Transcriptomic analysis to identify genes associated with hypothalamus vulnerability in aging mice with cognitive decline.

The normal aging process is accompanied by cognitive decline, and previous studies have indicated the crucial role of the hypothalamus in regulating both aging and cognition. However, the precise molecular mechanism underlying this relationship remains unclear. Therefore, this present study aimed to identify potential predictors of cognitive decline associated with aging specifically within the hypothalamus. To achieve this, we employed Morris water maze (MWM) testing to assess learning and memory differences between young and aged mice. Additionally, transcriptome sequencing was conducted on the hypothalamus of young and aged mice to identify potential genes. Subsequently, GO and KEGG analyses were performed to investigate the functions of differentially expressed genes (DEGs) and their associated biological pathways. Finally, the results obtained from sequencing analysis were further validated using qRT-PCR. Notably, MWM testing revealed a significant decrease in spatial learning and memory ability among aged mice. According to KEGG analysis, the DEGs primarily encompassed various biochemical signaling pathways related to immune system (e.g., C3; C4b; Ccl2; Ccl7; Cebpb; Clec7a; Col3a1; Cxcl10; Cxcl2; Fosb; Fosl1; Gbp5; H2-Ab1; Hspa1a; Hspa1b; Icam1; Il1b; Itga5; Itgax; Lilrb4a; Plaur; Ptprc; Serpine1; Tnfrsf10b; Tnfsf10), neurodegenerative disease (e.g., Atp2a1; Creb5; Fzd10; Hspa1a; Hspa1b; Il1b; Kcnj10; Nxf3; Slc6a3; Tubb6; Uba1y; Wnt9b), nervous system function (e.g., Chrna4; Chrna6; Creb5; Slc6a3),and aging (e.g., Creb5; Hspa1a; Hspa1b) among others. These identified genes may serve as potential predictors for cognitive function in elderly individuals and will provide a crucial foundation for further exploration into the underlying molecular mechanisms.

A Comprehensive Nursing Model Combined with High-Quality Nursing Intervention for Antiviral Therapy in Patients with Chronic Hepatitis B.

Objective: To investigate the effect of comprehensive nursing combined with high-quality nursing intervention on the compliance, anxiety, and mental state of patients with chronic hepatitis B undergoing antiviral therapy. Methods: A total of 100 patients with chronic hepatitis B admitted to China-Japan Union Hospital from December 2017 to August 2020 were recruited and assigned to receive either routine nursing (control group, n = 50) or comprehensive nursing plus high-quality nursing (observation group, n = 50) via the random number table method. The outcome measures included compliance, psychological state, and treatment effects. Results: Before the nursing, there was no significant difference in the compliance scores between the two groups of patients (P > 0.05). After the nursing, the observation group had higher compliance scores than the control group (P < 0.001). Before the intervention, the two groups had similar Self-Rating Anxiety Scale (SAS) scores (P > 0.05). After the intervention, patients in the observation group showed lower SAS scores and a lower incidence of negative emotions as compared to the control group (P < 0.001). The observation group showed a better outcome in terms of quality of life, Medical Coping Modes Questionnaire (MCMQ) scores, and the General Self-Efficacy Scale (GSES) scores when compared to those of the control group (P < 0.001). A higher treatment effective rate was witnessed in the observation group in contrast to the control group (P < 0.001). Conclusion: The comprehensive nursing model combined with high-quality nursing intervention improves the psychological state and compliance of patients with chronic hepatitis B, with favorable treatment efficiency, which shows good potential for clinical promotion.

Simvastatin in the Treatment of Colorectal Cancer: A Review.

Drug repositioning and drug reuse are the heated topics in the field of oncology in recent years. These two concepts refer to seeking effective drugs for cancer that are not originally intended to treat cancer. The survival benefits are then analyzed by combining the re-positioned drugs with conventional cancer treatment methods. Simvastatin is a clinically commonly used hyperlipidemia drug and exerts the effect of preventing cardiovascular diseases. Recent studies have found that simvastatin has great potential in the treatment of colorectal cancer, and a large number of clinical studies have used simvastatin as an adjuvant drug to help treat metastatic colorectal cancer.

Application of Music Therapy in General Surgical Treatment.

With the increasing application of music therapy in clinical practice, the effectiveness of music therapy in improving the negative emotions of patients, relieving pain, and adjusting the physiological state has also been receiving increasing recognization. Moreover, music therapy as adjuvant therapy for conventional treatment can achieve a better improvement in patient satisfaction and facilitate the acceptance of make music therapy by the medical industry. In addition to inevitable trauma, general surgery is criticized for its long treatment cycles and postoperative pain. With the continuous development of fast-track surgery (FTS), music therapy has received more attention in general surgical treatment. This study reviews the development history and prospects of music therapy in general surgery.

