Sirtuins in macrophage immune metabolism: A novel target for cardiovascular disorders.

Sirtuins (SIRT1-SIRT7), as a family of NAD+-dependent protein modifying enzymes, have various catalytic functions, such as deacetylases, dealkalylases, and deribonucleases. The Sirtuins family is directly or indirectly involved in pathophysiological processes such as glucolipid metabolism, oxidative stress, DNA repair and inflammatory response through various pathways and assumes an important role in several cardiovascular diseases such as atherosclerosis, myocardial infarction, hypertension and heart failure. A growing number of studies supports that metabolic and bioenergetic reprogramming directs the sequential process of inflammation. Failure of homeostatic restoration leads to many inflammatory diseases, and that macrophages are the central cells involving the inflammatory response and are the main source of inflammatory cytokines. Regulation of cellular metabolism has emerged as a fundamental process controlling macrophage function, but its exact signaling mechanisms remain to be revealed. Understanding the precise molecular basis of metabolic control of macrophage inflammatory processes may provide new approaches for targeting immune metabolism and inflammation. Here, we provide an update of studies in cardiovascular disease on the function and role of sirtuins in macrophage inflammation and metabolism, as well as drug candidates that may interfere with sirtuins, pointing to future prospects in this field.

Protection against peripheral artery disease injury by Ruan Jian Qing Mai formula via metabolic programming.

Ruan Jian Qing Mai formula (RJQM), a multicomponent herbal formula, has been widely used to treat peripheral arterial disease (PAD) in China. However, its active compounds and mechanisms of action are still unknown. First, RNA sequencing analysis of 15 healthy and 16 PAD samples showed that 524 PAD differential genes were significantly enriched in Go Ontology (ribonucleotide metabolic process, oxidoreductase complex, and electron transfer activity), Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA pathways (OXPHOS and TCA cycle), miRNA (MIR183), and kinase (PAK6). Fifty-three active ingredients in RJQM had similar structures to the seven drug molecules in CLUE. Then, network topology analysis of the 53 components-target-pathway-disease network yielded 10 active ingredients. Finally, computational toxicity estimations showed that the median lethal dose (LD50) of the 10 active ingredients was above 1000 mg/kg, and eight of them did not cause hepatotoxicity, mutagenicity, carcinogenicity, cytotoxicity, and immunotoxicity nor activate 12 toxic pathways. In conclusion, RJQM has a protection effect on PAD by regulating a complex molecular network. Part of the mechanism is associated with the regulation of OXPHOS by 10 active components, which may alleviate mitochondrial dysfunction and pathological metabolic programming.

Protection against COVID-19 injury by qingfei paidu decoction via anti-viral, anti-inflammatory activity and metabolic programming.

Qingfei Paidu decoction (QFPD), a multi-component herbal formula, has been widely used to treat COVID-19 in China. However, its active compounds and mechanisms of action are still unknown. Firstly, we divided QFPD into five functional units (FUs) according to the compatibility theory of traditional Chinese medicine. The corresponding common targets of the five FUs were all significantly enriched in Go Ontology (oxidoreductase activity, lipid metabolic process, homeostatic process, etc.), KEGG pathways (steroid biosynthesis, PPAR signaling pathway, adipocytokine signaling pathway, etc.), TTD diseases (chronic inflammatory diseases, asthma, chronic obstructive pulmonary Disease, etc.), miRNA (MIR183), kinase (CDK7) and TF (LXR). QFPD contained 257 specific targets in addition to HCoV, pneumonia and ACE2 co-expression proteins. Then, network topology analysis of the five components-target-pathway-disease networks yielded 67 active ingredients. In addition, ADMET estimations showed that 20 compounds passed the stringent lead-like criteria and in silico drug-likeness test with high gastrointestinal absorption and the median lethal dose (LD50 > 1600 mg/kg). Moreover, 4 specific ingredients (M3, S1, X2 and O2) and 5 common ingredients (MS1, MX16, SX1, WO1 and XO1) of QFPD presented good molecular docking score for 2019-nCov structure and non-structure proteins. Finally, drug perturbation of COVID-19 network robustness showed that all five FUs may protect COVID-19 independently, and target 8 specifically expressed drug-attacked nodes which were related to the bacterial and viral responses, immune system, signaling transduction, etc. In conclusion, our new FUNP analysis showed that QFPD had a protection effect on COVID-19 by regulating a complex molecular network with safety and efficacy. Part of the mechanism was associated with the regulation of anti-viral, anti-inflammatory activity and metabolic programming.

