Artesunate (ART) is a semi-synthetic derivative of artemisinin with well-established antimalarial activity. In this study, we demonstrate that ART treatment markedly attenuates disease severity in dextran sulfate sodium (DSS)-induced colitis. ART significantly reduces the accumulation of inflammatory neutrophils, monocytes, Th17 cells, and IL-17-producing ILCs and γδT cells in the colon, accompanied by suppression of pro-inflammatory gene expression, including Tnf, Il6, and Il1b, and upregulation of anti-inflammatory mediators such as Tgfb and Il10. In parallel, ART restores the expression of intestinal tight junction proteins ZO-1 and claudin-1, indicating improved epithelial barrier integrity. ART treatment inhibits the IL-17 production from both Th17 cells and other lymphocytes. ART also reshapes the gut microbiota, which contributes to protection against DSS-induced colitis. Notably, mesalazine co-treatment with ART augmented its protective efficacy against DSS-induced colitis. Collectively, these findings identify ART as a potent modulator of intestinal inflammation and barrier function, highlighting its therapeutic potential for mucosal inflammatory diseases.

Background Syringin (SRG) is well-known for its anti-inflammatory effects. However, its pharmacological mechanisms against rheumatoid arthritis (RA) are not fully understood. Materials and methods We assessed the anti-RA effects of SRG using a collagen-induced arthritis (CIA) rat model. And, we employed single-cell RNA sequencing (scRNA-seq) to analyze the changes in cell types and gene expression in the synovial tissues. Building on these observations, we investigated the effects of SRG on M1 macrophage polarization and RA-fibroblast-like synoviocytes (FLS) proliferation. Results Our findings highlighted the anti-RA effects of SRG on CIA rat. scRNA-seq of rat synovial tissues revealed significant changes in M1 and RA-FLS. Specifically, SRG decreased the levels of inflammatory factors in the supernatants of LPS and IFN-γ induced THP-1 cells and downregulated M1-polarized markers in these cells. Further analysis indicated that SRG's regulation of phosphodiesterase 4 (PDE4) and its associated factors was crucial for its anti-M1 polarization effects. Besides, we found that SRG inhibited the activation of FLS in vivo but showed no direct effects on RA-FLS in vitro. However, in RA-FLS, co-cultured with supernatant from SRG-treated M1-polarized THP-1 cells exhibited lower ability of cell proliferation and activation as compared to co-cultured with supernatant from M1-polarized THP-1 cells. Conclusion By integrating scRNA-seq analysis with in vivo and in vitro validations, our study revealed that SRG achieved its anti-RA effects by blocking the interaction between macrophages and RA-FLS, with PDE4 playing a central role. This study may provide a novel research paradigm in studying the multi-cell regulatory mechanisms of natural compounds.

Objective: To evaluate the effects of Wuhua herbal tea on chronic unpredictable mild stress (CUMS)-induced depression and explore its mechanism of action in combating depression. Methods: We tested the antidepressant effects of Wuhua herbal tea in a rat model of CUMS-induced depression using fluoxetine as a positive control. The rats were divided into four groups: control group, model group, fluoxetine group, and Wuhua herbal tea group. The rats underwent body weight measurements, sucrose preference test, and open-field test. Enzyme-linked immunosorbent assay kits were used to detect the serum levels of serotonin, dopamine, adrenocorticotropic hormone (ACTH), corticosterone, norepinephrine, and interleukin-6. Intergroup comparisons and detection of brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) mRNA expression in the hippocampus were performed using RT-PCR. Immunohistochemistry was used to identify the expression of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) proteins in hippocampal paraffin sections of CUMS rats. Results: Compared with the control group, the model group rats had depressive tendencies, exhibiting low vitality and interest in various behavioral indicators which were signs of despair. The Wuhua herbal tea group statistically increased the levels of serotonin and dopamine in the serum of CUMS rats to varying degrees (P = .015 and P = .002); reduced serum levels of ACTH, corticosterone, norepinephrine, and interleukin-6 (all P < .05); and decreased mRNA expression of BDNF, CREB, JAK2, and STAT3 in the hippocampus (all P < .05); and decreased p-STAT3 protein levels (P = .006). Conclusion: Wuhua herbal tea shows antidepressant potential in CUMS rats by modulating the HPA axis and inhibiting JAK2-STAT3 overactivation, alleviating neuroinflammation. It also restores BDNF-CREB pathway function, reducing depressive symptoms.

