Search

AbstractThe purpose of this work was to create and assess Lornoxicam (LOR) loaded Novasomes (Novas) for the efficient treatment of ulcerative colitis. The study was performed using a 23 factorial design to investigate the impact of several formulation variables. Three separate parameters were investigated: Surface Active agent (SAA) type (X1), LOR concentration (X2), and SAA: Oleic acid ratio (X3). The dependent responses included encapsulation efficiency (Y1: EE %), particle size (Y2: PS), zeta potential (Y3: ZP), and polydispersity index (Y4: PDI). The vesicles demonstrated remarkable LOR encapsulation efficiency, ranging from 81.32 ± 3.24 to 98.64 ± 0.99%. The vesicle sizes ranged from 329 ± 9.88 to 583.4 ± 9.04 nm with high negative zeta potential values. The release pattern for Novas’ LOR was biphasic and adhered to Higuchi’s model. An in-vivo study assessed how LOR-Novas affected rats’ acetic acid-induced ulcerative colitis (UC). The optimised LOR-Novas effectively reduced colonic ulceration (p < 0.05) and reduced the inflammatory pathway via inhibiting Toll-like receptor 4 (TLR4), Nuclear factor kappa β (NF-κβ) and inducible nitric oxide (iNO). At the same time, it elevated Silent information regulator-1(SIRT-1) and reduced glutathione (GSH) colon contents. Thus, the current study suggested that the formulation of LOR-Novas may be a viable treatment for ulcerative colitis. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of dihydromyricetin (DHM) on the activation of NLRP3 inflammasome induced by lipopolysaccharides (LPS) /adenosine triphosphate (ATP) in vascular endothelial cells. Methods Human umbilical vein endothelial cells (HUVECs) were cultured and randomly divided into the control group, LPS/ATP group, LPS/ATP+25 µmol/L DHM group, LPS/ATP+50 µmol/L DHM group and LPS/ATP+100 µmol/L DHM group, respectively. Except the control group, HUVECs in the other groups were treated with LPS (0. 5 µg/mL) for 3. 5 h and ATP (5 mmol/L) for 30 min. HUVECs in the DHM groups were pretreated with DHM (25, 50, and 100 µmol/L) for 1 h before stimulation with LPS/ATP. The expression levels of NLRP3, ASC, pro-caspase-1, cleaved caspase-1 and silent information regulator-1 (SIRT1) were determined by Western blotting. Pathway enrichment analysis of SIRT1 was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), target genes regulated by SIRT1 were analyzed and a network diagram was constructed using transcriptional regulatory network analysis; SIRT1 localization was detected by immunofluorescence; and the interaction mode between DHM and SIRT1 was analyzed by molecular docking. Results Compared with the blank control group, the expression levels of NLRP3, ASC, and cleaved caspase-1 protein were higher in the LPS/ATP group (all P<0. 05); compared with the LPS/ATP group, the expression levels of NLRP3, ASC, and cleaved caspase-1 protein were lower in all DHM groups (all P<0. 05). SIRT1 was mainly distributed in the nucleus of cells. Compared with the blank control group, the relative fluorescence intensity was weaker in the LPS/ ATP group (P<0.05); compared with the LPS/ATP group, the relative fluorescence intensity was stronger in the LPS/ ATP+100 µmol/L DHM group (P<0.05). The LPS/ATP group had significantly lower expression of SIRT1 protein than the blank control group (P<0.05); compared with the LPS/ATP group and the LPS/ATP+25 µmol/L DHM group, SIRT1 protein expression levels were higher in the LPS/ATP+50 µmol/L DHM group and LPS/ATP+100 µmol/L DHM group (all P<0.05). GO enrichment analysis revealed that the bioprocesses enriched were closely related to nutrient level response, while the cellular component enriched were closely related to the chromatin silencing complex. The molecular function enrichment analysis had a relation to molecular functions such as chromatin-DNA binding. KEGG pathway enrichment analysis showed that SIRT1 was involved in longevity regulation, lipid and atherosclerosis signaling pathways. Further study indicated that DHM could be embedded into the binding pocket of SIRT1. Conclusion DHM inhibits LPS/ ATP-induced activation of NLRP3 inflammasome probably by up-regulating the SIRT1 expression in HUVECs. [ABSTRACT FROM AUTHOR]

The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed.

The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed. [ABSTRACT FROM AUTHOR]

Abstract Dysregulated lipid profile with hypertriglyceridemia and increased low-density lipoprotein (LDL) is common in chronic kidney disease (CKD) whereas the reason is unclear. A similar phenomenon is found in the elder population. Silent information regulator-1 (SIRT1) associates with many modulators regulating lipid metabolism and results in increased expression of sterol regulatory element-binding proteins (SREBPs), which functions as a key modulator in lipid synthesis. Since CKD is being viewed as a premature aging model and SIRT1 is known to decrease during the process of aging, we hypothesize that SIRT1 level is reduced in the liver when CKD develops and eventually result in dysregulated lipid profile.

