Objective To explore the causal relationships between 13 micronutrients (copper, selenium, zinc, calcium, folate, iron, magnesium, vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, and vitamin E) and risk of tuberculosis (TB) through a two-sample Mendelian randomization (MR) study. Methods The Genome-Wide Association Study (GWAS) data about micronutrients and TB were obtained from the IEU Open GWAS and FinnGen Biobank, and Bayesian Weighted Mendelian Randomization (BWMR) and Inverse Variance Weighted (IVW) methods were employed to explore the causal relationship between micronutrients and risk of TB. The robustness and reliability of the results were assessed through horizontal pleiotropy tests, heterogeneity tests, and leave-one-out sensitivity analyses. Results The BWMR results indicated that iron (OR = 0.40, 95% CI : 0.20- 0.79, P = 0.008) and vitamin C (OR = 0.42, 95% CI : 0.20 - 0.87, P = 0.019) were protective factors against TB infection, while no causal relationships were found between other micronutrients with TB infection. The IVW method produced consistent results with BWMR. The results for other micronutrients were robust and reliable (P > 0.05), except for calcium-related Instrumental Variables (IVs), which exhibited heterogeneity (P < 0.05). Conclusion Iron and vitamin C may play a protective role in reducing the risk of TB, whereas the remaining micronutrients show no significant causal relationship with TB.

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Objective:To explore the molecular mechanism by which the methionine adenosyltransferase 2A (MAT2A)/β-catenin/zinc finger E-box binding homeobox 1 (ZEB1)/epithelial-mesenchymal transition (EMT) pathway regulates neural tube defect (NTD) through intracellular S-adenosylmethionine (SAM).Methods:A mouse NTD model was induced using the SAM metabolic disorder inhibitor ethionine. Eighty specific pathogen-free C57BL/6 mice were divided into three groups: a normal group (36 mice), an ethionine group (46 mice), and an ethionine+SAM group (44 mice). Phosphate-buffered saline (PBS), ethionine, and ethionine+SAM were respectively injected intraperitoneally on embryonic day 7.5 (E7.5), and the mice were sacrificed on E10.5. Embryonic tissues were collected, and the morphology of embryos in each group was observed under a stereomicroscope. The interaction between ethionine and MAT2A was analyzed using Autodock software. The expression levels of MAT2A, β-catenin, ZEB1, and EMT-related proteins in the brain tissues of embryos from the three groups were measured using immunofluorescence, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). Variance analysis was used for intergroup comparisons.Results:(1) Autodock analysis results showed that MAT2A binds to ethionine through covalent bonds, exhibiting a complementary effect, thereby accelerating the expression of MAT2A. (2) After successful construction of the NTD model, normal embryos were plump with well-developed brains. NTD embryos showed delayed development, obvious anencephaly, unclosed neural tubes, and asymmetry. (3) The levels of SAM and SAH in the embryonic tissues of the ethionine group were significantly lower than those in the normal group (1 737.56±95.64 vs. 872.33±205.11, and 89.17±9.50 vs. 51.25±9.48, respectively). The SAM and SAH levels in the ethionine+SAM group was 1 197.00±222.27 and 66.61±12.25, significantly higher than those in the ethionine group ( P<0.017). Compared with the normal group and the ethionine+SAM group, the expression of MAT2A mRNA in the embryonic brain tissue of the ethionine group was significantly upregulated (1.00±0.00, 1.59±0.52, and 2.42±0.53, respectively, F=49.64, P<0.001; pairwise comparisons between groups P<0.017). (4) Compared with the normal group, the expression of Ctnnb1 in the ethionine group was reduced, and the expression of Ctnnb1 in the ethionine+SAM group was higher than that in the ethionine group (1.00±0.00, 0.38±0.16, and 0.76±0.10, respectively, F=149.03, P<0.001; pairwise comparisons between groups P<0.017). (5) The expression of ZEB1 in the ethionine group was higher than that in the normal group and the ethionine+SAM group (2.91±0.55, 1.00±0.00, and 1.61±0.20, respectively, F=150.01, P<0.001; pairwise comparisons between groups P<0.017). (6) The expression levels of E-cadherin and Vimentin in the ethionine group were lower than those in the normal group. In contrast, the expression of N-cadherin was higher than that in the normal group. After SAM supplementation, the expression levels of E-cadherin and Vimentin were upregulated, and the expression level of N-cadherin was downregulated (0.54±0.12, 1.00±0.00, and 0.72±0.14, respectively, F=87.44; 0.53±0.17, 1.00±0.00, and 0.76±0.09, F=87.44; 3.11±0.53, 1.00±0.00, and 2.13±0.56, F=95.54; all P<0.001; pairwise comparisons within the same index group P<0.017]). Conclusions:Ethionine promotes the expression of MAT2A, leading to reduced SAM production. Ethionine regulates the level of ZEB1 by increasing MAT2A and inhibits the EMT process to interfere with methionine cycle metabolism, ultimately resulting in NTD.

