Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Nicotinamide adenine dinucleotide (NAD⁺) is a central and pleiotropic metabolite involved in multiple cellular energy metabolism, such as cell signaling, DNA repair, protein modifications, and so on. Evidence suggests that NAD⁺ levels decline with age, obesity, and hypertension, which are all significant CVD risk factors. In addition, the therapeutic elevation of NAD⁺ levels reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances antioxidation and metabolism in vascular cells of humans with vascular disorders. In preclinical animal models, NAD⁺ boosting also extends the health span, prevents metabolic syndrome, and decreases blood pressure. Moreover, NAD⁺ storage by genetic, pharmacological, or natural dietary NAD⁺-increasing strategies has recently been shown to be effective in improving the pathophysiology of cardiac and vascular health in different animal models and humans. Here, we discuss NAD⁺-related mechanisms pivotal for vascular health and summarize recent research on NAD⁺ and its association with vascular health and disease, including hypertension, atherosclerosis, and coronary artery disease. This review also assesses various NAD⁺ precursors for their clinical efficacy and the efficiency of NAD⁺ elevation in the prevention or treatment of major CVDs, potentially guiding new therapeutic strategies.
Humans ; Cardiovascular Diseases/physiopathology* ; NAD/metabolism* ; Animals ; Hypertension/metabolism*

Objective:To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province.Methods:A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Approval Number: 2019 Medical Ethics Review No. 67). Results:Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c. 1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c. 467G>A (p.Gly156Asp) and c. 1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c. 1297G>C (p.Ala433Pro) and c. 1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and may affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. Conclusion:The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c. 1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.

Successful cloning through somatic cell nuclear transfer (SCNT) faces significant challenges due to epigenetic obstacles. Recent studies have highlighted the roles of H3K4me3 and H3K27me3 as potential contributors to these obstacles. However, the underlying mechanisms remain largely unclear. In this study, we generated genome-wide maps of H3K4me3 and H3K27me3 in mouse pre-implantation NT embryos. Our analysis revealed that aberrantly over-represented broad H3K4me3 domain and H3K27me3 signal lead to increased bivalent marks at gene promoters in NT embryos compared with naturally fertilized (NF) embryos at the 2-cell stage, which may link to relatively low levels of H3K36me3 in NT 2-cell embryos. Notably, the overexpression of Setd2, a H3K36me3 methyltransferase, successfully restored multiple epigenetic marks, including H3K36me3, H3K4me3, and H3K27me3. In addition, it reinstated the expression levels of ZGA-related genes by reestablishing H3K36me3 at gene body regions, which excluded H3K27me3 from bivalent promoters, ultimately improving cloning efficiency. These findings highlight the excessive bivalent state at gene promoters as a potent barrier and emphasize the removal of these barriers as a promising approach for achieving higher cloning efficiency.
Animals ; Mice ; Histone-Lysine N-Methyltransferase/biosynthesis* ; Histones/genetics* ; Nuclear Transfer Techniques ; Female ; Gene Expression Regulation, Developmental ; Promoter Regions, Genetic ; Epigenesis, Genetic ; Embryo, Mammalian/metabolism*

Medical device related infections caused by bacteria are common complications in clinical practice,and preventing bacterial colonization on the surface of medical materials is one of the important challenges in the medical field.Therefore,there is an urgent need to construct medical coatings that combine antibacterial properties and biocompatibility.In this study,a γ-polyglutamic acid(γ-PGA)complex with long-chain alkyl quaternary ammonium salts formed by electrostatic and hydrophobic interactions was prepared,which was insoluble in water but soluble in organic solvents(e.g.,ethanol),and was capable of constructing antimicrobial coatings on the surfaces of medical materials in a simple and efficient manner.The bactericidal effect of the coating was verified using viable bacteria counting experiments,and the results showed that the bactericidal rate of the coated thermoplastic polyurethane(TPU)membrane against Staphylococcus aureus was greater than 99.9%compared with that of the uncoated TPU membrane.In addition,a cytotoxicity assay was performed using the L929 fibroblast and cell proliferation detection kit(CCK-8),which showed that the survival rate of L929 fibroblasts on coated TPU was greater than 90%.Meanwhile,the hemolysis rate of coated erythrocytes was tested using fresh rabbit red blood cells(RBCs),and the hemolysis rate on the coated TPU surface was 1.5%.The above results indicated that the coating had good biocompatibility.The preparation method of medical antibacterial coating reported in this study provided a new idea for preventing bacterial infections related to implantable/interventional medical devices.

