Mechanisms Underlying the Therapeutic Effects of Nicotinamide Mononucleotide in Treating High-Fat Diet-induced Hypertrophic Cardiomyopathy based on GEO Datasets, Network Pharmacology, and Molecular Docking.

BACKGROUND: The beneficial effects of nicotinamide mononucleotide (NMN) on heart disease have been reported, but the effects of NMN on high-fat diet-induced hypertrophic cardiomyopathy (HCM) and its mechanisms of action are unclear. In this study, we systematically explored the effects and mechanism of action of NMN in HCM using network pharmacology and molecular docking. METHODS: Active targets of NMN were obtained from SWISS, CNKI, PubMed, DrugBank, BingingDB, and ZINC databases. HCM-related targets were retrieved from GEO datasets combined with GeneCards, OMIM, PharmGKB, and DisGeNET databases. A Protein-Protein Interaction (PPI) network was built to screen the core targets. DAVID was used for GO and KEGG pathway enrichment analyses. The tissue and organ distribution of targets was evaluated. Interactions between potential targets and active compounds were assessed by molecular docking. A molecular dynamics simulation was conducted for the optimal core protein-compound complexes obtained by molecular docking. RESULTS: In total, 265 active targets of NMN and 3918 potential targets of HCM were identified. A topological analysis of the PPI network revealed 10 core targets. GO and KEGG pathway enrichment analyses indicated that the effects of NMN were mediated by genes related to inflammation, apoptosis, and oxidative stress, as well as the FOXO and PI3K-Akt signaling pathways. Molecular docking and molecular dynamics simulations revealed good binding ability between the active compounds and screened targets. CONCLUSION: The possible targets and pathways of NMN in the treatment of HCM have been successfully predicted by this investigation. It provides a novel approach for further investigation into the molecular processes of NMN in HCM treatment.

Correlation between Non-HDL-C/HDL-C and Aß1-42 levels in cerebral infarction-related cognitive dysfunction.

OBJECTIVE: Cerebral infarction treatments are most effective if used early after stroke symptoms occur. Also, early detection is crucial for delaying and improving cognitive impairment. This study investigated the relationship between the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (Non-HDL-C/HDL-C), which reflects the entire burden of the cholesterol transported in atherogenic lipoproteins, and the level of ß-amyloid 1-42 (Aß-1-42), a major component of cerebrovascular amyloid deposits, in peripheral blood and cognitive dysfunction secondary to cerebral infarction. METHODS: A total of 83 patients with cerebral infarction admitted to Bozhou People's Hospital between June 2019 and June 2022 were assessed. The patients were divided into two groups based on their Mini-Mental State Scale (MMSE) scores: cognitive dysfunction group (n = 30) and non-cognitive dysfunction group (n = 53). In addition, a control group comprising 34 patients with transient cerebral insufficiency or cerebrovascular stenosis was selected. The groups were compared in terms of various clinical factors, including gender, age, hypertension, hyperlipidemia, lipid indexes, Non-HDL-C/HDL-C, and Aß1-42 levels. Logistic regression analysis was used to identify the risk factors associated with cognitive dysfunction. RESULTS: The results showed that hypertensive patients with cognitive dysfunction secondary to cerebral infarction had a higher proportion of frontal lobe, temporal lobe, and thalamus involvement and lower scores on the MMSE compared to the non-cognitive impairment group and control group (p < 0.05). Additionally, the levels of homocysteine (HCY), Non-HDL-C/HDL-C, and Aß1-42 in peripheral blood were significantly higher in hypertensive patients with cognitive dysfunction compared to the other two groups (all p < 0.05) and were identified as risk factors for cognitive dysfunction secondary to cerebral infarction. Peripheral blood levels of Non-HDL-C/HDL-C and Aß1-42 are risk factors for secondary cognitive dysfunction following a cerebral infarction. CONCLUSION: These data have important clinical implications for understanding the mechanisms underlying cognitive dysfunction in individuals with cerebrovascular disorders, potentially leading to new early interventions for preventing or treating such diseases.

