The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.

Objective: To investigate the chemical compositions of Maxing Shigan Decoction (麻杏石甘汤, MXSGD) and elucidate its anti-influenza A virus (IAV) mechanism from prediction to validation. Methods: Ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the chemical compositions of MXSGD. Network pharmacology theories were used to screen and identify shared targets of both the potential targets of active ingredients of MXSGD and IAV. A protein-protein interaction (PPI) network was then constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The binding stability between core bioactive compounds and key targets was validated by molecular docking and dynamic simulations. A total of 24 BALB/c mice were infected with IAV to build IAV mouse models. After successful modelling, the mouse models were randomly divided into model, MXSGD high-dose (2.8 g/kg), MXSGD low-dose (1.4 g/kg), and oseltamivir (20.14 mg/kg) groups, with an additional normal mice as control group (n = 6 per group). The treatments were administered by gavage daily between 8:00 a.m. and 10:00 a.m. for five consecutive days. Upon completion of the administration, the body weight ratio, lung index, protein content in the bronchoalveolar lavage fluid (BALF), and the levels of inflammatory factors including interleukin (IL)-6 and tumor necrosis factor (TNF)-α in mice were measured to preliminarily analyze the therapeutic efficacy of MXSGD against IAV infection. Furthermore, the expression levels of mechanistic target of rapamycin (mTOR), hypoxia inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) proteins in the HIF-1 signaling pathway, which was enriched by network pharmacology, were detected by Western blot. Results: A total of 212 chemical components in MXSGD were identified by the UPLC-MS/MS method. These chemical components can be classified into 9 primary categories and 31 secondary categories. After intersecting the chemical component targets with IAV-related targets, a total of 567 potential MXSGD components targeting IAV were identified. The construction of PPI network and the results of both GO and KEGG enrichment analyses revealed that the anti-IAV effects of MXSGD were associated with multiple pathways, including apoptosis, TNF, HIF-1, and IL-17 signaling pathways. The results of molecular docking demonstrated that the binding energies between the core compound 1-methoxyphaseollin and key targets including HIF-1α, mTOR, and VEGF were all lower than – 5.0 kcal/mol. Furthermore, molecular dynamics simulations confirmed the structural stability of the resulting complexes. Animal experiments showed that compared with the normal controls, IAV-infected mice showed significantly reduced body weight ratio, markedly increased lung index, protein content in BALF, and the levels of inflammatory factors such as IL-6 and TNF-α (P < 0.01), thereby causing damage to the lung tissue; consequently, the expression levels of mTOR, HIF-1α, and VEGF proteins in the lung tissues of these mice were significantly elevated (P < 0.01). However, after MXSGD treatment, the mouse models presented a significant increase in body weight ratio, as well as marked decreases in lung index, protein content in BALF, and the levels of inflammatory factors including IL-6 and TNF-α (P < 0.01). Furthermore, the therapy alleviated IAV-induced injuries and significantly downregulated the expression levels of mTOR, HIF-1α, and VEGF proteins in lung tissues (P < 0.01 or P < 0.05). Conclusion MXSGD exerts anti-IAV effects through multi-component, multi-target, and multi-pathway synergism. Among them, 1-methoxyphaseollin is identified as a potential key component, which alleviates virus-induced lung injury and inflammatory response via the regulation of HIF-1 signaling pathway, providing experimental evidence for the clinical application of MXSGD.

Chemical modifications of nitrogenous bases or ribosemoieties are common in RNA molecules and these RNA modifications regu-late tumor progression by modulating gene expression in malignancies.Therefore,delving into the role of RNA modifications in tumor pro-gression is essential for understanding tumor progression mechanisms and developing intervention strategies.Mitochondria are crucial for maintaining the energy state of malignant tumor cells.Recent studies have indicated that RNA modifications and tumor mitochondria are closely connected,implying that mitochondrial function within tumors can be disrupted due to RNA modifications.This article focuses on the role and underlying mechanisms of RNA modifications in tumor mitochondria,offering crucial insights for a deeper understanding of the reg-ulatory mechanisms of tumor metabolism and the development of new innovative therapeutic strategies.

