Current medicinal chemistry最新文献

Introduction: The causality between thyroid disorders and Gastroesophageal Reflux Disease (GERD) remains to be deciphered. This two-sample Mendelian Randomization (MR) study was performed to elucidate the causal association between GERD and thyroid diseases and functions.

Methods: Summary statistics for GERD were retrieved from a published GWAS dataset deposited in the Integrative Epidemiology Unit OpenGWAS database. Thyroid hormone level data were obtained from the ThyroidOmics Consortium, and genetic variants associated with thyroid disorders were sourced from the FinnGen Project. MR statistical analyses used the Inverse Variance Weighted (IVW) algorithm, followed by various sensitivity and reliability analyses. Odds Ratio (OR) and beta coefficient (β) with 95% Confidence Interval (CI) were estimated for categorical and continuous outcomes, respectively. The significant causal association was determined based on a Bonferroni-corrected threshold of p-value < 0.0021 (calculated as 0.05/24 trait pairs).

Results: The findings of MR analysis tend to favor the causality of GERD for hyperthyroidism (IVW: OR = 1.517, 95% CI: 1.164 to 1.978, p = 2.04E-03) but not the other thyroid disorders. The reverse MR estimates suggested that thyroid disorders may not affect the susceptibility of GERD. Moreover, genetic proxied GERD was significantly negatively associated with circulating Thyroid Stimulating Hormone (TSH) level (IVW: β = -0.048, 95% CI: -0.078 to -0.019, p = 1.17E-03), whereas the causality of this enteropathy on Free Triiodothyronine (FT3), Free Thyroxine (FT4), Total Triiodothyronine (TT3), FT3/FT4 ratio, and TT3/FT4 ratio (and vice versa) is unfounded.

Discussion: This MR study indicates that the genetic liability to GERD is significantly detrimental to hyperthyroidism risk and the homeostasis of TSH.

Conclusion: The findings suggest that effective GERD management could mitigate hyperthyroidism risk.

Background: Coronary atherosclerotic disease (CAD), clinically manifesting as progressive coronary atherosclerosis (As), involves endothelial cell (EC) dysfunction. HYMAI may contribute to atherogenesis by acting on ECs, but its regulation of endothelial injury and role in As pathogenesis remain unclear.

Methods: HYMAI expression was assessed via PCR array in blood samples from healthy individuals, patients with premature coronary atherosclerotic disease (PCAD), and patients with mature coronary atherosclerotic disease (MCAD) (each group consisting of 4 males and 2 females). Using male ApoE-/- and LDLR-/- mice fed with a high-fat diet (HFD) to model As, we evaluated the effects of endothelial-specific HYMAI overexpression on aortic lesions. Autophagy and apoptosis were analyzed in ox-LDL-treated human coronary artery endothelial cells (HCAECs).

Results: HYMAI levels increased sequentially in healthy individuals, PCAD, and MCAD patients. In HFD-fed ApoE-/- and LDLR-/- mice, aortic atherosclerosis progressed with age, while HYMAI expression in aortic tissue declined. HYMAI overexpression in ECs promoted autophagy and attenuated atherosclerosis. in vitro, ox-LDL suppressed HYMAI, triggering autophagic inhibition and apoptotic activation in HCAECs. HYMAI overexpression rescued ox-LDL-impaired autophagy and suppressed apoptosis through the miR-19a-3p/ATG14 pathway. miR-19a-3p overexpression reversed autophagic rescue and promoted apoptosis by repressing ATG14.

Discussion: HYMAI upregulation counteracts ox-LDL-treated endothelial autophagic inhibition via the miR-19a-3p/ATG14 pathway, rescuing apoptosis and attenuating As in both in vivo and in vitro settings.

Conclusion: Our results demonstrated that HYMAI attenuated As progression in As mice and ox-LDL-treated HCAECs by enhancing endothelial autophagy through the miR-19a-3p/ATG14 axis. These findings establish HYMAI as a novel regulatory mechanism and provide a potential druggable target for As and CAD.

Introduction: "Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment.

Method: This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into "penumbra freezing" and "non-penumbra freezing" groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with "penumbra freezing." Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes.

Results: Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the "penumbra freezing" group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the "non-penumbra freezing" group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the "penumbra freezing" group (304.63 ± 52.44 mg/L) than in the "non-penumbra freezing" group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of "non-penumbra freezing" beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers.

Discussion: ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology.

Conclusions: ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for "penumbra freezing," suggesting the potential to extend the treatment window.