Effects of Nicotinamide Mononucleotide Supplementation on Muscle and Liver Functions Among the Middle-Aged and Elderly: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Nicotinamide Mononucleotide (NMN) has gained attention as a precursor to Nicotinamide Adenine Dinucleotide (NAD+) in recent years, commonly utilized in anti-aging therapies. The anti-aging effects of NMN on muscle and liver functions in middleaged and elderly people are still unclear. OBJECTIVE: Based on available randomized controlled trials, we conducted a meta-analysis to evaluate the impact of NMN on muscle and liver functions in middle-aged and elderly individuals. METHODS: We conducted searches on three electronic databases (PubMed, Embase, Web of Science) for randomized controlled trials involving NMN interventions in middle-aged and elderly populations. Through the Cochrane Handbook, we assessed the specific methodological quality. All statistical analyses were obtained by Stata15, and statistical significance was set as P<0.05. RESULTS: There were 412 participants from 9 studies in this meta-analysis. Based on changes in gait speed (SMD: 0.34 m/s, 95%CI [0.03, 0.66] p = 0.033), NMN had significant effects on muscle mass. Moreover, NMN had a better effect on ALT (SMD: -0.29 IU/L, 95%CI [-0.55, -0.03] p = 0.028). Subgroup analysis indicated that administering a small dose of NMN exerted the most prominent impact on Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). CONCLUSION: NMN has positive efficacy in enhancing muscle function, reducing insulin resistance and lowering aminotransferase levels in middle-aged and elderly individuals. NMN is an encouraging and considerable drug for anti-aging treatment.

Saponins from Panax japonicus improve neuronal mitochondrial injury of aging rats.

CONTEXT: Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-oxidative and anti-aging effects. OBJECTIVE: We evaluated the neuroprotective effects of SPJ on aging rats. MATERIALS AND METHODS: Sprague-Dawley rats (18-months-old) were randomly divided into aging and SPJ groups (n = 8). Five-month-old rats were taken as the adult control (n = 8). The rats were fed a normal chow diet or the SPJ-containing diet (10 or 30 mg/kg) for 4 months. An in vitro model was established by d-galactose (d-Gal) in the SH-SY5Y cell line and pretreated with SPJ (25 and 50 µg/mL). The neuroprotection of SPJ was evaluated via Nissl staining, flow cytometry, transmission electron microscopy and Western blotting in vivo and in vitro. RESULTS: SPJ improved the neuronal degeneration and mitochondrial morphology that are associated with aging. Meanwhile, SPJ up-regulated the protein levels of mitofusin 2 (Mfn2) and optic atrophy 1 (Opa1) and down-regulated the protein level of dynamin-like protein 1 (Drp1) in the hippocampus of aging rats (p < 0.05 or p < 0.01 vs. 22 M). The in vitro studies also demonstrated that SPJ attenuated d-Gal-induced cell senescence concomitant with the improvement in mitochondrial function; SPJ, also up-regulated the Mfn2 and Opa1 protein levels, whereas the Drp1 protein level (p < 0.05 or p < 0.01 vs. d-Gal group) was down-regulated. DISCUSSION AND CONCLUSIONS: Further research on the elderly population will contribute to the development and utilization of SPJ for the treatment of neurodegenerative disorders.

Allocation of Land Factors in China Looking Forward to 2035: Planning and Market.

Land factors are natural resources with fundamental and strategic significance in the achievement of China's 2035 modernization goals. Dilemmas caused by market-oriented or planning-oriented allocation of land factors urgently call for new theoretical guidance and mode. After conducting a systematic review of the literature, this paper built a new framework from the perspective of production-living-ecological spaces to facilitate a better understanding of China's land factors allocation looking forward to 2035. Inductive and deductive methods were both used to interpret the applications of planning and market in land factors allocation. Our results show that: (1) The allocation of land factors for production space is truth-oriented and needs the guidance of market efficiency. The essential feature of "production" as the driving force in production space requires that the allocation of land factors in production space must "respect rules, give play to the agglomeration effect, and rationally carry out regional economic layout". (2) For the allocation of land factors for living space, it is necessary to pursue a kindness-oriented approach and establish a reasonable housing supply system based on people. Among them, the ordinary commercial housing and improving housing should rely on market forces to achieve multi-subject supply, while affordable housing should be ensured through government intervention in a multi-channel way. (3) For the allocation of land factors in ecological space, aesthetic-oriented planning should follow the rule of territorial differentiation and realize the transformation of ecological function into ecological value through market mechanisms. Top-down planning and bottom-up market represents the logic of overall and individual rationality, respectively. The effective allocation of land factors requires the utilization of both planning and market forces. However, the intersection needs be guided by boundary selection theory. This research indicates that "middle-around" theory could be a possible theoretical solution for future study.