OBJECTIVE: To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province. METHODS: A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Ethics Number: 2019 Medical Ethics Review No. 67). RESULTS: Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c.1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c.467G>A (p.Gly156Asp) and c.1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c.1297G>C (p.Ala433Pro) and c.1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. CONCLUSION The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c.1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.
Humans ; Amino Acid Metabolism, Inborn Errors/epidemiology* ; Glutaryl-CoA Dehydrogenase/chemistry* ; Infant, Newborn ; Female ; Neonatal Screening/methods* ; Male ; Brain Diseases, Metabolic/epidemiology* ; China/epidemiology* ; Retrospective Studies ; Mutation ; Genetic Variation ; Glutarates

Objective To investigate the expression and clinical significance of 12 plasma cytokines in patients with pancreatic cancer.Methods The study included 120 patients with pancreatic cancer diagnosed and treated at Qingdao University Affiliated Hospital and 68 healthy controls from March 2023 to June 2024.The levels of 12 plasma cytokines,including interleukin(IL)-1 β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12P,IL-17,interferon(IFN)-α,IFN-γ,and tumor necrosis factor(TNF)-α,were detected using mul-tiplex bead-based flow immunoassay.The levels of tumor markers carcinoembryonic antigen(CEA),carbohydrate antigen 19-9(CA19-9)and carbohydrate antigen 72-4(CA 72-4)in the serum of pancreatic cancer patients were detected by electrochemilumines-cence,while carbohydrate antigen 242(CA242)were detected by chemiluminescence methods.The correlation between the expression levels of differentially expressed cytokines and those of tumor markers was analyzed using Spearman's rank correlation.Results The plasma levels of 9 cytokines(IL-1 β,IL-4,IL-5,IL-6,IL-8,IL-10,IL-17,IFN-α,and IFN-γ)in the patients with pancreatic canc-er were significantly higher than those in controls(all P＜0.05).The levels of IL-1 β,IL-6,IL-8,IL-10,and IL-17 in the advanced pancreatic cancer group were significantly higher than those in the early-stage group(P＜0.05).The plasma IL-6 level in the poorly dif-ferentiated pancreatic cancer group was significantly higher than that in the well-differentiated group(P＜0.05).The serum levels of CEA,CA19-9,CA242,and CA72-4 in the advanced pancreatic cancer group were significantly higher than those in the early-stage group(P＜0.05).The serum CEA level in the poorly differentiated pancreatic cancer group was significantly higher than that in the moderately differentiated pancreatic cancer group(P＜0.05).After four cycles of chemotherapy,IL-8 levels in the disease control group were significantly reduced compared to pre-treatment levels(P＜0.05),while IL-6,IL-8,and IL-10 levels in the disease progression group were significantly elevated compared to pre-treatment levels(all P＜0.05).In the patients with pancreatic cancer,plasma IL-6 levels were positively correlated with serum CEA levels(rs=0.238,P＜0.01)and serum CA19-9 levels(rs=0.186,P＜0.05).The plasma IL-10 levels were positively correlated with serum CA72-4(rs=0.220,P＜0.05)levels in the patients.Conclusion Nine cyto-kines in plasma,such as IL-6,etc.may be involved in the formation of the inflammatory microenvironment of pancreatic cancer,as well as in the proliferation and differentiation of tumor cells.The determination of their plasma levels should be helpful for the assessing disease conditions and therapeutic effects.