Reactive oxygen species (ROS) play a pivotal role in cellular damage and the signaling processes, with their production significantly influenced by antimicrobial agents such as β-lactam antibiotics. This review explores the dual role of β-lactam antibiotics and comparable agents, where relevant in antimicrobial therapy, and their significant impact on cellular oxidative stress through the production of ROS. These antibiotics not only disrupt bacterial cell wall synthesis by binding to DD-transpeptidase domains but also induce the formation of ROS, leading to protein damage via chemical modifications into quinone-like products. This process generates advanced oxidation protein products (AOPPs) that influence gene expression related to protein repair. Furthermore, β-lactam antibiotics uniquely expedite the degradation of cellular proteins, affecting the solute carrier family and leading to transcriptional reprogramming. Despite their efficacy in combating bacterial infections, the production of ROS by these antibiotics also poses risks, including oxidative damage and potential antibiotic resistance. Understanding these mechanisms provides insights into optimizing therapeutic strategies and mitigating adverse effects associated with β-lactam and comparable agents, where relevant.

Introduction: Diffuse large B-cell lymphoma (DLBCL) pathogenesis is poorly understood, with limited causal evidence linking circulating inflammatory proteins (CIPs) and metabolites to disease risk. Observational studies face challenges from confounding and reverse causation, while existing Mendelian randomization (MR) analyses lack bidirectional designs and multi-omics integration.

Methods: A bidirectional two-sample MR design was applied using inverse-variance weighting (IVW). Genetic instruments for 91 CIPs derived from Olink proteomic data (14,824 participants). DLBCL genetic associations (1,050 cases; 314,193 controls) were obtained from FinnGen (R10 release). Data for 1,091 blood metabolites and 309 metabolite ratios were sourced from the GWAS Catalog.

Results: Ten CIPs exhibited causal effects on DLBCL. Risk-increasing proteins included: IL-10 (OR=1.46, 95%CI=1.05-2.03), TSLP (1.37,1.01-1.84), IL-17C (1.34,1.05-1.72), NRTN (1.30,1.02-1.66), OPG (1.29,1.01-1.66), and MCP1 (1.26,1.04-1.52). Protective proteins included: CD40 (0.82,0.67-1.00), CXCL9 (0.78,0.61-0.98), CD5 (0.77,0.61-0.97), and MCP3 (0.76,0.58-0.99). Reverse causation was absent for 7 proteins. Mediation analysis revealed 17.2% (p=0.048) of CD5's protective effect was mediated by 1-methylhistidine.

Discussion: These findings establish CIPs as causal factors in DLBCL pathogenesis and identify metabolite-mediated pathways as novel mechanistic links. The bidirectional design and multi-omics integration overcome key limitations of prior research, though statistical power for some mediation tests was limited by metabolite GWAS sample sizes.

Conclusion: Plasma inflammatory proteins causally influence DLBCL risk, partially mediated by metabolites. This underscores metabolite pathways as potential targets for therapeutic intervention.

Introduction: Klotho is a multifunctional protein with anti-aging properties that plays a role in regulating vitamin D and phosphate metabolism. Sarcopenia is characterized by the loss of muscle mass and strength and is an important public health concern due to its negative effects on health. The aim of this study was to investigate the association between α-Klotho levels and the frequency of sarcopenia in a diverse population.

Methods: This study analyzed data from 1,250 participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. Participants were divided into four subgroups based on serum α-Klotho levels. Sarcopenia was assessed using skeletal muscle index and handgrip strength measurements. Multivariable logistic regression analysis was used to determine the association between serum α-Klotho levels and sarcopenia.

Results: There was a significant difference in serum α-Klotho levels between patients with sarcopenia and patients without sarcopenia. In an unadjusted multivariable logistic regression model, higher α-Klotho serum levels were associated with a lower risk of sarcopenia (p < 0.05). This trend was maintained in the partially adjusted model, indicating that higher levels of α-Klotho were associated with a lower risk of sarcopenia. However, the fully adjusted model did not show significance.

Discussion: Several factors significantly influence the relationship between serum α-Klotho levels and sarcopenia, including sex, ethnicity, alcohol consumption, body mass index (BMI), vitamin D levels, and disease status. Our findings indicate that the risk of sarcopenia is elevated in individuals within the lowest quartile of serum α-Klotho levels. Furthermore, a negative correlation exists between α-Klotho levels and grip strength, observed in both the overall sample and the aging-related subgroup. These results highlight the necessity for further investigation into the complex interplay between α-Klotho and grip strength, particularly in the context of sarcopenia associated with renal disease.

Conclusion: Serum α-Klotho levels in different populations are negatively correlated with the risk of sarcopenia, suggesting that α-Klotho may be involved in the occurrence and development of sarcopenia. Therefore, measuring α-Klotho levels in clinical practice may be a valuable diagnostic tool to identify individuals at high risk of developing sarcopenia.