Background: In neonatal rats, MK-801 treatments can produce schizophrenia-like symptoms. Crocin is a water soluble carotenoid in Saffron that exerts potent neuroprotective effects. This work aimed to demonstrate the function of crocin in the alleviation of motor and cognitive impairments elicited by MK-801 in a neonatal rodent schizophrenia model, and to illustrate the underlying molecular mechanisms. Methods: Rats were treated with vehicle, MK-801 (1 mg/kg), MK-801 + 25 mg/kg crocin, or MK-801 + 50 mg/kg crocin. Motor learning and coordination, locomotion and exploratory activities, as well as spatial memory were assessed using the rotarod test, pen field test, and the Morris water maze test, respectively. Relative mRNA and protein levels of genes of interest were analyzed using qRT-PCR and Western blot assays, respectively. Results: In the hippocampus of rats with MK-801-elicited schizophrenia, administration of crocin elevated the expression of silent information regulator-1 (SIRT1) and brain derived neurotrophic factor (BDNF), and relieved the oxidative stress. The learning deficits and motor perturbations caused by MK-801 treatments were also alleviated by the crocin administration. Conclusion: Collectively, crocin has exerted neuroprotective effects in the rat model of MK-801-elicited schizophrenia, via regulations of SIRT1 and downstream BDNF expression in the hippocampus.

Background & Aims Tetrandrine (Tet) has been reported to have anti-inflammatory effects and protect from the ischemic strokes. The NLRP3 inflammasome plays a key role in cerebral ischemia/reperfusion (I/R)-induced inflammatory lesions. However, the molecular mechanisms of Tet related to the progression of cerebral ischemia are still unclear. Therefore, the aim of this study was to investigate the possible effects of Tet on cerebral ischemia and the related mechanisms involved in NLRP3 inflammasome. Methods C57BL/6J mice used as a cerebral I/R injury model underwent middle cerebral artery occlusion (MCAO) for 2 h following reperfusion for 24 h. Tet (30 mg/kg/day, i.p.) was administered for seven days and 30 min before and after MCAO. Their brain tissues were evaluated for NLRP3 inflammasome and Sirtuin-1 (Sirt-1) expression. An intracerebroventricular injection of Sirt-1 siRNA was administered to assess the activation of the NLRP3 inflammasome. Results Tet significantly reduced the neurological deficits, infarction volume, and cerebral water content in MCAO mice. Moreover, it inhibited I/R-induced over expression of NLRP3, cleaved caspase-1, interleukin (IL)-1β, IL-18, and Sirt-1. Sirt-1 knockdown with siRNA greatly blocked the Tet-induced reduction of neurological severity score and infarct volume, and reversed the inhibition of NLRP3 inflammasome activation. Conclusion Our results demonstrate that Tet has benefits for cerebral I/R injury, which are partially related to the suppression of NLRP3 inflammasome activation via upregulating Sirt-1.

The aim of this study was to assess the expression of Th17-associated gene, AMPs genes and SIRT-1 protein in patients with inflammatory bowel disease (IBD). Material and Methods: We studied a group of 20 IBD patients, together with 20 subjects served as controls. Colonoscopy, terminal ileoscopy, and colonoscopic biopsy were performed for histopathology diagnosis, and quantitative gene expression of Th17-associated gene, CAMP, Elafin and SLPI by real-time PCR. SIRT-1 protein level expression was assessed by western blot. Results: The expression of the four studied genes—elafin, SLPI, CAMP and Th17-associated gene—by relative quantification was higher in the patient group than in the control group. A statistically significant positive correlation was found between SLPI and elafin in the patient group (r= 0.8325 P

In neonatal rats, MK-801 treatments can produce schizophrenia-like symptoms. Crocin is a water soluble carotenoid in Saffron that exerts potent neuroprotective effects. This work aimed to demonstrate the function of crocin in the alleviation of motor and cognitive impairments elicited by MK-801 in a neonatal rodent schizophrenia model, and to illustrate the underlying molecular mechanisms. Rats were treated with vehicle, MK-801 (1 mg/kg), MK-801 + 25 mg/kg crocin, or MK-801 + 50 mg/kg crocin. Motor learning and coordination, locomotion and exploratory activities, as well as spatial memory were assessed using the rotarod test, pen field test, and the Morris water maze test, respectively. Relative mRNA and protein levels of genes of interest were analyzed using qRT-PCR and Western blot assays, respectively. In the hippocampus of rats with MK-801-elicited schizophrenia, administration of crocin elevated the expression of silent information regulator-1 (SIRT1) and brain derived neurotrophic factor (BDNF), and relieved the oxidative stress. The learning deficits and motor perturbations caused by MK-801 treatments were also alleviated by the crocin administration. Collectively, crocin has exerted neuroprotective effects in the rat model of MK-801-elicited schizophrenia, via regulations of SIRT1 and downstream BDNF expression in the hippocampus. • Crocin restores MK-801-repressed production of SIRT1 and BDNF. • Crocin restores CREB phosphorylation in the MK-801-treated rat hippocampus. • Crocin relieves oxidative stress in the MK-801-treated rat hippocampus. • Crocin attenuates behavioural deficits in MK-801-treated rats. • Crocin improves spatial learning of MK-801-treated rats. [ABSTRACT FROM AUTHOR]