainage. Brain drainage was studied by optical imaging of the lymphatic excretion of dye from the brain to the deep cervical lymph nodes, as well as by assessing the water content in brain tissues and the intracranial pressure. Histological and immunohistochemical methods were used to study apoptosis, proliferation and migration of CD8+ cells from the peripheral lymphatic system to glioblastoma.

Results: We clearly show that the network of the meningeal lymphatic vessels and brain drainage reduced in 24-month-old rats vs. 6-month-old animals (p < 0.001), which is accompanied by a decrease in resistance to the development of glioblastoma. Photobiomodulation significantly increases survival in 6-month-old (p < 0.001), but not in 24-month-old rats via an improvement of the functions of the meningeal lymphatic vessels, including a facilitating the traffic of protective CD8+ cells to glioblastoma (p < 0.001), reducing intracranial pressure and brain edema. The blockade of lymphatic communication between the peripheral and meningeal lymphatic systems completely suppresses the therapeutic effects of photobiomodulation in 6-month-old rats (p < 0.001).

Conclusion: Thus, photobiomodulation is an effective method of stimulation of brain drainage and immunity increasing resistance to glioblastoma progression in early but not in late ontogenesis due to the age-related decline in the functions of the meningeal lymphatic vessels.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Early diagnosis and treatment of AD are of paramount importance, with the concept of biomarkers being intrinsically linked to diagnosis and therapy. Biomarkers are indices that can be objectively measured to indicate normal biological processes, pathological conditions, or responses to therapeutic interventions. In 2023, the National Institute on Aging and Alzheimer's Association released updated clinical diagnostic guidelines, refining the 2018 research framework. These guidelines categorize AD biomarkers into three types: core AD biomarkers, non-specific biomarkers of tissue response related to AD pathophysiology, and biomarkers for non-AD comorbidities, thus enhancing the amyloid/tau/x/neurodegeneration (ATX(N)) framework. This article aimed to provide a comprehensive overview of the advancements within the ATX(N) framework and the progress in the study of various biomarkers under this framework. It analyzes how biomarkers can facilitate early disease diagnosis, discusses the challenges of translating biomarkers into effective treatments, and explores their therapeutic prospects.

Background: Exploring the pathological mechanism of colorectal cancer (CRC) onset and advancement is critical to clinical diagnosis and treatment. In this context, our study brings a novel perspective by investigating the role and regulatory mechanism of E74 Like ETS Transcription Factor 1 (ELF1) in CRC, a topic that has not been extensively explored.

Methods: Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting (WB) assays were used to detect the expression of ELF1 in CRC cells. Sh-ELF1, ELF1 overexpresses lentivirus (Oe-ELF1), and Oe-Doublecortin Like Kinase 1 (DCLK1) were constructed and transfected into CRC cells. Transfection efficiency and the expression of stemness, as well as epithelial-mesenchymal transition (EMT)-related proteins were detected using RT-qPCR and WB assays. Cell proliferation and sphere-forming ability were detected using Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EdU) staining, and sphere formation assay. Cell migration and invasion were detected using wound healing and transwell assay. The tube-forming ability of human umbilical vein endothelial cells (HUVEC) cells was detected using tubular formation experiments. To investigate the regulatory mechanism of ELF1, the crosstalk between ELF1 and downstream DCLK1 was predicated and verified using the JASPAR database, luciferase reporter gene, and Chromatin Immunoprecipitation (ChIP) assay.

Results: Results of the present study demonstrated that ELF1 expression was upregulated in CRC cells (p < 0.001). ELF1 silence significantly inhibited CRC cell proliferation, stemness, invasion, migration, and angiogenesis (p < 0.001). ELF1 silence also suppressed the expressions of Nanog Homeobox (Nanog), SRY-Box Transcription Factor 2 (Sox2), Octamer-Binding Transcription Factor 4 (OCT4), N-cadherin, and Vimentin while increasing the expression of E-cadherin (p < 0.001). Besides, ELF1 could positively regulate DCLK1 expression. However, the results of subsequent experiments revealed that DCLK1 overexpression partially offset the inhibitory effects of ELF1 knockdown on CRC cell proliferation, stemness, invasion, migration, and angiogenesis (p < 0.01).

Conclusion: In summary, our study provides compelling evidence that ELF1 up-regulates DCLK1 expression, thereby promoting the malignant progression and stemness of colorectal cancer. These findings significantly contribute to our understanding of the regulatory mechanisms in CRC and may have implications for future therapeutic strategies.

