Molecular Medicine最新文献

Rare diseases refer to a group of neglected diseases with low prevalence that face challenges in diagnostics as well as therapeutics due to phenotypic heterogeneity and ineffective clinical trials. In this study, we evaluated two novel analogs of hydroxyethylamine & phthalimide (LTC-181 and LTC-1717) for their potential effect on the epimerase activity of mutant GNE proteins associated with GNE myopathy. GNE gene encodes a key bifunctional sialic acid biosynthetic enzyme, UDP-N-acetyl Glucosamine 2-epimerase/N-acetyl Mannosamine Kinase; GNE). The compounds have significantly increased the epimerase activity of r-F307C-GNE and r-A555V-GNE mutant proteins in vitro. Reduced GNE epimerase activity and sialic acid content in muscle cell-based model for GNE function (SKM-GNEHz) was increased by 2-fold after addition of these compounds. The proteomic study showed that the compounds affected cytoskeletal organization, autophagy and muscle atrophy. Also, treatment with analogs enhanced the cell viability of SKM-GNEHz cells with increased F-actin polymerization and cell migration, thereby, restoring GNE deficient function. Additionally, effect of these compounds was observed with enhanced autophagy and reduced muscle atrophy function in GNE deficient muscle cell. Docking and interaction studies showed that LTC-1717 stabilize GNE better than LTC-181, indicating better therapeutic potential. Overall, this study indicates that HEA-phthalimide analog could be promising leads for treating GNE myopathy.

Throughout a person's lifetime, thyroid hormones (THs) have an outsized impact on cardiovascular health from prenatal heart development to adult cardiac contractile function and blood pressure regulation. Maintaining a healthy functioning hypothalamic-thyroid axis is crucial for preventing cardiac-related and all-cause mortality. Patients with moderate to severe heart failure (HF) often manifest with low or borderline-low TH function. In this review article, we examine the potential of TH therapy in HF management by highlighting outcomes from recent clinical studies. We also address the need for a serum-based biomarker such as brain natriuretic peptide (BNP) that indicates disease stage of HF and that also correlates with cardiac tissue TH status. Recent and newer therapeutic strategies (including the combination of Triiodothyronine and Thyroxine) to advance the management of patients living with HF are proposed including a reassessment of what is normal thyroid status in these patients and the potential of TH treatment.

Multiple myeloma (MM) with high-risk (HR) genetic abnormalities has poor prognosis, despite the use of novel therapeutic agents. However, the individual contribution of specific HR genetic abnormalities or their co-occurrence to poor outcomes, especially in the era of novel agents, remains unclear. This study evaluated the impact of multi-hit TP53 (del(17p) and TP53 mutation or ≥ 2 TP53 mutations) compared with other HR abnormalities on progression-free survival (PFS), overall survival (OS) and blood signature in a real-world cohort of 204 patients with MM treated with novel agents (median follow-up 28 months). Patients with multi-hit TP53 (10.4%) had the shortest PFS and OS compared with those with single HR abnormalities (p ≤ 0.011) or with co-occurrence of ≥ 2 other HR abnormalities (p ≤ 0.002), regardless of therapy line. The relative risk of early progression in patients with multi-hit TP53 was almost three times higher than that of patients with other HR abnormalities. The prevalence of TP53 alterations increased in later disease stages: multi-hit TP53 was detected in 7.6% of patients with ≤ 1 prior therapy line and in 36.4% of patients with ≥ 2 prior lines. Patients with multi-hit TP53 also differed in blood signature, particularly in counts of white blood cells, lymphocytes, serum creatinine and β2-microglobulin levels compared with those with other HR abnormalities. In conclusion, multi-hit TP53 is associated with the poorest survival among all HR subgroups in MM. Considering that TP53 alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and TP53 mutations. Patients with multi-hit TP53 should be prioritized for inclusion in trials of novel therapeutic strategies.

Background: Microgravity alters immune cell function, potentially compromising host defense during spaceflight. Because appropriate immune regulation is also critical in chronic inflammatory and autoimmune conditions, insights from spaceflight biology may have broader implications for human health. Monocyte activation via the p44/42 MAPK pathway is central to inflammatory responses, yet the influence of microgravity on this signaling cascade remains incompletely understood. This study aimed to determine how microgravity affects basal and lipopolysaccharide (LPS)-stimulated ERK1/2 kinases (also known as p44/42 MAP kinases) activity in human monocytes, focusing on signaling state redistribution at both single-cell and population levels.

Methods: Monocytes were cultured during spaceflight under either normal gravity (1G) or microgravity (µG) and exposed to LPS or control conditions. MAPK activity was quantified and analysed to assess basal signaling, stimulus responsiveness, and variability within the population.

Results: Basal MAPK activity was significantly elevated in µG compared with 1G monocytes (p = 0.0181). LPS stimulation robustly increased MAPK activity in 1G cells (p = 0.0267) but not in µG (p = 0.6752). Although baseline signaling was higher in µG, LPS responses in µG and 1G were not significantly different (p = 0.7905). Under microgravity, the cell population displayed broader signaling distribution and a larger non-responsive fraction. Although baseline signaling was higher in µG net LPS responsiveness was diminished compared with 1G.

Conclusion: Microgravity redistributes monocyte signaling states, increasing basal ERK1/2 activity while attenuating rapid stimulus-induced activation and expanding the non-responsive cell fraction. These findings provide new mechanistic insight into how microgravity shapes immune signaling and highlight cellular heterogenety as a critical determinant of immune regulation during spaceflight.