Identification of potential crucial genes associated with the pathogenesis and prognosis of prostate cancer.

Aim: Prostate cancer (PCa) is the sixth leading cause of cancer-related deaths in men throughout the world. This study aimed to investigate genes associated with the pathogenesis and prognosis of PCa. Materials & methods: Data of PCa cases were obtained from public datasets and were analyzed using an integrated bioinformatics strategy. Results: A total of 969 differential expression genes were identified. Moreover, GSE16560 and The Cancer Genome Atlas (TCGA) data showed a prognostic prompt function of the nine-gene signature, as well as in PCa with Gleason 7. Finally, majority of the nine hub genes were associated with drug sensitivity, mutational landscape, immune infiltrates and clinical characteristics of PCa. Conclusion: The nine-gene signature was correlated with drug sensitivity, mutational landscape, immune infiltrates, clinical characteristics and survival from PCa.

Phylogeographic patterns and conservation implications of the endangered Chinese giant salamander.

Understanding genetic diversity patterns of endangered species is an important premise for biodiversity conservation. The critically endangered salamander Andrias davidianus, endemic to central and southern mainland in China, has suffered from sharp range and population size declines over the past three decades. However, the levels and patterns of genetic diversity of A. davidianus populations in wild remain poorly understood. Herein, we explore the levels and phylogeographic patterns of genetic diversity of wild-caught A. davidianus using larvae and adult collection with the aid of sequence variation in (a) the mitochondrial DNA (mtDNA) fragments (n = 320 individuals; 33 localities), (b) 19 whole mtDNA genomes, and (c) nuclear recombinase activating gene 2 (RAG2; n = 88 individuals; 19 localities). Phylogenetic analyses based on mtDNA datasets uncovered seven divergent mitochondrial clades (A-G), which likely originated in association with the uplifting of mountains during the Late Miocene, specific habitat requirements, barriers including mountains and drainages and lower dispersal ability. The distributions of clades were geographic partitioned and confined in neighboring regions. Furthermore, we discovered some mountains, rivers, and provinces harbored more than one clades. RAG2 analyses revealed no obvious geographic patterns among the five alleles detected. Our study depicts a relatively intact distribution map of A. davidianus clades in natural species range and provides important knowledge that can be used to improve monitoring programs and develop a conservation strategy for this critically endangered organism.

A New Species of Sulcospira (Gastropoda: Pachychilidae) from Hunan, China.

A new species of pachychilid freshwater gastropod, Sulcospira hunanensis sp. nov., is described from Hunan Province, China, based on morphological and molecular evidence. The new species is distinguished from its congeners by a combination of characters, including elongated shell with eight to nine whorls, spiral whorls with ribs, and stomach with outer and inner crescentic pads not connected to each other. Sulcospira hunanensis sp. nov. is the first confirmed report of this genus from Hunan Province, China. It is anticipated that further species will be found in this region, which currently remain unknown. Furthermore, based on morphological and molecular evidence, this study is the first record of Sulcospira tonkiniana in Guangxi Zhuang Autonomous Region, China, with Sulcospira krempfi supported as a synonym of Sulcospira tonkiniana.

[Expression and significance of ß adrenergic receptors in a model of left ventricular mechanical unloading].

OBJECTIVE: To study the expression and significance of ß adrenergic receptors mRNA in a model of left ventricular mechanical unloading, and explore the change in cardiomyocyte in molecular level after left ventricular unloading. METHODS: Heart failure was reproduced in Lewis rats by ligating left anterior descending (LAD) artery. After 4 weeks, the failing hearts and right lungs were heterotopically transplanted into the abdomen of the recipients by anastomosing their ascending aorta to the recipients' descending aorta in the heart transplantation group. Two weeks after transplantation, heart weight, left ventricular weight, myocyte diameter and myocardial fibrosis were determined , and ß adrenergics receptors mRNA expression was essayed by real-time polymerase chain reaction (PCR). Seven normal Lewis rats served as control. RESULTS: The weight of the enlarged heart, left ventricular weight and myocyte diameter of the failing hearts were decreased to normal after transplantation. The levels of ß1- and ß2- adrenergic receptors mRNA expression were significantly lowered in heart failure group compared with that of normal group(0.09 ± 0.03 vs. 0.18 ± 0.04, 0.07 ± 0.06 vs. 0.12 ± 0.02, both P <0.05). The level of ß2- adrenergic receptor mRNA expression in heart transplantation group (0.11 ± 0.05) rose to normal (P>0.05), but ß1- adrenergic receptor mRNA expression (0.08 ± 0.06) was lower in heart transplantation group than that in normal group (P<0.05). CONCLUSION: Myocardium reverse remodeling after left ventricular unloading is accompanied by the change in cardiomyocyte in molecular level , such as the change in ß adrenergic receptors , which may involve in the improvement of heart function after being supported by left ventricular assist device.