The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.
Humans ; Aging/physiology* ; Communicable Diseases/immunology* ; Immunosenescence/physiology* ; Inflammation/immunology* ; Genomic Instability

Influenza is an acute viral respiratory infection that has caused high morbidity and mortality worldwide. Influenza A virus (IAV) has been found to activate multiple programmed cell death pathways, including ferroptosis. Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. However, little is known about how influenza viruses induce ferroptosis in the host cells. In this study, based on network pharmacology, we predicted the mechanism of action of Maxing Shigan decoction (MXSGD) in IAV-induced ferroptosis, and found that this process was related to biological processes, cellular components, molecular function and multiple signaling pathways, where the hypoxia inducible factor-1(HIF-1) signaling pathway plays a significant role. Subsequently, we constructed the mouse lung epithelial (MLE-12) cell model by IAV-infected in vitro cell experiments, and revealed that IAV infection induced cellular ferroptosis that was characterized by mitochondrial damage, increased reactive oxygen species (ROS) release, increased total iron and iron ion contents, decreased expression of ferroptosis marker gene recombinant glutathione peroxidase 4 (GPX4), increased expression of acyl-CoA synthetase long chain family member 4 (ACSL4), and enhanced activation of hypoxia inducible factor-1α (HIF-1α), induced nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in the HIF-1 signaling pathway. Treatment with MXSGD effectively reduced intracellular viral load, while reducing ROS, total iron and ferrous ion contents, repairing mitochondrial results and inhibiting the expression of cellular ferroptosis and the HIF-1 signaling pathway. Finally, based on animal experiments, it was found that MXSGD effectively alleviated pulmonary congestion, edema and inflammation in IAV-infected mice, and inhibited the expression of ferroptosis-related protein and the HIF-1 signaling pathway in lung tissues.
Animals ; Mice ; Ferroptosis ; Network Pharmacology ; Reactive Oxygen Species ; Vascular Endothelial Growth Factor A ; Influenza A virus ; Iron ; Hypoxia

Objective:To explore the feasibility of the AI intelligent reconstruction model based on knee joint magnetic resonance data developed by Nuctech Company Limited for evaluating knee cartilage injury.Methods:Thirty-three patients (a total of forty-one knees) who were hospitalized with severe knee osteoarthritis in Beijing Tsinghua Changgung Hospital from May 2021 to April 2022 were selected. All of them were planned to be performed total knee arthroplasty (TKA) for the treatment of knee osteoarthritis. Fifteen males with an average age of 71±5 years old and twenty six females with an average age of 71±9 years old were included in this study. There were 19 cases of left knee and 22 cases of right knee. Thin layer MRI examination on the patients' knee joints was performed before the surgery, and artificial intelligence model based on the thin layer MRI data of the knee joint was reconstructed. The cartilage part of the model was selected and corrected by Principal Component Analysis (PCA) in order to realize model straightening. The tibial plateau cartilage of knee joint which intercepted during operation was classified according to the International Cartilage Repair Society (ICRS). Finally the results were compared with the ICRS classification results of knee artificial intelligence reconstruction model and artificial recognition of knee joint MRI images.Results:Compared with the grade of cartilage injury intercepted during our operation which was according to the ICRS classification, the sensitivity of artificial intelligence reconstruction model for the diagnosis of cartilage injury with ICRS classification grade four was 93.1%. The specificity of artificial intelligence reconstruction model was 91.4%. The positive predictive value (PPV) of artificial intelligence reconstruction model was 92.2%. And the negative predictive value (NPV) of artificial intelligence reconstruction model was 80.3%. The area under ROC curve (AUC) was 0.92. The ICRS classification consistency between artificial intelligence model and physical inspection results was good with kappa value 0.81 ( P<0.001) . In the aspect of artificial recognition of cartilage injury grading in MRI images, the sensitivity of artificial recognition was 92.10% compared with the manual identification of cartilage injury classification in MRI images. The specificity of artificial recognition was 91.60%. The positive predictive value (PPV) of artificial recognition was 97.20% and the negative predictive value (NPV) of artificial recognition was 78.8%. The kappa value of the cartilage injury classification in MRI images consistency between artificial recognition and manual identification was 0.79 ( P<0.001). Conclusion:Based on the evaluation of cartilage injury by AI reconstruction model of knee joint, the sensitivity and specificity of the diagnosis of ICRS grade IV cartilage injury can be acceptable, but still needs to be improved.