Protocatechuic Acid-Mediated miR-219a-5p Activation Inhibits the p66shc Oxidant Pathway to Alleviate Alcoholic Liver Injury.

Alcohol abuse has become common worldwide and has been recognized as a major cause of chronic alcoholic liver disease (ALD). ALD encompasses a complex process that includes a broad scope of hepatic lesions, ranging from steatosis to cirrhosis. In particular, reactive oxygen species (ROS) are mainly involved. Numerous studies have shown that p66shc plays a significant role in ALD. Protocatechuic acid (PCA), a dihydroxybenzoic acid that is naturally found in green tea, vegetables, and fruits, has efficient free radical scavenging effects. In this study, we aimed to assess the protective effect of PCA on ALD and to evaluate the microRNA- (miRNA-) p66shc-mediated reduction of ROS formation in ALD. Our results demonstrated that PCA treatment significantly decreased p66shc expression and downstream ROS formation in ALD. miR-219a-5p, which was identified by bioinformatics and experimental analysis, was enhanced by PCA and subsequently suppressed p66shc expression. Importantly, p66shc played an essential role in the protection of PCA-stimulated miR-219a-5p overexpression. Overall, these findings show that PCA-stimulated miR-219a-5p expression mitigates ALD by reducing p66shc-mediated ROS formation. This study may contribute to the development of therapeutic interventions for ALD.

Salvianolic acid A alleviates chronic ethanol-induced liver injury via promotion of ß-catenin nuclear accumulation by restoring SIRT1 in rats.

In recent years, alcoholic liver disease (ALD) has emerged as a growing public health problem worldwide. ß-catenin plays an important role in the growth, development, regeneration and metabolic activity of the liver. Salvianolic acid A (SalA) is a water-soluble component from the root extract of Salvia miltiorrhiza Bunge, and its effect on ALD has not yet been investigated. This study aimed to investigate the effect of SalA on chronic alcohol-induced liver injury and to explore the role of SIRT1-mediated ß-catenin deacetylation in such an effect. In this study, SalA treatment significantly alleviated the accumulation of lipid droplets and reduced the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), alcohol and ammonia levels in rats. SalA enhanced ethanol and ammonia metabolism and maintained mitochondrial homeostasis. Moreover, SalA restored the activity of the major ethanol-metabolizing enzymes and oxidative stress functions in the liver. Importantly, we found that SalA treatment effectively inhibited the ethanol-mediated decrease in nuclear ß-catenin by upregulating SIRT1 in the liver. SIRT1 then deacetylated ß-catenin to promote its accumulation in the nucleus, thereby preventing alcohol-induced liver injury. The results demonstrate that the SIRT1/ß-catenin pathway is a key therapeutic target in liver injury caused by chronic alcohol exposure and that SalA protects against alcohol-induced liver injury via the SIRT1-mediated deacetylation of ß-catenin.

Inhibition of p66Shc-mediated mitochondrial apoptosis via targeting prolyl-isomerase Pin1 attenuates intestinal ischemia/reperfusion injury in rats.

Intestinal epithelial oxidative stress and apoptosis constitute key pathogenic mechanisms underlying intestinal ischemia/reperfusion (I/R) injury. We previously reported that the adaptor 66 kDa isoform of the adaptor molecule ShcA (p66Shc)-mediated pro-apoptotic pathway was activated after intestinal I/R. However, the upstream regulators of the p66Shc pathway involved in intestinal I/R remain to be fully identified. Here, we focused on the role of a prolyl-isomerase, peptidyl-prolyl cis-trans isomerase (Pin1), in the regulation of p66Shc activity during intestinal I/R. Intestinal I/R was induced in rats by superior mesenteric artery (SMA) occlusion. Juglone (Pin1 inhibitor) or vehicle was injected intraperitoneally before I/R challenge. Caco-2 cells were exposed to hypoxia/reoxygenation (H/R) in vitro to simulate an in vivo I/R model. We found that p66Shc was significantly up-regulated in the I/R intestine and that this up-regulation resulted in the accumulation of intestinal mitochondrial reactive oxygen species (ROS) and massive epithelial apoptosis. Moreover, intestinal I/R resulted in elevated protein expression and enzyme activity of Pin1 as well as increased interaction between Pin1 and p66Shc. This Pin1 activation was responsible for the translocation of p66Shc to the mitochondria during intestinal I/R, as Pin1 suppression by juglone or siRNA markedly blunted p66Shc mitochondrial translocation and the subsequent ROS generation and cellular apoptosis. Additionally, Pin1 inhibition alleviated gut damage and secondary lung injury, leading to improvement of survival after I/R. Collectively, our findings demonstrate for the first time that Pin1 inhibition protects against intestinal I/R injury, which could be partially attributed to the p66Shc-mediated mitochondrial apoptosis pathway. This may represent a novel prophylactic target for intestinal I/R injury.