OBJECTIVE To investigate the effects of combined exposure of silica nanoparticles(SiNPs)and a high-fat diet(HFD)on aortic vascular fibrosis in rats and explore the underlying mecha-nisms.METHODS Transmission electron microscopy and a particle size analyzer were used to analyze the size and dispersion of SiNPs.Male Wistar rats were randomly divided into four groups:standard diet control group(STD-control),standard diet SiNPs group(STD+SiNPs),high-fat diet control group(HFD-control),and high-fat diet SiNPs group(HFD+SiNPs).The rats received intratracheal instillation of SiNPs(10 mg·kg-1)or saline combined with either an STD or HFD every four days for 90 days.Small animal ultrasound was used to evaluate vascular function and structure.Hematoxylin and eosin(HE)staining and Masson's staining were performed to analyze aortic pathology and fibrosis.Biochemical assays were conducted to measure superoxide dismutase(SOD)activity,malondialdehyde(MDA)contents,and the ratio of reduced gluta-thione/glutathione disulfide(GSH/GSSG).Immunohistochemistry and Western blotting were used to analyze the expression levels of mitophagy-related proteins phospha-tase and PTEN induced kinase 1(PINK1),E3 ubiquitinligase(Parkin),microtubule-associated protein 1 light chain 3B(LC3B),and P62,as well as vascular fibrosis marker proteins alpha-smooth muscle actin(α-SMA),typeⅠcollagen(Col-Ⅰ),and typeⅢcollagen(Col-Ⅲ).RESULTS Transmission electron micros-copy analysis showed that SiNPs had a uniform size(51.24±8.54)nm,regular morphology,and good dispersion.Compared with the STD-control group,the STD+SiNPs group exhibited a significant reduc-tion in the end-diastolic diameter of the left common carotid artery and aorta,along with a significant increase in intima-media thickness.Additionally,SOD activity decreased,MDA contents increased,and the GSH/GSSG ratio declined,indicating that SiNPs exposure induced oxidative damage and vascular dysfunction in the aorta.Pathological staining revealed that SiNPs caused inflammatory infiltration and vascular fibrosis in the aortic intima of rats.Notably,HFD exacerbated the vascular toxicity induced by SiNPs,suggesting a synergistic effect of their combined exposure.Mechanistically,immunohistochem-istry and Western blotting results showed that the combined exposure to SiNPs and HFD significantly upregulated the expressions of PINK1,Parkin,LC3BⅡ/Ⅰ,P62,α-SMA,Col-Ⅰ,and Col-Ⅲin the aorta.These findings suggested that SiNPs and HFD co-exposure might activate PINK1/Parkin-mediated mitophagy,contributing to the progression of aortic fibrosis.CONCLUSION Combined exposure to SiNPs and HFD might induce mitophagy through the PINK1/Parkin signaling pathway,leading to decreased vascular antioxidant capacity and fibrosis.These findings provided new evidence for the joint impact of SiNPs exposure and metabolic disorders on cardiovascular health.

Objective:To conduct a cost-utility analysis of Tuberculosis Preventive Treatment(TPT)strategies for Latent Tuberculosis Infection(LTBI)individuals,providing a scientific basis for the implementation of TPT strategies and fund allocation.Methods:Based on a simulated population of 100 000 LTBI individuals,a decision tree-Markov Model was constructed to compare the cost-utility of six TPT strategies over 20 years.Results:Compared with no treatment,3HP-SAT,3HP-DOT,3HR-SAT,3HR-DOT and Vaccae could prevent 91.08％,94.15％,83.49％,87.18％and 53.13％of ATB cases,respectively,and avoid 3.55％,3.70％,3.30％,3.43％,and 2.06％of LTBI individuals from dying of ATB.Except for Vaccae,other schemes could reduce costs and improve QALYs,being absolutely dominant strategies,while Vaccae was a relatively dominant strategy.3HP under DOT was more cost-utility than that under SAT.Sensitivity analysis showed that the utility value of curing ATB was the only parameter affecting the ICUR result,and the model result was stable and reliable.When the WTP threshold was greater than 41 608.54 yuan/QALY,3HP-DOT was better than 3HP-SAT;otherwise,3HP-SAT was the optimal strategy.Conclusion:TPT for LTBI individuals has high cost-utility value.Clarifying the advantages of short-course therapy helps promote the implementation of TPT strategies and contributes to achieving the goal of"ending tuberculosis".