Introduction: Hepatocellular Carcinoma (HCC) exhibits high recurrence rates, particularly when accompanied by Microvascular Invasion (MVI). We identified MVI-related biomarkers and established a prognostic model for personalized HCC treatment.

Methods: Data were downloaded from The Cancer Genome Atlas (TCGA) and HCCDB databases. Key radiomics features were identified using the support vector machine-recursive feature elimination (SVM-RFE) algorithm, and differential expression analysis was performed with DESeq2. This was followed by functional enrichment analysis using the clusterProfiler package. Through univariate and Lasso regression analyses, we constructed a robust RiskScore model to effectively stratify HCC patients into distinct risk groups based on the median RiskScore value. The model prediction performance was evaluated using ROC curves and Kaplan-Meier (KM) analysis. We used the CIBERSORT algorithm to characterize immune cell infiltration patterns and conducted GSEA to identify differentially activated pathways between the risk groups.

Results: Radiomic analysis revealed four significant features strongly associated with MVI, enabling the construction of a nomogram model with robust classification performance (AUC = 0.742). Subsequent analysis identified 241 overlapping MVI-related Differentially Expressed Genes (DEGs) enriched in critical tumor proliferation and invasion pathways. A 10-gene RiskScore model was developed, demonstrating excellent prognostic discrimination in training and validation cohorts. CIBERSORT analysis revealed significant correlations between specific immune cell infiltration and the 10 genes. GSEA analysis showed significant enrichment of cell cycle regulation pathways in the high-risk group, suggesting their important role in MVI.

Discussion: The RiskScore was established using MVI-related features for prognosis assessment in HCC.

Conclusion: Our findings provided novel biomarkers and a theoretical basis for the early diagnosis and personalized treatment of HCC.

Alzheimer's disease (AD) is the most prevalent form of dementia among older adults worldwide. Amidst several hypotheses to explain the pathobiology of the disease are biochemical indicators such as β-amyloid (Aβ) plaques; neurofibrillary tangles, caused by hyperphosphorylated tau protein; oxidative stress; metal dyshomeostasis; low levels of acetylcholine, and neuroinflammation. Considering the multifactorial nature of AD, there has been an increase in research for novel multitarget compounds, mainly utilizing molecular hybridization for drug design. In this review, we focus on the 8-hydroxyquinoline moiety, a privileged metal-binding agent with Aβ antiaggregating properties, and its derivatives, aiming to have an effect on multiple molecular targets. Furthermore, the most prominent structure-activity relationships found on the analyzed compounds, along with the most promising strategies explored by researchers, are discussed. That way, we hope to provide a comprehensive perspective on the development of anti- Alzheimer agents based on the 8-hydroxyquinoline moiety in the last decade.

Connexin43 (Cx43), encoded by the GJA1 gene, plays a crucial role in the formation of hemichannels and the assembly of gap junctions between adjacent cells, facilitating the efficient transport of ions and small molecules. Increasingly studies have revealed the regulatory roles of Cx43 in endothelial cells. Cx43 is not only implicated in the normal function of endothelial cells such as regulating the endothelial barrier, promoting endothelial angiogenesis, regulating vascular tone, and other subtle regulations, but also contributed to endothelial dysfunction, including inflammatory responses, endothelial cell death, and increased endothelial permeability. Here we provide a summary of the current understanding of Cx43 in the pathogenesis of atherosclerosis, hypertension, stroke, and diabetes. In addition, the potential therapeutic approaches targeting Cx43 are also proposed.

Background: Endothelins are a family of vasoconstrictive peptides known for their high potency. They are mainly synthesized and secreted by the endothelial cells lining the blood vessels in response to various stimuli. Their main physiological role is the regulation of vascular tone, affecting blood pressure and tissue perfusion.

Objective: The aim of this review was to evaluate the importance of Endothelin-1 (ET-1) plasma levels as a marker in diagnosis, disease burden, or development, due to its vascular effects.

Methods: Data from several studies in different organ systems, collected over the last thirty years, were collected. A statistical analysis was performed to reveal any similarities and differences among them.

Results: ET-1 was found to be increased in arterial and pulmonary hypertension. Plasma ET-1 was elevated in patients with heart failure, autoimmune disease, chronic kidney disease, and liver failure. In all these cases, ET-1 was increased at least twice the maximum of normal plasma concentration in healthy subjects, in a similar pattern, independently of the disease background. More importantly, plasma ET-I levels increased even more according to the severity of the disease, not necessarily in a linear manner.

Conclusion: Endothelin-1 appears to increase similarly across various pathological conditions, making it a potential biomarker for overall human physiological status.