Articular cartilage is a crucial tissue structure in humans.With ongoing exploration of joint tissue structure and the emergence of innovative biotechnological organoids,various sources of stem cells can be selected for induction to differentiate into articular cartilaginous organoids based on the articular cartilage tissue structure,which can be applied to the treatment of cartilage defects,drug testing,and precision medicine and biological development.This article presents a review of the research progress concerning articular cartilaginous organoids,in order to provide a reference for clinical practice.

Articular cartilage is a crucial tissue structure in humans.With ongoing exploration of joint tissue structure and the emergence of innovative biotechnological organoids,various sources of stem cells can be selected for induction to differentiate into articular cartilaginous organoids based on the articular cartilage tissue structure,which can be applied to the treatment of cartilage defects,drug testing,and precision medicine and biological development.This article presents a review of the research progress concerning articular cartilaginous organoids,in order to provide a reference for clinical practice.

Objective To investigate the expression and clinical significance of 12 plasma cytokines in patients with pancreatic cancer.Methods The study included 120 patients with pancreatic cancer diagnosed and treated at Qingdao University Affiliated Hospital and 68 healthy controls from March 2023 to June 2024.The levels of 12 plasma cytokines,including interleukin(IL)-1 β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12P,IL-17,interferon(IFN)-α,IFN-γ,and tumor necrosis factor(TNF)-α,were detected using mul-tiplex bead-based flow immunoassay.The levels of tumor markers carcinoembryonic antigen(CEA),carbohydrate antigen 19-9(CA19-9)and carbohydrate antigen 72-4(CA 72-4)in the serum of pancreatic cancer patients were detected by electrochemilumines-cence,while carbohydrate antigen 242(CA242)were detected by chemiluminescence methods.The correlation between the expression levels of differentially expressed cytokines and those of tumor markers was analyzed using Spearman's rank correlation.Results The plasma levels of 9 cytokines(IL-1 β,IL-4,IL-5,IL-6,IL-8,IL-10,IL-17,IFN-α,and IFN-γ)in the patients with pancreatic canc-er were significantly higher than those in controls(all P＜0.05).The levels of IL-1 β,IL-6,IL-8,IL-10,and IL-17 in the advanced pancreatic cancer group were significantly higher than those in the early-stage group(P＜0.05).The plasma IL-6 level in the poorly dif-ferentiated pancreatic cancer group was significantly higher than that in the well-differentiated group(P＜0.05).The serum levels of CEA,CA19-9,CA242,and CA72-4 in the advanced pancreatic cancer group were significantly higher than those in the early-stage group(P＜0.05).The serum CEA level in the poorly differentiated pancreatic cancer group was significantly higher than that in the moderately differentiated pancreatic cancer group(P＜0.05).After four cycles of chemotherapy,IL-8 levels in the disease control group were significantly reduced compared to pre-treatment levels(P＜0.05),while IL-6,IL-8,and IL-10 levels in the disease progression group were significantly elevated compared to pre-treatment levels(all P＜0.05).In the patients with pancreatic cancer,plasma IL-6 levels were positively correlated with serum CEA levels(rs=0.238,P＜0.01)and serum CA19-9 levels(rs=0.186,P＜0.05).The plasma IL-10 levels were positively correlated with serum CA72-4(rs=0.220,P＜0.05)levels in the patients.Conclusion Nine cyto-kines in plasma,such as IL-6,etc.may be involved in the formation of the inflammatory microenvironment of pancreatic cancer,as well as in the proliferation and differentiation of tumor cells.The determination of their plasma levels should be helpful for the assessing disease conditions and therapeutic effects.

Objective:To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province.Methods:A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Approval Number: 2019 Medical Ethics Review No. 67). Results:Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c. 1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c. 467G>A (p.Gly156Asp) and c. 1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c. 1297G>C (p.Ala433Pro) and c. 1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and may affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. Conclusion:The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c. 1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.