Background: The retromolar canal (RMC) is an extension of the mandibular canal located in the distal region of the mandibular third molar. Accurately detecting the RMC using conventional two-dimensional images is challenging, potentially leading to anesthetic failure and sensory disorders. This study aims to explore the clinical application of a radiomic model based on panoramic radiographs in detecting the RMC.

Methods: A retrospective collection of cone beam computed tomography (CBCT) and panoramic radiographs was conducted on 800 patients, covering 1555 hemimandibles. CBCT images served as the gold standard for confirming the presence of RMC. A dataset comprising 846 retromolar regions was established for model training and testing, with an 8:2 ratio. On the panoramic radiographs, the retromolar regions were delineated as the regions of interest, and radiomic features were extracted and selected. Support vector machine (SVM), logistic regression (LR), k-nearest neighbors (KNN), and multilayer perceptron (MLP) were employed to construct detection models for the RMC. The performance of these algorithms was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA), and the area under the receiver operating characteristics curve (AUC) values were compared with those of a dentist and a radiologist.

Results: The RMC was identified in 423 (27.2%) out of 1555 hemimandibles on CBCT images. The four algorithms, particularly SVM and MLP, demonstrated outstanding classification abilities in detecting the RMC, with AUC values ranging from 0.831 to 0.895 in the training set and from 0.719 to 0.808 in the testing set. These results significantly surpassed those of the dentist and radiologist (p < 0.05).

Conclusion: Radiomics based on panoramic radiographs exhibit a high detection capability for the RMC, emphasizing its considerable clinical application value.

Background: The relationship between hematocrit (HCT) levels and the occurrence of major adverse cardiovascular events (MACEs) in patients with acute myocardial infarction (AMI) remains unexplored. A better understanding of this interplay may enhance the prognosis and management of AMI patients.

Methods: Between January 2021 and August 2022, clinical data were collected from patients diagnosed with AMI at 10 tertiary healthcare institutions in China. A total of 1946 eligible participants were included and divided into three groups based on sex-specific tertiles of HCT levels upon admission: 648 patients with low HCT levels, 649 patients with intermediate HCT levels, and 649 patients with high HCT levels. Follow-up approaches included hospital outpatient visits, inpatient stays, and telephone calls for 180 days. The primary endpoint was the occurrence of MACEs. Influential factors, including general information, admission status, and supplementary examination results that differed across the cohorts, were analyzed. Cox regression analysis was employed to evaluate the 180-day MACE rates and HCT levels in patients with AMI. To assess the reliability of the findings, three sensitivity analyses and subgroup analyses were performed.

Results: During this time, 136 individuals in the low HCT group, 77 in the intermediate HCT group, and 73 in the high HCT group experienced endpoint events. With all covariates controlled, the Cox regression analysis indicated that the low HCT group had a higher risk of MACEs compared to the intermediate HCT group [hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.07-1.95, p = 0.017]. The low HCT group also presented a higher risk of acute coronary syndrome (HR = 1.57, 95% CI = 1.06-2.32, p = 0.024). However, the high and intermediate HCT groups exhibited comparable prognoses for AMI. The limited cubic spline plot revealed that HCT values between 41.58% and 45.36% implied a protective effect against MACEs. These results were further verified by sensitivity analysis, and the subgroup analysis showed no variable interaction.

Conclusions: Our findings indicate that low HCT levels in patients with AMI increase the incidence of MACEs within 180 days, offering new insights into the prognosis and management of AMI patients.

Clinical trial registration: ChiCTR2200066456.

A vast range of neurological conditions impacting the central and peripheral nervous system are caused by ion channel dysfunctions, which are collectively referred to as channelopathies. These disorders, which are frequently autoimmune or genetic in nature, present as a variety of clinical syndromes, such as migraine, epilepsy, ataxia, neuropathic pain, and intermittent paralysis. The pathogenic mechanisms underlying these illnesses have been uncovered by recent developments in molecular genetics and electrophysiological research, opening up new avenues for accurate diagnosis and specialized treatment approaches. With an emphasis on important genetic variations and clinical manifestations, this study offers a targeted synthesis of channelopathies of the central and peripheral nervous system. By providing the most recent information on these complex disorders, this review aims to help physicians identify and treat channelopathies.