[Inhibitory effect of valproic acid on xenografted Kasumi-1 tumor growth in nude mouse and its mechanism].

OBJECTIVE: To investigate in vivo inhibitory effect of histone deacetylase (HDAC) inhibitor valproic acid (VPA) on xenografted Kasumi-1 tumor in nude mice and its mechanism. METHODS: Xenografted Kasumi-1 tumor mouse model was established by subcutaneous inoculation of Kasumi-1 cells. Xenotransplanted nude mice were assigned into control or VPA treatment groups. Volume of the xenografted tumors was measured and compared between the two groups. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) was applied to detection of tumor cell apoptosis. The gene expression of GM-CSF, HDAC1, Ac-H3 and survivin was studied with semi-quantitative RT-PCR and Western blotting. ChIP method was used to assay the effects of VPA on acetylation of histone H3 within GM-CSF promoter region. RESULTS: (1) VAP significantly inhibited xenografted Kasumi-1 tumor growth. The calculated inhibition rate was 57.25%. (2) Morphologic study showed that VPA induced differentiation and apoptosis of Kasumi-1 tumor cells. The apoptosis index of VAP treatment group [(3.661 +/- 0.768)%] was significantly higher than that of control group [(0.267 +/- 0.110)%]. (3) Comparing to those in control group, the level of nuclear HDAC1 protein was significantly decreased, the Ac-H3 protein expression level was increased, the mRNA and protein expression levels of GM-CSF and acetylation of histone H3 were remarkably increased, and the gene expression level of survivin significantly decreased in VPA treatment group. CONCLUSION: VAP significantly inhibits xenografted Kasumi-1 tumor growth and induces tumor cell differentiation and apoptosis. The mechanism may be decrease of survivin gene expression, inhibition of nuclear expression of HDAC, promotion of histone protein acetylation level and acetylation of histone H3 within GM-CSF promoter region, and increase of GM-CSF transcription.

[Therapeutic effect of autologous bone marrow stem cell transplantation in the treatment of severe liver damage].

OBJECTIVE: To evaluate the effect of autologous bone marrow stem cell transplantation in the treatment of severe liver damage. METHODS: Autologous bone marrow (50 ml) was harvested from 6 patients aged 44 to 69 years admitted for severe liver damage. Human bone marrow stem cells (HMSCs) were isolated and transplanted in to the patients' liver. At l, 4, 8, and 12 weeks after the transplantation, the changes in ALT, ALB, Cr, TB, PT and the clinical symptoms of the patients were observed. RESULTS: The transplantation of autologous bone marrow stem cells resulted in obvious improvement of the liver function. At 12 weeks after the transplantation, ALT was reduced from 98.4 IU/L to 41.5 IU/L, TB from 136.5 µmol/L to 78.4 µmol/L, Cr from 112.3 µmol/L to 72.1 µmol/L, and ALB rose from 23.3 g/L to 32.6 g/L. The survival of the patients was 100% at 12 weeks, but one patient died at 7 months after the transplantation. The symptoms of the patients were also alleviated after the transplantation. At 12 weeks after transplantation, 3 patients reported improved appetite, 3 showed recovery of physical strength, and 2 showed lessened abdominal swelling. No serious adverse complications in association with the transplantation were found in the in 4 patients available to the follow-up. CONCLUSION: Autologous bone marrow stem cell transplantation can improve the liver function of patients with severe liver damage without causing serious complications.

[Effects of histone deacetylase inhibitor on the expression of angiogenesis related factors in Kasumi-1 leukemic cell line].