Significant Role of Long Non-coding RNAs in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, with clinical manifestations of resting tremor, akinesia (or bradykinesia), rigidity, and postural instability. However, the molecular pathogenesis of PD is still unclear, and its effective treatments are limited. Substantial evidence demonstrates that long non-coding RNAs (lncRNAs) have important functions in various human diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases. Therefore, the main purpose of this study is to review the role of lncRNAs in the pathogenesis of PD. METHODS: The role of lncRNAs in the pathogenesis of PD is summarized by reviewing Pubmed. RESULTS: Thirty different lncRNAs are aberrantly expressed in PD and promote or inhibit PD by mediating ubiquitin-proteasome system, autophagy-lysosomal pathway, dopamine (DA) neuronal apoptosis, mitochondrial function, oxidative stress, and neuroinflammation. CONCLUSION: In this direction, lncRNA may contribute to the treatment of PD as a diagnostic and therapeutic target for PD.

Metabolic heterogeneity of gastric cancer cell lines / 中国药理学与毒理学杂志

OBJECTIVE Gastric cancer is one of the most common malignant tumors,and the inci-dence rate is the highest in all kinds of tumors in China. However,it remains unclear that how signifi-cantly gastric cells are dependent on glycolysis,and which type of gastric cells are sensitive to glycolysis inhibition. In this study, several kind of gastric cancer cell lines were used as the research object, and the metabolic characteristics of different cell lines were systematically analyzed to provide theoretical support for the accurate treatment of gastric cancer. METHODS We examined the energy metabolism of four gastric cancer cell lines(MGC-803,SGC-7901,HGC-27 and BGC-823)by using glycolysis inhibitor, 2-deoxy-D-glucose(2-DG)and inhibitor of oxidative phosphorylation,oligomycin.Oxygen consumption rates(OCR)and L-lactate were also measured with an XF96 Analyzer(Seahorse Biosciences)to deter-mine the significance of metabolism of oxidative phosphorylation and aerobic glycolysisin gastric cells. In addition, western blot was used to detect the contribution of AMP-activated protein kinase (AMPK), and anti-apoptotic proteins(Bcl-2 and survivin)to clarify the mechanism of death or survival of gastric cancer cells treated by 2-DG or oligomycin. RESULTS In this study, it was shown that the growth of gastric cell lines were suppressed by 2-DG.However,the sensitivity to 2-DG was quite different among cell lines:IC 50 of 2-DG was from 3.28 mmol·L-1(MGC-803)to 15.57 mmol·L-1(BGC-823).MGC-803 was relatively sensitive to 2-DG (IC 50:3.28 mmol·L-1), consumed more glucose and produced more lactate (waste product of glycolysis) than the three other cell lines. Consequently, MGC-803 could be more dependent on glycolysis than other cell lines, which was further confirmed by the fact that glucose (+)FCS(-)medium showed more growth and survival than glucose(-)FCS(+)medium.Alternatively, BGC-823, most resistant to 2-DG (IC50: 15.57 mmol·L- 1), was most sensitive to oligomycin, and showed more growth and survival in glucose(-)FCS(+)medium than in glucose(+)FCS(-)medium. Thus,we had reasons to think BGC-823 cells depended on oxidative phosphorylation for energy production. In BGC-823,AMPK,which is activated when ATP becomes limiting,was rapidly phosphorylated by 2-DG, and expression of Bcl-2 was augmented,which might result in resistance to 2-DG.Interestingly,AMPK phosphorylation and augmentation of Bcl-2 expression by 2-DG were not observed in MGC-803,which is 2-DG sensitive. CONCLUSION There is a large metabolic difference between gastric cancer cell lines,which will facilitate the future gastric cancer therapy by targeting metabolic pathways.