Icariin protects against intestinal ischemia-reperfusion injury.

BACKGROUND: This study investigated the role of Sirtuin 1 (SIRT1)/forkhead box O3 (FOXO3) pathway, and a possible protective function for Icariin (ICA), in intestinal ischemia-reperfusion (I/R) injury and hypoxia-reoxygenation (H/R) injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were pretreated with different doses of ICA (30 and 60 mg/kg) or olive oil as control 1 h before intestinal I/R. Caco-2 cells were pretreated with different concentrations of ICA (25, 50, and 100 µg/mL) and then subjected to H/R-induced injury. RESULTS: The in vivo results demonstrated that ICA pretreatment significantly improved I/R-induced tissue damage and decreased serum tumor necrosis factor α and interleukin-6 levels. Changes of manganese superoxide dismutase, Bcl-2, and Bim were also reversed by ICA, and apoptosis was reduced. Importantly, the protective effects of ICA were positively associated with SIRT1 activation. Increased SIRT1 expression, as well as decreased acetylated FOXO3 expression, was observed in Caco-2 cells pretreated with ICA. Additionally, the protective effects of ICA were abrogated in the presence of SIRT1 inhibitor nicotinamide. This suggests that ICA exerts a protective effect upon H/R injury through activation of SIRT1/FOXO3 signaling pathway. Accordingly, the SIRT1 activator resveratrol achieved a similar protective effect as ICA on H/R injury, whereas cellular damage resulting from H/R was exacerbated by SIRT1 knockdown and nicotinamide. CONCLUSIONS: SIRT1, activated by ICA, protects intestinal epithelial cells from I/R injury by inducing FOXO3 deacetylation both in vivo and in vitro These findings suggest that the SIRT1/FOXO3 pathway can be a target for therapeutic approaches intended to minimize injury resulting from intestinal dysfunction.

Novel role of resveratrol: suppression of high-mobility group protein box 1 nucleocytoplasmic translocation by the upregulation of sirtuin 1 in sepsis-induced liver injury.

BACKGROUND: High-mobility group protein box 1 (HMGB1) is essential in the response to injury during sepsis. We hypothesized that resveratrol (RESV) administration would inhibit nuclear-cytoplasmic HMGB1 translocation in hepatocytes, which is associated with sirtuin 1 (SIRT1) upregulation. We investigated the regulatory role of SIRT1 in HMGB1 nucleocytoplasmic translocation and its effect on sepsis-induced liver injury. METHODS: Rats were randomly assigned to pretreatment with RESV (60 mg/kg per day), nicotinamide (60 mg/kg per day), or vehicle (olive oil), which was administered by gavage for 3 days directly before cecal ligation and puncture was performed to induce sepsis. Parallel control groups were established. Rats were killed 24 h after surgery, and cytokine production, histology, apoptosis, SIRT1, serum HMGB1, nuclear and cytoplasmic HMGB1/ac-HMGB1, and the interaction between SIRT1 and HMGB1 were evaluated. In vitro evaluations were performed in human liver L02 cells subjected to lipopolysaccharide-induced injury, and siRNA-mediated SIRT1 knockdown experiments were performed. RESULTS: Sepsis-induced serum aminotransferase activities and proinflammatory chemokine levels were reduced by RESV pretreatment, which also improved liver histological parameters in association with SIRT1 upregulation. Resveratrol inhibited HMGB1 cytoplasmic translocation. Nicotinamide, an SIRT1 inhibitor, reduced the SIRT1-mediated suppression of HMGB1 translocation and aggravated cecal ligation and puncture-induced liver damage. Sirtuin 1 knockdown in vitro confirmed that RESV increased the SIRT1-mediated repression of HMGB1 translocation. In vivo, SIRT1 and HMGB1 physically interacted in the nucleus, and SIRT1 regulated HMGB1 acetylation in response to septic liver injury. CONCLUSIONS: Resveratrol protects against sepsis-induced liver injury through the SIRT1-mediated HMGB1 nucleocytoplasmic translocation pathway, a new potential therapeutic target in sepsis-induced liver injury.