N ⁶-methyladenosine (m⁶A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m⁶A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m⁶A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Objective:To establish a nomogram model for predicting the risk of coronary artery disease in elderly patients with acute myocardial infarction (AMI).Methods:The clinical data of elderly patients with AMI who underwent coronary angiography in the department of cardiology of Cangzhou Central Hospital from July 2015 to March 2020 were analyzed, including age, gender, smoking history, underlying diseases, family history, blood pressure, left ventricular ejection fraction (LVEF), and several biochemical indicators at admission, such as total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein [Lp(a)], apolipoproteins (ApoA, ApoB), ApoA/B ratio, total bilirubin (TBil), direct bilirubin (DBil), indirect bilirubin (IBil), fasting blood glucose (FBG) and uric acid (UA). Patients were divided into model group (2 484 cases) and validation group (683 cases) according to the ratio of 8∶2. According to Gensini score, the model group and validation group were divided into mild lesion group (0-20 points) and severe lesion group (≥81 points). The differences of each index between different coronary lesion degree groups were compared. Lasso regression and Logistic regression were used to analyze the risk factors of aggravating coronary lesion risk in elderly patients with AMI, and then the nomogram prediction model was established for evaluation and external validation.Results:① In the model group, there were significant differences in the family history of coronary heart disease, FBG and HDL-C between the mild lesion group (411 cases) and the severe lesion group (417 cases) [family history of coronary heart disease: 3.6% vs. 7.7%, FBG (mmol/L): 5.88±1.74 vs. 6.43±2.06, HDL-C (mmol/L): 1.48±0.69 vs. 1.28±0.28, all P < 0.05]. In the validation group, there were significant differences between the mild lesion group (153 cases) and the severe lesion group [132 cases; FBG (mmol/L): 5.58±0.88 vs. 6.85±0.79, HDL-C (mmol/L): 1.59±0.32 vs. 1.16±0.21, both P < 0.05]. ② Lasso regression analysis showed that family history of coronary heart disease, FBG, and HDL-C were risk factors of coronary artery disease in elderly patients with AMI, with coefficients 0.118, 0.767, and -0.558, respectively. Logistic regression analysis showed that FBG [odds ratio ( OR) = 1.479, 95% confidence interval (95% CI) was 1.051-2.082, P = 0.025] and HDL-C ( OR = 0.386, 95% CI was 0.270-0.553, P < 0.001] were independent risk factors of coronary artery disease in elderly patients with AMI. ③ According to the rank score of FBG and HDL-C, the nomogram prediction risk model of aggravating coronary artery disease degree was established for each patient. It was concluded that the risk of coronary artery disease in elderly people with higher FBG level and (or) lower HDL-C level was significantly increased. ④ The nomogram model constructed with the model group data predicted the risk concordance index (C-index) was 0.689, and the C-index of the external validation group was 0.709. Conclusions:FBG and HDL-C are independent risk factors for aggravating coronary artery disease in elderly patients with AMI. The nomogram model of aggravating coronary artery disease in elderly patients with AMI has good predictive ability, which can provide more intuitive research methods and clinical value for preventing the aggravation of coronary artery disease in elderly patients.

Objective:To compare 5-year overall survival (OS) and disease free survival (DFS) between preoperative three dimensional conformal radiotherapy (3DCRT) and volumetric medulated arc therapy (VMAT) concurrently combined with chemotherapy for locally advanced rectum cancer (LARC), and analyze the value of induction and/or consolidation chemotherapy in these circumstances.Methods:334 patients with LARC treated with preoperative 3DCRT (172 cases) and VMAT (162 cases) concurrently combined with chemotherapy, main protocol XELOX (capecitabine plus oxaplatin), and subsequent surgery in Sun Yat-sen University from May 2007 to April 2013 were retrospectively analyzed. The radiation prescription dose for VMAT group was 50 Gy 25 fractions for planning target volume1(PTV 1), and 46 Gy 25 fractions for PTV 2. The radiation prescription dose for 3DCRT group was 46 Gy 23 fractions for PTV 2. One hundred and eighty-five cases of all received preoperative concurrent chemoradiotherapy (namely, CCRT group), 149 cases received preoperative concurrent chemoradiotherapy plus median 2 courses (1-7 courses) induction and/or consolidation chemotherapy (namely, CCRT±induction chemotherapy±consolidation chemotherapy group), whose main chemotherapy protocol was XELOX. Difference of 5-year OS and DFS between 3DCRT and VMAT group was compared. The rate differences of acute toxicity during chemoradiotherapy, postoperative complications, ypCR, and survival between CCRT group and CCRT±induction chemotherapy±consolidation chemotherapy group were analyzed. Results:After a median follow-up of 62.3 months (2.4-119months) for the 334 patients, no any significant difference for 5-year OS (79.0% vs. 83.2%, P=0.442) and 5-year DFS (77.0% vs. 82.1%, P=0.231) between 3DCRT and VMAT group was observed. There was no any significant difference for the Grade 3 hematological toxicity (7.0% vs. 12.1%, P=0.114) and non-hematological toxicity (14.1% vs. 16.8%, P=0.491) during chemoradiotherapy, postoperative complications (17.3% vs. 17.4%, P=0.971), ypCR rate (25.4% vs. 30.2%, P=0.329), 5-year OS (80.5% vs. 82.0%, P=0.714) and 5-year DFS (78.8% vs. 81%, P=0.479) between CCRT group and CCRT±induction chemotherapy±consolidation chemotherapy group. Conclusions:Compared with 3DCRT, the physics advantage of VMAT technique does not significantly convert into clinical benefits and improve 5-year OS and DFS, even further boosting radiation dose to the gross tumor volume. It is safe for median 2 courses of induction and/or consolidation chemotherapy before and or after preoperative concurrent chemoradiotherapy in the treatment of LARC, though it does not significantly improve ypCR rate and survival.