Methylmalonic acidemia (MMAemia) is an inborn error of organic acid metabolism characterized by the accumulation of toxic metabolites-including methylmalonic acid (MMA), 2-methylcitric acid (2-MCA), propionic acid (PA), homocysteine (Hcy), ammonia, and lactate-due to defects in methylmalonyl-CoA mutase or impaired cobalamin metabolism. These metabolites exert profound effects on the central nervous system, contributing to neurological injury through tightly interconnected mechanisms, including mitochondrial dysfunction, neuroinflammation, and excitotoxicity. This review synthesizes current evidence on how these metabolites trigger neurological dysfunction, integrating findings from clinical studies, animal models, and cellular systems. We also highlight the increasingly recognized role of aberrant post-translational modifications (e.g., methylmalonylation, propionylation, lactylation) in disrupting metabolic network architecture and reprogramming cellular metabolism. Despite advances in supportive therapies, intracerebral metabolite accumulation remains a therapeutic challenge. We discuss emerging strategies targeting mitochondrial protection, redox homeostasis, and inflammation-including enzyme replacement, gene therapy, antioxidant regimens, and exosome-based delivery. A deeper mechanistic understanding of metabolite-driven neurotoxicity is critical to the development of targeted interventions that can improve neurological outcomes in MMAemia.

Osteoarthritis (OA) is a global problem that seriously affects human health. At present, there is still a lack of effective drugs to treat OA. Therefore, we need to find more drugs with preventive and therapeutic effects on OA. In this study, we obtained single-cell RNA sequencing (scRNA-seq) and bulk-RNA seq datasets from Gene Expression Omnibus (GEO). By using high-dimensional weighted correlation network analysis (hdWGCNA), random forest method and protein-protein interaction (PPI) network analyses, five key genes (CXCL8, CCL20, MMP3, BIRC3 and ICAM1) related to OA were identified and the RT-qPCR experiments verified the differential expression of CXCL8, CCL20 and BIRC3 between Triclocarban (TCC) treated zebrafishes and controls. The SAVERUNNER algorithm predicted 42 candidate drugs. Mendelian randomization (MR) of the candidate drugs showed that the increased expression of TUBB1 led to a reduced risk of OA (β = -0.08, P-value = 4.56E-04), while Cabazitaxel (a microtubule dynamics inhibitor commonly used in the treatment of advanced prostate cancer) inhibits the expression of TUBB1, thus increases the risk of OA. Pitavastatin (a statin lipid-lowering drug that can reduce blood lipid levels and the risk of cardiovascular diseases) target genes expression (for HMGCR [Formula: see text]= 0.13, P-value = 2.67E-06, for ITGAL [Formula: see text]= 0.08, P-value = 6.57E-08) leads to an increased risk of OA, while Pitavastatin inhibits the expression of target genes, thus reduces risk of OA. The zebrafish experiments showed that Pitavastatin can increase the joint space of TCC treated OA zebrafish, while Cabazitaxel can decrease the joint space of TCC treated OA zebrafish. The RT-qPCR results of zebrafish verified that Pitavastatin inhibited the expression of HMGCR, while Cabazitaxel inhibited the expression of TUBB1. Our study suggested that Pitavastatin has therapeutic effects on OA, while Cabazitaxel increases the risk of OA.

Background: Adipose tissue influences cardiometabolic health through its endocrine activity and its role in regulating inflammation, lipid metabolism, and cardiovascular function. The expression of cardiac-associated genes within adipose tissue may reflect or contribute to cardiometabolic risk, yet this relationship remains poorly understood. This study investigates the expression profiles of the cardiac function associated genes GJA1, DES, DSP and SMOC2 in human adipose tissue, and analyses their associations with cardiometabolic traits. Additionally, we explore epigenomic mechanisms that may underlie their differential gene expression.

Methods: Expression profiling and functional enrichment analyses were conducted to identify depot-specific cardiac gene expression patterns. Quantitative PCR validated gene expression in paired subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples from 78 individuals with obesity. Gene expression was further validated in three independent cohorts (N = 1,548 total). Associations with clinical traits were assessed using Spearman correlations and multivariate linear regression, adjusted for age, sex, and BMI. Integration with transcriptomic and proteomic datasets publicly available from the Adipose Tissue Knowledge Portal was performed to strengthen clinical relevance. Epigenomic profiling using genome-wide ChIP-seq for histone marks (H3K4me3, H3K4me1, H3K27ac, H3K27me3) was conducted in paired SAT and OVAT samples from five individuals.

Results: DES, DSP, GJA1, and SMOC2 were significantly upregulated in OVAT compared to SAT. DES, DSP, and SMOC2 showed consistent expression patterns across all cohorts, while GJA1 exhibited context-dependent regulation. Gene expression in SAT was negatively correlated with cardiometabolic traits, including blood pressure, insulin resistance, and liver function markers. These associations were confirmed by regression analysis and supported by publicly available multi-omics data. Epigenetic analyses revealed OVAT-specific enrichment of active histone marks and reduced repressive marks, supporting higher differential transcriptional activity in OVAT.

Conclusions: Depot-specific gene expression of DES, DSP, and SMOC2 in adipose tissue is robustly linked to cardiometabolic traits and supported by distinct epigenetic landscapes in OVAT vs SAT, highlighting their potential as novel biomarkers for cardiometabolic health.