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.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective: To investigate the effects of C1q tumor necrosis factor⁃related protein 3 (CTRP3) ⁃enhanced Sendai virus (SeV) vector⁃overexpressing Gata4 , Mef2c , and Tbx5 (SeVGMT) in the treatment of myocardial in⁃farction (MI) mice and to analyze whether ubiquitin carboxyl⁃terminal hydrolase L1 (UCHL1) mediates this thera⁃peutic pathway. Methods: The mice were divided into 7 groups ( n = 12) : Sham group , MI group , SeVGMT group , CTRP3⁃Lv group , UCHL1 ⁃sh group , SeVGMT + CTRP3⁃Lv group , and SeVGMT + CTRP3⁃Lv + UCHL1 ⁃sh group. In the Sham group , only the skin was incised without ligation , while the coronary artery was ligated 2 - 3 mm below the left atrial appendage in mice in other groups. PBS was injected at three points in the myocardial infarction boundary in the Sham and MI groups 30 minutes after ligation. Mice in other groups were injected with SeVGMT , CTRP3-Lv , or UCHL1-sh according to their grouping. Four weeks after treatment , fractional shortening (FS) , ejection fraction (EF) , left ventricular end-diastolic diameter (LVIDd) , left ventricular end-systolic diameter (LVIDs) , heart rate (HR) , mean arterial pressure (MAP) , serum creatine kinase isoenzyme MB (CK-MB) , myocardial troponin I ( cTnI) and lactate dehydrogenase ( LDH) levels , and myocardial tumor necrosis factor-α (TNF-α ) , interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels in mice were detected. The pathological changes of myocardial tissue were detected by 2 , 3 , 5-triphenyltetrazolium chloride ( TTC) , hematoxylin-eosin ( HE) , Masson trichrome and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The mRNA expressions of CTRP3 and UCHL1 were detected by qRT-PCR. The protein expressions of CTRP3 , UCHL1 , collagen Ⅰ , collagen Ⅲ , Bcl-2-associated X (Bax) and B-cell lymphoma/leukemia-2 (Bcl-2) in myocardial tissue were detected by Western blot or immunohistochemical staining. Results: Compared with SeVGMT group and CTRP3-Lv group , the levels of EF , FS , HR and MAP in SeVGMT + CTRP3-Lv group increased (P < 0. 05) . The levels of LVIDd , LVIDs , CK-MB , cTnI , LDH , TNF-α , IL-1β and IL-6 decreased (P < 0. 05) . MI area , fibrosis area and TUNEL positive rate decreased (P < 0. 05) , the protein levels collagen Ⅰ , collagen Ⅲ and Bax decreased (P < 0. 05) , and Bcl-2 protein levels increased (P < 0. 05) . The mRNA and protein levels and relative staining intensity of CTRP3 and UCHL1 increased (P < 0. 05) . Compared with SeVGMT + CTRP3-Lv group , the addition of UCHL1-sh treatment ( SeVGMT + CTRP3-Lv + UCHL1-sh group) significantly weakened the influence of SeVGMT + CTRP3-Lv on the above indexes (P < 0. 05) . Conclusion CTRP3 mediated UCHL1 enhances the therapeutic effect of SeVGMT reprogrammed CFs on MI in mice.

Objective To systematically evaluate the risk factors for new-onset atrial fibrillation (NOAF) after off-pump coronary bypass grafting (OPCABG). Methods PubMed, EMbase, Web of Science, The Cochrane Library, Wanfang data, CBM, VIP, and CNKI databases were systematically searched by computer to collect studies related to the risk factors for NOAF after OPCABG from the establishment of the database to July 2023. Literature screening and quality evaluation were conducted independently by two researchers. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the literature. RevMan 5.3 and Stata15.0 were used for meta-analysis. Results Finally, 19 case-control studies related to the risk factors for NOAF after OPCABG were included, all of which were high-quality literature with NOS score≥6 points, with a total of 7019 subjects. The results of meta-analysis showed that the following factors were associated with NOAF after OPCABG: (1) the patient’s own factors: age (MD=3.51, 95%CI 2.39 to 4.63, P<0.01); (2) preoperative factors: history of hypertension (OR=1.17, 95%CI 1.04 to 1.32, P=0.01), history of myocardial infarction (OR=1.21, 95%CI 1.06 to 1.38, P<0.01), history of percutaneous coronary intervention (OR=2.22, 95%CI 1.03 to 4.77, P=0.04), EuroSCOREⅡ score (MD=0.59, 95%CI 0.25 to 0.94, P<0.01), low-density lipoprotein (MD=0.11, 95%CI 0.02 to 0.20, P=0.02), left atrial diameter (MD=1.64, 95%CI 0.24 to 3.04, P=0.02); (3) postoperative and treatment factors: left ventricular end-diastolic diameter (MD=1.16, 95%CI 0.33 to 1.99, P<0.01), left ventricular ejection fraction (MD=0.90, 95%CI 0.07 to 1.73, P=0.03), mechanical ventilation time (MD=2.78, 95%CI 1.65 to 3.90, P<0.01), B-type natriuretic peptide (MD=219.67, 95%CI 27.46 to 411.88, P=0.03), ICU retention time (MD=7.07, 95%CI 5.64 to 8.50, P<0.01). Conclusion The existing evidence shows that age, history of hypertension, history of myocardial infarction, history of percutaneous coronary intervention, preoperative EuroSCOREⅡscore, preoperative low-density lipoprotein, preoperative left atrial diameter, postoperative left ventricular end-diastolic diameter, postoperative left ventricular ejection fraction, postoperative mechanical ventilation time, postoperative B-type natriuretic peptide, and postoperative ICU retention time are risk factors for NOAF after OPCABG. Clinical attention should be paid to the above factors to achieve early identification, thereby reducing the incidence of NOAF after OPCABG and improving the clinical prognosis of patients.

