Southeast University Affiliated Zhonda Hospital

Evaluate the cost utility of menopausal hormone therapy for women in China.

A bespoke Markov cost utility model was developed to evaluate a cohort of symptomatic perimenopausal women (>45 years) with intact uterus in China in accordance with China's Pharmacoeconomic guideline. Short (5-year) and long (10-year) treatment durations were evaluated over a lifetime model time horizon with 12-month cycle duration. Societal and healthcare payer perspectives were evaluated in the context of a primary care provider/prescriber, outpatient setting with inpatient care for patients with chronic conditions. Disease risk and mortality parameters were derived from focused literature searches, and China Diagnosis-related Group cost data was included. Comprehensive scenario, univariate and probabilistic sensitivity analysis were undertaken along with independent validation. This is the first model to include MHT-related disease risks.

According to base case results, the total cost for MHT was 22,516$ (150,106¥) and total quality adjusted life years 12.32 versus total cost of no MHT 30,824$ (205,495¥) and total quality adjusted life years 11.16 resulting in a dominant incremental cost effectiveness ratio of -7,184$ (-47,898¥) per QALY. Results hold true over a range of univariate deterministic sensitivity and scenario analyses. Probabilistic analysis showed a 91% probability of being cost effective at a willingness to pay threshold of three times Gross Domestic Product per capita in China.

Contingent on the structure and assumptions of the model, combination of estradiol plus dydrogesterone MHT is potentially cost saving in symptomatic women over the age of 45 years in China.

Mounting evidence has implicated the RNA m⁶A methylation catalyzed by METTL3 in a wide range of physiological and pathological processes, including tumorigenesis. The detailed m⁶A landscape and molecular mechanism of METTL3 in prostate cancer (PCa) remains ill-defined. We find that METTL3 is overexpressed in PCa and correlates with worse patient survival. Functional studies establish METTL3 as an oncoprotein dependent on its m⁶A enzymatic activity in both AR⁺ and AR^- PCa cells. To dissect the regulatory network of m⁶A pathway in PCa, we map the m⁶A landscape in clinical tumor samples using m⁶A-seq and identify genome-wide METTL3-binding transcripts via RIP-seq. Mechanistically, we discover RRBP1 as a direct METTL3 target in which METTL3 stabilizes RRBP1 mRNA in an m⁶A-dependent manner. RRBP1 positively correlates with METTL3 expression in PCa cohorts and exerts an oncogenic role in aggressive PCa cells. Leveraging the 3D structural protein-protein interaction between METTL3 and METTL14, we successfully develop two potential METTL3 peptide inhibitors (RM3 and RSM3) that effectively suppress cancer cell proliferation in vitro and tumor growth in vivo. Collectively, our study reveals a novel METTL3/m⁶A/RRBP1 axis in enhancing aggressive traits of PCa, which can be therapeutically targeted by small-peptide METTL3 antagonists.

Type 2 diabetes-associated cognitive dysfunction (DCD) is a chronic complication of diabetes that has gained international attention. The medicinal compound Banxia Xiexin Decoction (BXXXD) from traditional Chinese medicine (TCM) has shown potential in improving insulin resistance, regulating endoplasmic reticulum stress (ERS), and inhibiting cell apoptosis through various pathways. However, the specific mechanism of action and medical value of BXXXD remain unclear.

We utilized TCMSP databases to screen the chemical constituents of BXXXD and identified DCD disease targets through relevant databases. By using Stitch and String databases, we imported the data into Cytoscape 3.8.0 software to construct a protein-protein interaction (PPI) network and subsequently identified core targets through network topology analysis. The core targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The results were further validated through in vitro experiments.

Network pharmacology analysis revealed the screening of 1490 DCD-related targets and 190 agents present in BXXXD. The topological analysis and enrichment analysis conducted using Cytoscape software identified 34 core targets. Additionally, GO and KEGG pathway analyses yielded 104 biological targets and 97 pathways, respectively. BXXXD exhibited its potential in treating DCD by controlling synaptic plasticity and conduction, suppressing apoptosis, reducing inflammation, and acting as an antioxidant. In a high glucose (HG) environment, the expression of JNK, Foxo3a, SIRT1, ATG7, Lamp2, and LC3 was downregulated. BXXXD intervention on HT22 cells potentially involved inhibiting excessive oxidative stress, promoting neuronal autophagy, and increasing the expression levels of JNK, SIRT1, Foxo3a, ATG7, Lamp2, and LC3. Furthermore, the neuroprotective effect of BXXXD was partially blocked by SP600125, while quercetin enhanced the favorable role of BXXXD in the HG environment.

BXXXD exerts its effects on DCD through multiple components, targets, levels, and pathways. It modulates the JNK/SIRT1/Foxo3a signaling pathway to mitigate autophagy inhibition and apoptotic damage in HT22 cells induced by HG. These findings provide valuable perspectives and concepts for future clinical trials and fundamental research.