Fish-oil emulsion (omega-3 polyunsaturated fatty acids) attenuates acute lung injury induced by intestinal ischemia-reperfusion through Adenosine 5'-monophosphate-activated protein kinase-sirtuin1 pathway.

BACKGROUND: Activated macrophage infiltration into the lungs is paramount in the pathogenesis of acute lung injury (ALI) induced by intestinal ischemia-reperfusion (I/R). Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a potent activator of the Adenosine 5'-monophosphate-activated protein kinase-sirtuin1 (AMPK/SIRT1) pathway against macrophage inflammation. We aimed to evaluate whether ω-3 PUFAs may protect against ALI induced by intestinal I/R via the AMPK/SIRT1 pathway. METHODS: Ischemia in male Wistar rats was induced by superior mesenteric artery occlusion for 60 min and reperfusion for 240 min. One milliliter per day of fish-oil emulsion (FO emulsion, containing major ingredients as ω-3 PUFAs) or normal saline (control) was administered by intraperitoneal injection for three consecutive days to each animal. All animals were sacrificed at the end of reperfusion. Blood and tissue samples were collected for analysis. RESULTS: Intestinal I/R caused intestinal and lung injury, evidenced by severe lung tissue edema and macrophage infiltration. Pretreatment with FO emulsion improved the integrity of microscopic structures in the intestine and lungs. Intestinal I/R induced the expression of macrophage-derived mediators (macrophage migration inhibitory factor and macrophage chemoattractant protein-1), inflammatory factors (nuclear factor κB, tumor necrosis factor α, interleukin 6, and interleukin 1ß), and proapoptosis factor p66shc. There was a decrease in the expression of AMPK, SIRT1, and claudin 5. FO emulsion significantly inhibited macrophage infiltration into the lungs, inflammatory factor expression, and p66shc phosphorylation. Importantly, FO emulsion restored AMPK, SIRT1, and claudin 5 in the lungs. CONCLUSIONS: Pretreatment with ω-3 PUFAs effectively protects intestinal and lung injury induced by intestinal I/R, reduces macrophage infiltration, suppresses inflammation, inhibits lung apoptosis, and improves the lung endothelial barrier after intestinal I/R in a manner dependent on AMPK/SIRT1. Thus, there is a potential for developing AMPK/SIRT1 as a novel target for patients with intestinal I/R-induced ALI.

Suppression of the p66shc adapter protein by protocatechuic acid prevents the development of lung injury induced by intestinal ischemia reperfusion in mice.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) causes severe histological injury, reactive oxygen species activation, and cell apoptosis in the lung. In this study, we investigated, using a murine intestinal I/R model, the effect of a polyphenolic compound, protocatechuic acid (PCA), in modulation of ShcA and in protection of the lung from I/R-induced injury. METHODS: Fifty ICR mice were randomly divided into five groups, including a control group, intestinal I/R group, control + PCA group, I/R + PCA low-dose group, and I/R + PCA high-dose group. The I/R and I/R + PCA groups were subjected to mesenteric arterial ischemia for 45 minutes and reperfusion for 90 minutes. The control and control + PCA groups underwent a surgical procedure that included isolation of the superior mesenteric artery without occlusion. In all PCA-pretreated groups, the mice received intraperitoneal PCA administration for three consecutive days. Serum specimens were collected for measuring tumor necrosis factor-α and interleukin 6, while lung tissues were harvested for histopathologic assessment including glutathione (GSH) and GSH peroxidase assay. Lung expression of p66shc, phosphorylated p66shc, manganese superoxide dismutase, caspace-3, and Bcl-xL were determined by Western blotting for protein level and semiquantitative reverse transcription-polymerase chain reaction analysis for mRNA level. RESULTS: PCA pretreatment markedly reduced I/R-induced lung injury as indicated by histological alterations; the decreases in tumor necrosis factor-α, interleukin 6, and caspase-3 expression levels; and the increases in GSH, GSH peroxidase, manganese superoxide dismutase, and Bcl-xL levels in the lung. Moreover, PCA treatment down-regulated p66shc expression and phosphorylation. CONCLUSION: PCA has a significant protective effect in lung injury induced by intestinal I/R. The protective effect of PCA may be attributed to the suppression of p66shc and the modulation of downstream antioxidative/antiapoptotic factors.

Protective effect of carnosol on lung injury induced by intestinal ischemia/reperfusion.