Aortic stenosis is a valve disease characterized by dynamic and continuous changes in structure and function of left ventricle.Left ventricular remodeling,which embodies pathological changes in myocardial cellular and ventricular geometry,is an important prognostic factor of patients with aortic stenosis.Aortic valve replacement is the only effective treatment for severe aortic stenosis.Current guideline recommendations for interventions are based on symptoms and left ventricular ejection fraction.With the improvements of modern imaging technology,different patterns of remodeling,including hypertrophy and fibrosis,could be identified now.Studies also explored the close association between left ventricular remodeling and function in the setting of aortic stenosis.In this review,we aim to elucidate the characteristic imaging features and potential mechanisms of left ventricular remodeling,and further,we highlight the clinical value of specific imaging features and clinical application of modern imaging methods in the evaluation,risk stratification,and intervention decision-making for patients with aortic stenosis.

Objective To explore the anti-depression mechanism of Kai-Xin-San(KXS)via regulation of neurogenesis in hippocampus of depression-like mice.Methods The extracts of KXS were prepared and the anti-depression effects of KXS were evaluated by behavioral tests on chronic unpredictable mild stress(CUMS)induced depression-like mice.Evaluating depression-like behavior in CUMS mice through sucrose preference test,forced swimming test,tail suspension test,and other methods.Neurogenesis in hippocampus were determined by immunofluorescence assay.In addition,effects of KXS on regulating nestin expression and Wnt/b-catenin signaling pathway were explored by western blotting analysis.Amounts of cortisol,corticotropin-releasing factor(CRF),adrenocorticotropic hormone(ACTH),brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF)were determined by ELISA tests.Mouse primary neural stem cells(NSC)was used to evaluate the effect of KXS on promoting its proliferation by immunofluorescence assay.In addition,effects of KXS on regulating nestin and Wnt/β-catenin signaling pathway were also explored by Western blotting analysis.Results KXS significantly ameliorated the depression-like behaviors in presence of increased sucrose preference rate and decreased immobile time of tail suspension and forced swimming.KXS significantly promoted the neurogenesis in the hippocampus and expressions of nestin,reduced the expressions of cortisol,CRF,ACTH,increased the expressions of BDNF,NGF,and regulated Wnt/β-catenin signaling pathway.KXS also promoted the proliferation of NSCs and expressions of nestin,enhanced the translocation of b-catenin into nucleus,and regulated the expressions of proteins of Wnt/β-catenin signaling pathway.Conclusion KXS promoted neurogenesis in hippocampus and regulated Wnt/β-catenin pathway,which might contribute to its antidepressant effect.

Objective Evaluation of the effect and mechanism research of Qi-Shen-Yi-Zhi formula on improving learning and memory ability in mice injected with Aβ1-42 in hippocampus.Methods Alzheimer's disease model mice were constructed by injecting β amyloid peptide 1-42 into hippocampus and treated with water extracts of Qi-Shen-Yi-Zhi formula.The cognitive abilities of mice were assessed using Morris water maze and Y maze tests,which measure learning and memory capabilities.HE staining was used to observe the damage and TUNEL method was used to determine apoptosis of hippocampus.Detection of the expression of oxidative factors,inflammatory factors,and related antioxidant proteins and apoptotic proteins in the hippocampal tissue of a mouse model of dementia.Results Both high-dose and low-dose groups of Qi-Shen-Yi-Zhi formula significantly improved cognitive dysfunction in mice injected with Aβ1-42 in hippocampus,and attenuated the damage and apoptosis of the hippocampus.It also inhibited oxidative stress and downregulated the expressions of inflammatory factors IL-6,IL-1β and TNF-a,increased the expression of antioxidant proteins Nrf2 and HO-1,and regulated the expressions of apoptotic proteins Caspase-9,Caspase-3,Bax and Bcl-2.Conclusion Qi-Shen-Yi-Zhi formula improves the learning and memory abilities of mice injected with Aβ1-42 in hippocampus,which might be related to the attenuation of oxidative stress and neuronal inflammation of hippocampus.

BACKGROUND:Recent studies have shown that connective tissue growth factor not only participates in the development of neurons,but also participates in the pathogenesis of neurodegenerative diseases,depression,epilepsy,etc.It can also be used as a therapeutic target to develop related drugs,thereby improving the patients'quality of life. OBJECTIVE:To summarize the biological functions of connective tissue growth factor and the mechanisms involved in neurodegenerative diseases and depression,as well as the progress in intervention with connective tissue growth factor and related emerging treatments. METHODS:The first author searched relevant articles published from January 1996 to December 2022 in PubMed and Web of Science.The key words were"connective tissue growth factor,nervous system,depression,Alzheimer disease,epilepsy,Parkinson disease,epilepsy,amyotrophic lateral sclerosis,FG-3019"in English.After reading,screening and sorting,the articles consistent with the content of the review were collected.Finally,51 articles were selected for review. RESULTS AND CONCLUSION:Connective tissue growth factor participates in multiple biological activities such as fibrosis,cell adhesion,and cell development under different conditions through four different structural domains.Connective tissue growth factor is up-regulated in lesion sites of neurodegenerative diseases,depression and epilepsy.After interfering with the expression of connective tissue growth factor,the symptoms improve or disappear,suggesting that connective tissue growth factor plays an important role in the progression of these diseases.The development of novel therapeutic strategies and intervention targets around connective tissue growth factor is very promising therapeutic research.More research is needed to identify the mechanism of action to transfer from basic medical studies to clinical studies and to achieve safer and more effective treatments.