OBJECTIVE To provide a reference for standardizing the conduct of positron-emitting radiopharmaceuticals'phase 0 clinical trials(hereinafter referred to as"phase 0 clinical trials")and advancing the development of innovative drug by medical institutions.METHODS Initiated by the First Affiliated Hospital of Jinan University,a panel of experts consisting of pharmacy,clinical medicine and medical ethics from multiple institutions was established to investigate the current landscape,and discuss the necessary conditions,procedures,and other aspects for conducting phase 0 clinical trials in medical institutions by integrating relevant national policies,regulations and expert consensus.Finally,an agreement was reached to formulate this consensus.RESULTS&CONCLUSIONS Currently,most medical institutions have deficiencies in pharmaceutical care during the management of radiopharmaceuticals and the phase 0 clinical trials.In conjunction with the Expert Consensus on the Establishment of Nuclear Pharmacist Positions,this consensus explicitly defines the responsibilities of nuclear pharmacists in the phase 0 clinical trials on the basis of the Expert Consensus for the Application of Positron Emission Tomography Radioligands for Translational Study in the Phase 0 Clinical Trials(2020 edition),providing a guidance for high-quality participation of nuclear pharmacists from medical institutions in China in phase 0 clinical research.Additionally,in consideration of some constraints imposed by current relevant regulations,this consensus also proposes strategic recommendations,such as encouraging medical institutions to form a consortium,leading to the establishment of dedicated bases or industrial parks,holding significant implications to strengthen institutional capacity for advancing radiopharmaceutical innovation through phase 0 clinical trials.

OBJECTIVE To investigate the effects of combined exposure of silica nanoparticles(SiNPs)and a high-fat diet(HFD)on aortic vascular fibrosis in rats and explore the underlying mecha-nisms.METHODS Transmission electron microscopy and a particle size analyzer were used to analyze the size and dispersion of SiNPs.Male Wistar rats were randomly divided into four groups:standard diet control group(STD-control),standard diet SiNPs group(STD+SiNPs),high-fat diet control group(HFD-control),and high-fat diet SiNPs group(HFD+SiNPs).The rats received intratracheal instillation of SiNPs(10 mg·kg-1)or saline combined with either an STD or HFD every four days for 90 days.Small animal ultrasound was used to evaluate vascular function and structure.Hematoxylin and eosin(HE)staining and Masson's staining were performed to analyze aortic pathology and fibrosis.Biochemical assays were conducted to measure superoxide dismutase(SOD)activity,malondialdehyde(MDA)contents,and the ratio of reduced gluta-thione/glutathione disulfide(GSH/GSSG).Immunohistochemistry and Western blotting were used to analyze the expression levels of mitophagy-related proteins phospha-tase and PTEN induced kinase 1(PINK1),E3 ubiquitinligase(Parkin),microtubule-associated protein 1 light chain 3B(LC3B),and P62,as well as vascular fibrosis marker proteins alpha-smooth muscle actin(α-SMA),typeⅠcollagen(Col-Ⅰ),and typeⅢcollagen(Col-Ⅲ).RESULTS Transmission electron micros-copy analysis showed that SiNPs had a uniform size(51.24±8.54)nm,regular morphology,and good dispersion.Compared with the STD-control group,the STD+SiNPs group exhibited a significant reduc-tion in the end-diastolic diameter of the left common carotid artery and aorta,along with a significant increase in intima-media thickness.Additionally,SOD activity decreased,MDA contents increased,and the GSH/GSSG ratio declined,indicating that SiNPs exposure induced oxidative damage and vascular dysfunction in the aorta.Pathological staining revealed that SiNPs caused inflammatory infiltration and vascular fibrosis in the aortic intima of rats.Notably,HFD exacerbated the vascular toxicity induced by SiNPs,suggesting a synergistic effect of their combined exposure.Mechanistically,immunohistochem-istry and Western blotting results showed that the combined exposure to SiNPs and HFD significantly upregulated the expressions of PINK1,Parkin,LC3BⅡ/Ⅰ,P62,α-SMA,Col-Ⅰ,and Col-Ⅲin the aorta.These findings suggested that SiNPs and HFD co-exposure might activate PINK1/Parkin-mediated mitophagy,contributing to the progression of aortic fibrosis.CONCLUSION Combined exposure to SiNPs and HFD might induce mitophagy through the PINK1/Parkin signaling pathway,leading to decreased vascular antioxidant capacity and fibrosis.These findings provided new evidence for the joint impact of SiNPs exposure and metabolic disorders on cardiovascular health.