Anti-esophagus cancer activity and mechanism of DN3,a novel natural diterpenoid derivative,as a dual inhibitor of glycolysis and oxidative phosphorylation / 中国药理学与毒理学杂志

OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3, a novel natural diterpenoid derivative. METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT, and by using human esophageal carcinoma cells xenografted into athymic mice model in vivo. The specific mechanisms of DN3, as a dual inhibitor of glycolysis and oxidative phos-phorylation(OXPHOS)were explored through cell and molecular biology techniques.For instance,the manner of cancer cell death induced by DN3 was characterized by hoechst33342, FITC-Annexin V/PI staining and flow cytometric analysis,then these changes of glucose consumption,glucose uptake and lactate production in glycolysis, as well as oxygen consumption rate (OCR) and ATP content in OXPHOS caused by DN3 were performed separately through related kits and SeahorseBioscience XF24 Extra-cellular Flux Analyzer.Furthermore,in order to obtain a clear understanding of the inhibition of DN3 to glycolysis and OXPHOS, these regulatory factors were investigated by Western blot, such as PI3K/AKT, c-Myc and p53 of glycolysis, Bax and HK2 of mitochondrial function. RESULTS DN3 inhibited the growth of esophagus cancer cell EC9706, EC109 and EC1 cells in a dose and time dependent manner,but showed no significant effects on human esophageal epithelial cells(HEECs).DN3 caused significant G2/M arrest of esophagus cancer cell lines and induced apoptosis of these cell lines, which indicated DN3 inhibited the growth of esophagus cancer cell through blocking cell cycle and inducing apoptosis in a dose and time-dependent manner. Importantly, 8 μM DN3 decreased the extracellular acidification rate (ECAR) by 45% in EC109, which indicated glycolysis was inhibited by DN3. Mean-while, DN3 decreased the oxygen consumption rate (OCR) and the OCR linked to intracellular ATP production in EC109 cells,but that was not obvious in HEECs,so which indicated that DN3 could selec-tively block OXPHOS of cancer cells. In addition, the accumulation of reactive oxygen species (ROS) and the drop of mitochondrial membrane potential (MMP) were also observed in EC109 incubated by DN3,which suggested mitochondrial biological function was disturbed.Furthermore,the expression of PI3K/AKT, c-Myc and HK2 related to glycolysis were down-regulated by DN3, but the p53 and Bax were up-regulated in esophageal carcinoma cells. The changes of these enzymes accounted for the decreased glycolysisand OXPHOS in esophageal carcinoma cells treated by DN3. CONCLUSION The new compound DN3 has a strong anti-esophageal carcinoma activity,and it is tolerable that DN3 is seen as a dual inhibitor of glycolysis and oxidative phosphorylation.

Antitumor activityand mechanism of JD20,a newly synthetic analog of natural ent-kaurane diterpenoid / 中国药理学与毒理学杂志

OBJECTIVE To study the anti-tumor activity and molecular mechanism of natural diter-pene derivative JD20 in vitro. METHODS Screening the sensitive of gastric carcinoma cell lines to JD20 by cytotoxicity test for 24 h.Cell morphology was evaluated by using DAPI.After staining of can-cer cells with PI or annexin V-FITC/PI respectively,the cell cycle and apoptosis induced by JD20 were detectded by flow cytometry. The change in cell membrane potential was detected by JC-1 test kit. Western blot method was used to detect the apoptosis-related protein. RESULTS The novel natural kaurane diterpene derivative JD20 had a significant inhibitory effect on tumor cells and was particularly active on gastric cancer cell lines HGC-27 (IC50=4.72 ± 1.37 μmol·L- 1) and MGC-803 (IC50=7.36 ± 0.86 μmol·L-1).Further studies found that JD20 resulted in thecell cycle arrest in the G2/M phase,and induced a significant apoptosis in HGC-27. In addition, JD20 also caused the drop of mitochondrial membrane potential of HGC-27 within a short time (3 h). Furthermore, the Western blotting analysis showed that JD20 could induce the up-regulation of p53,Bax and Bim protein expression in gastric can-cer cells,and the releasing of cytochrome c from the mitochondria into the cytoplasm,as well as the ac-tivation of casepase-9/3.CONCLUSION The natural kaurane diterpene derivative JD20 can inhibit the proliferation of various human cancer cells by blocking the cell cycle and inducing apoptosis, and its mechanism of inducing apoptosis may be related to the mitochondria-mediated apoptosis pathway.