OBJECTIVE: To investigate the effects of two histone deacetylase (HDAC) inhibitors, valproic acid (VPA) and TSA, on the expression of vascular endothelial growth factor (VEGF) and its receptor KDR of the leukemia cell line Kasumi-1 cells, and to explore their potential mechanism in leukemia angiogenesis. METHOD: Kasumi-1 cells were treated with VPA and TSA at different concentrations for 3 days. The mRNA and protein expression levels of VEGF and KDR were determined by semi-quantitative RT-PCR and Western blot, and the bFGF mRNA by semi-quantitative RT-PCR. RESULTS: As compared with that of control groups, VPA at 3 mmol/L downregulated the VEGF mRNA expression level for VEGF(121) from 0.632 ± 0.014 to 0.034 ± 0.004 and for VEGF(165) from 0.526 ± 0.021 to 0.015 ± 0.001, for KDR mRNA from 0.258 ± 0.034 to 0.038 ± 0.000, and for bFGF mRNA from 0.228 ± 0.017 to 0.086 ± 0.015. TSA downregulated the VEGF mRNA and KDR mRNA at concentration of 100 nmol/L, but its effect on bFGF mRNA only at higher concentration. CONCLUSION: HDAC inhibitors might inhibit the leukemia angiogenesis by regulating the expression of VEGF and its recptor.

[Role of Ommaya reservoir in the management of neonates with post-hemorrhagic hydrocephalus].

OBJECTIVE: Intra-ventricular hemorrhage (IVH) is one of the most serious complications of preterm infants. Significant numbers of the surviving infants with severe IVH go on to develop post-hemorrhagic hydrocephalus (PHH). The management of PHH remains a very challenging problem for both neonatologists and pediatric neurosurgeons. This study aimed to evaluate the efficacy and safety of the use of Ommaya reservoirs and serial cerebrospinal fluid (CSF) drainage in the management of a series of neonates with PHH. METHOD: Between January 1, 2003 and December 30, 2005, 15 consecutive newborn infants with IVH grades III to IV, complicated with progressive ventricular dilatation, underwent placement of an Ommaya reservoir. CSF was intermittently aspirated percutaneously from the reservoir. The amount and frequency of CSF aspiration were based on the clinical presentation and the follow-up results of serial cranial ultrasonograms or CT scans. The changes of CSF cell counts and chemistries were also followed. Patients whose progressive ventricular dilatation persisted despite serial CSF aspiration through Ommaya reservoir eventually had ventriculo-peritoneal shunts (V-P shunt) placed. All the patients were followed up in the outpatient clinic after discharge from the hospital and the neurodevelopmental outcomes were evaluated through 18-36 months of age. RESULT: A total of 15 infants were included in this series. Of them, 11 were preterm infants who were at gestational ages of 29 to 34 weeks and 4 infants were full-term. All of the 4 full term infants presented with progressive ventricular dilatation after suffering from the intra-cranial hemorrhage (3 infants were due to vitamin K deficiency and 1 was due to birth trauma). Thirteen infants had grade III IVH, and 2 had grade IV IVH based on initial cranial ultrasonographic and CT scans. The mean age when IVH was diagnosed was (9 +/- 1) days in preterm infants and (22 +/- 7) days in full-term infants; the mean age when Ommaya reservoir was placed was (18 +/- 11) days in preterm infants and (31 +/- 7) days in full-term infants. All the infants tolerated the surgical procedure well. The Ommaya reservoir was tapped for an average of (21.5 +/- 4.6) times per patient. The mean CSF volume per tap was (10.2 +/- 1.3) ml/kg. The values of CSF protein, glucose and cell counts slowly reached normal levels at approximately 3 - 5 weeks after the placement of the reservoir. The velocity of head circumference increase per week was less than 1 cm in 13 patients in 1 - 4 weeks after the placement of the reservoir and the size of ventricles decreased gradually. By 12 - 18 months, 12 infants had normal size ventricles, and 1 patient still had mild ventricular dilation at 36 months. Two infants developed progressive hydrocephalus after serial CSF aspiration through Ommaya reservoir. One infant had a V-P shunt placed at 2 months of age and another infant died at 3 months of age at home after parents refused further therapy. Complications consisted of reservoir leaking and CSF infection at 16th day of placement in one patient after repeated tapping. By the end of 18 - 36 months of follow-up, 11 of 14 infants were considered normal, two patients had mild impairment in neurodevelopmental outcome (both had spastic bilateral lower limbs paresis, and one of whom also had amblyopia) and the other had seizure disorder. CONCLUSION: The results from this series indicate that the placement of an Ommaya reservoir is relatively safe in newborn infants and is useful in the initial management of neonates with PHH and may be beneficial in improving their neurodevelopmental outcomes. A multicenter randomized trial may be needed to further validate the results of this report.