Objective:To conduct a cost-utility analysis of Tuberculosis Preventive Treatment(TPT)strategies for Latent Tuberculosis Infection(LTBI)individuals,providing a scientific basis for the implementation of TPT strategies and fund allocation.Methods:Based on a simulated population of 100 000 LTBI individuals,a decision tree-Markov Model was constructed to compare the cost-utility of six TPT strategies over 20 years.Results:Compared with no treatment,3HP-SAT,3HP-DOT,3HR-SAT,3HR-DOT and Vaccae could prevent 91.08％,94.15％,83.49％,87.18％and 53.13％of ATB cases,respectively,and avoid 3.55％,3.70％,3.30％,3.43％,and 2.06％of LTBI individuals from dying of ATB.Except for Vaccae,other schemes could reduce costs and improve QALYs,being absolutely dominant strategies,while Vaccae was a relatively dominant strategy.3HP under DOT was more cost-utility than that under SAT.Sensitivity analysis showed that the utility value of curing ATB was the only parameter affecting the ICUR result,and the model result was stable and reliable.When the WTP threshold was greater than 41 608.54 yuan/QALY,3HP-DOT was better than 3HP-SAT;otherwise,3HP-SAT was the optimal strategy.Conclusion:TPT for LTBI individuals has high cost-utility value.Clarifying the advantages of short-course therapy helps promote the implementation of TPT strategies and contributes to achieving the goal of"ending tuberculosis".

Objective:To explore the molecular mechanism by which the methionine adenosyltransferase 2A (MAT2A)/β-catenin/zinc finger E-box binding homeobox 1 (ZEB1)/epithelial-mesenchymal transition (EMT) pathway regulates neural tube defect (NTD) through intracellular S-adenosylmethionine (SAM).Methods:A mouse NTD model was induced using the SAM metabolic disorder inhibitor ethionine. Eighty specific pathogen-free C57BL/6 mice were divided into three groups: a normal group (36 mice), an ethionine group (46 mice), and an ethionine+SAM group (44 mice). Phosphate-buffered saline (PBS), ethionine, and ethionine+SAM were respectively injected intraperitoneally on embryonic day 7.5 (E7.5), and the mice were sacrificed on E10.5. Embryonic tissues were collected, and the morphology of embryos in each group was observed under a stereomicroscope. The interaction between ethionine and MAT2A was analyzed using Autodock software. The expression levels of MAT2A, β-catenin, ZEB1, and EMT-related proteins in the brain tissues of embryos from the three groups were measured using immunofluorescence, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). Variance analysis was used for intergroup comparisons.Results:(1) Autodock analysis results showed that MAT2A binds to ethionine through covalent bonds, exhibiting a complementary effect, thereby accelerating the expression of MAT2A. (2) After successful construction of the NTD model, normal embryos were plump with well-developed brains. NTD embryos showed delayed development, obvious anencephaly, unclosed neural tubes, and asymmetry. (3) The levels of SAM and SAH in the embryonic tissues of the ethionine group were significantly lower than those in the normal group (1 737.56±95.64 vs. 872.33±205.11, and 89.17±9.50 vs. 51.25±9.48, respectively). The SAM and SAH levels in the ethionine+SAM group was 1 197.00±222.27 and 66.61±12.25, significantly higher than those in the ethionine group ( P<0.017). Compared with the normal group and the ethionine+SAM group, the expression of MAT2A mRNA in the embryonic brain tissue of the ethionine group was significantly upregulated (1.00±0.00, 1.59±0.52, and 2.42±0.53, respectively, F=49.64, P<0.001; pairwise comparisons between groups P<0.017). (4) Compared with the normal group, the expression of Ctnnb1 in the ethionine group was reduced, and the expression of Ctnnb1 in the ethionine+SAM group was higher than that in the ethionine group (1.00±0.00, 0.38±0.16, and 0.76±0.10, respectively, F=149.03, P<0.001; pairwise comparisons between groups P<0.017). (5) The expression of ZEB1 in the ethionine group was higher than that in the normal group and the ethionine+SAM group (2.91±0.55, 1.00±0.00, and 1.61±0.20, respectively, F=150.01, P<0.001; pairwise comparisons between groups P<0.017). (6) The expression levels of E-cadherin and Vimentin in the ethionine group were lower than those in the normal group. In contrast, the expression of N-cadherin was higher than that in the normal group. After SAM supplementation, the expression levels of E-cadherin and Vimentin were upregulated, and the expression level of N-cadherin was downregulated (0.54±0.12, 1.00±0.00, and 0.72±0.14, respectively, F=87.44; 0.53±0.17, 1.00±0.00, and 0.76±0.09, F=87.44; 3.11±0.53, 1.00±0.00, and 2.13±0.56, F=95.54; all P<0.001; pairwise comparisons within the same index group P<0.017]). Conclusions:Ethionine promotes the expression of MAT2A, leading to reduced SAM production. Ethionine regulates the level of ZEB1 by increasing MAT2A and inhibits the EMT process to interfere with methionine cycle metabolism, ultimately resulting in NTD.