PURPOSE: Carnosol is a phenolic diterpene that has potent antioxidant and anti-inflammatory activities. The purpose of this study was to investigate the preconditioning effects of carnosol on lung injury induced by intestinal ischemia/reperfusion (II/R). METHODS: Rats were divided into control, II/R, and carnosol groups. The II/R model was established by clamping the superior mesenteric artery for 1 h and reperfusion at 2, 4, and 6 h after ischemia. The carnosol group received 3 mg/kg carnosol intraperitoneally 1 h before the operation. The rats were then euthanized, and blood and lung specimens were obtained for analysis. RESULTS: The II/R induced lung injury, characterized by histological changes and significant increasing of bronchoalveolar lavage fluid protein. The activity of lung tissue superoxide was weakened, the tissue myeloperoxidase activity and serum interleukin-6 level increased significantly in II/R groups. A strong positive expression of lung intercellular adhesion molecule-1 (ICAM-1) and nuclear factor kappa B (NF-kappaB) were observed. Pretreatment with carnosol markedly reduced lung injury by increasing the tissue superoxide activity and decreasing the myeloperoxidase activity and interleukin-6 level, which was parallel to the decreased expression of ICAM-1 and NF-kappaB. CONCLUSION: Carnosol was able to ablate lung injury induced by II/R, partly attributed to the inhibition of NF-kappaB activation.

Protection of Veratrum nigrum L. var. ussuriense Nakai alkaloids against ischemia-reperfusion injury of the rat liver.

AIM: To investigate the protective effects and possible mechanisms of Veratrum nigrum L.var. ussuriense Nakai alkaloids (VnA) on hepatic ischemia/reperfusion (I/R) injury in rats. METHODS: Forty male Wistar rats were randomly divided into four experimental groups (n = 10 in each): (A) Control group (the sham operation group); (B) I/R group (pretreated with normal saline); (C) Small-dose (10 microg/kg) VnA pretreatment group; (D) Large-dose (20 microg/kg) VnA pretreatment group. Hepatic ischemia/reperfusion (Hepatic I/R) was induced by occlusion of the portal vein and the hepatic artery for 90 min, followed by reperfusion for 240 min. The pretreatment groups were administered with VnA intraperitoneally, 30 min before surgery, while the control group and I/R group were given equal volumes of normal saline. Superoxide dismutase (SOD) activity, myeloperoxidase (MPO) activity and nitric oxide (NO) content in the liver tissue at the end of reperfusion were determined and liver function was measured. The expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin (ES) were detected by immunohistochemical examinations and Western blot analyses. RESULTS: The results showed that hepatic I/R elicited a significant increase in the plasma levels of alanine aminotransferase (ALT: 74.53 +/- 2.58 IU/L vs 1512.54 +/- 200.76 IU/L, P < 0.01) and lactic dehydrogenase (LDH: 473.48 +/- 52.17 IU/L vs 5821.53 +/- 163.69 IU/L, P < 0.01), as well as the levels of MPO (1.97 +/- 0.11 U/g vs 2.57 +/- 0.13 U/g, P < 0.01) and NO (69.37 +/- 1.52 micromol/g protein vs 78.39 +/- 2.28 micromol/g protein, P < 0.01) in the liver tissue, all of which were reduced by pretreatment with VnA, respectively (ALT: 1512.54 +/- 200.76 IU/L vs 977.93 +/- 89.62 IU/L, 909.81 +/- 132.76 IU/L, P < 0.01, P < 0.01; LDH: 5821.53 +/- 163.69 IU/L vs 3015.44 +/- 253.01 IU/L, 2448.75 +/- 169.4 IU/L, P < 0.01, P < 0.01; MPO: 2.57 +/- 0.13 U/g vs 2.13 +/- 0.13 U/g, 2.07 +/- 0.05 U/g, P < 0.01, P < 0.01; NO: 78.39 +/- 2.28 micromol/g protein vs 71.11 +/- 1.73 micromol/g protein, 68.58 +/- 1.95 micromol/g protein, P < 0.05, P < 0.01). The activity of SOD (361.75 +/- 16.22 U/mg protein vs 263.19 +/- 12.10 U/mg protein, P < 0.01) in the liver tissue was decreased after I/R, which was enhanced by VnA pretreatment (263.19 +/- 12.10 U/mg protein vs 299.40 +/- 10.80 U/mg protein, 302.09 +/- 14.80 U/mg protein, P < 0.05, P < 0.05). Simultaneously, the histological evidence of liver hemorrhage, polymorphonuclear neutrophil infiltration and the overexpression of ICAM-1 and E-selectin in the liver tissue were observed, all of which were attenuated in the VnA pretreated groups. CONCLUSION: The results demonstrate that VnA pretreatment exerts significant protection against hepatic I/R injury in rats. The protective effects are possibly associated with enhancement of antioxidant capacity, reduction of inflammatory responses and suppressed expression of ICAM-1 and E-selectin.