Breast cancer, as the most prevalent female malignancy, leads the cancer-related death in women worldwide. Local anesthetic chloroprocaine exhibits antitumor potential, but its specific functions and underlying molecular mechanisms in breast cancer remain unclear. Here, we demonstrated chloroprocaine significantly inhibited proliferation, invasion and induced apoptosis of breast cancer cells in vitro. Tumor growth and pulmonary metastasis were also suppressed in BABL/c nude mice model with chloroprocaine treatment. LINC00494 was identified as one of the most downregulated long noncoding RNAs in chloroprocaine-treated breast cancer cells by high-throughput sequencing. Futhermore, high level of LINC00494 was positively associated with poor outcome of breast cancer patients. LINC00494 acted as a "miRNAs sponge" to compete with MED19 for the biding of miR-3619-5p, led to the upregulation of MED19. LINC00494/miR-3619-5p/MED19 axis participated in chloroprocaine-mediated inhibition of proliferation, invasion and promotion of apoptosis of breast cancer cells. Consequently, our finding suggested local anesthetic chloroprocaine attenuated breast cancer aggressiveness through LINC00494-mediated signaling pathway, which detailly revealed the clinical value of chloroprocaine during breast cancer treatment.

OBJECTIVE:To investigate the application value of amide proton transfer (APT) magnetic resonance imaging in evaluating brain damage in patients with obstructive sleep apnea (OSA). MATERIALS AND METHODS:49 OSA patients and 25 healthy individuals matched for age and sex were included as case and control groups. All study participants underwent conventional 3D T1WI and APT imaging of the head. The APT values were measured in each of the brain regions of interest (ROI). To compare the differences in APT values of each brain region between the case and control groups, to compare the differences in the efficacy of APT values of each brain region in diagnosing OSA, and to investigate the correlation between APT values of each brain region and Apnea Hypopnea Index (AHI) and minimum blood oxygen saturation. RESULTS:Compared to the control group, patients with OSA had elevated APT values in several brain regions (P < 0.05), and the diagnostic efficacy of the combined diagnosis of OSA by multiple brain regions is better than that by each brain region alone.Left frontal APT values were positively correlated with AHI in the case group (r = 0.33, P = 0.020).In the case group, the APT values of bilateral frontal lobe, parietal lobe, occipital lobe, left temporal lobe, right thalamus, left internal capsule, left lenticular nucleus, right cerebellar hemisphere and splenium of corpus callosum were negatively correlated with the minimum blood oxygen saturation, and the APT values for each of the above ROIs were positively correlated. CONCLUSION:APT imaging has a certain value in evaluating brain damage in OSA patients, which may provide a new objective imaging basis for the clinical diagnosis of OSA.

We applied network pharmacology and molecular docking analyses to study the efficacy of Broussonin E (BRE) in acute respiratory distress syndrome (ARDS) treatment and to determine the core components, potential targets, and mechanism of action of BRE. The SwissTargetprediction and SEA databases were used to predict BRE targets, and the GeneCards and OMIM databases were used to predict ARDS-related genes. The drug targets and disease targets were mapped to obtain an intersecting drug target gene network, which was then uploaded into the String database for protein–protein interaction network analysis. The intersecting gene was also uploaded into the DAVID database for gene ontology enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis. Molecular docking analysis was performed to verify the interaction of BRE with the key targets. Finally, to validate the experiment in vivo, we established an oleic acid-induced ARDS rat model and evaluated the protective effect of BRE on ARDS by histological evaluation and enzyme-linked immunosorbent assay. Overall, 79 targets of BRE and 3974 targets of ARDS were predicted, and 79 targets were obtained after intersection. Key genes such as HSP90AA1, JUN, ESR1, MTOR, and PIK3CA play important roles in the nucleus and cytoplasm by regulating the tumor necrosis factor, nuclear factor-κB, and PI3K-Akt signaling pathways. Molecular docking results showed that small molecules of BRE could freely bind to the active site of the target proteins. In vivo experiments showed that BRE could reduce ARDS-related histopathological changes, release of inflammatory factors, and infiltration of macrophages and oxidative stress reaction. BRE exerts its therapeutic effect on ARDS through target and multiple pathways. This study also predicted the potential mechanism of BRE on ARDS, which provides the theoretical basis for in-depth and comprehensive studies of BRE treatment on ARDS.

Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.

Deep learning has been widely used in source code classification tasks, such as code classification according to their functionalities, code authorship attribution, and vulnerability detection. Unfortunately, the black-box nature of deep learning makes it hard to interpret and understand why a classifier (i.e., classification model) makes a particular prediction on a given example. This lack of interpretability (or explainability) might have hindered their adoption by practitioners because it is not clear when they should or should not trust a classifier's prediction. The lack of interpretability has motivated a number of studies in recent years. However, existing methods are neither robust nor able to cope with out-of-distribution examples. In this paper, we propose a novel method to produce Robust interpreters for a given deep learning-based code classifier; the method is dubbed Robin. The key idea behind Robin is a novel hybrid structure combining an interpreter and two approximators, while leveraging the ideas of adversarial training and data augmentation. Experimental results show that on average the interpreter produced by Robin achieves a 6.11% higher fidelity (evaluated on the classifier), 67.22% higher fidelity (evaluated on the approximator), and 15.87x higher robustness than that of the three existing interpreters we evaluated. Moreover, the interpreter is 47.31% less affected by out-of-distribution examples than that of LEMNA.

Acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar–capillary barrier, resulting in severe alveolar edema and inflammation. D-tagatose (TAG) is a low-calorie fructose isomer with diverse biological activities whose role in ARDS has never been explored. We found that TAG protects lung tissues from injury in the oleic acid-induced rat model of ARDS. Seventeen male Sprague–Dawley rats were randomly assigned to 3 groups: Sham (n = 5), ARDS (n = 6), and TAG + ARDS (n = 6). The treatment groups were injected with oleic acid to induce ARDS, and the TAG + ARDS group was given TAG 3 days before the induction. After the treatments, the effect of TAG was evaluated by blood gas analysis and observing the gross and histological structure of the lung. The results showed that TAG significantly improved the oxygenation function, reduced the respiratory acidosis and the inflammatory response. TAG also improved the vascular permeability in ARDS rats and promoted the differentiation of alveolar type II cells, maintaining the stability of the alveolar structure. This protective effect of TAG on the lung may be achieved by activating the PTEN/PI3K/AKT pathway. Thus, TAG protects against oleic acid-induced ARDS in rats, suggesting a new clinical strategy for treating the condition.

Introduction:Trace element metabolism disorders are often secondary to disorders of glucose metabolism in diabetes. Although 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] could ameliorate abnormal glucose metabolism in the development of diabetes, the effect on trace element metabolism is unclear. The objective of this study was to evaluate the influence of 1,25(OH)2D3 on urinary excretions of trace elements in Zucker diabetic fatty (ZDF) rats.Methods:At 6 weeks of age, male ZDF (n = 40) rats were subdivided into four groups: diabetic model (ZDF), low-dose (ZDF + VL, 2 μg/kg⋅bw), middle-dose (ZDF + VM, 8 μg/kg⋅bw) and high-dose (ZDF + VH, 16 μg/kg⋅bw) 1,25(OH)2D3 groups. Another 10 Zucker lean (ZL) rats served as a control group. All rats were given vitamin D deficient Purina #5008 chow and the intervention groups were given the corresponding dose of 1,25(OH)2D3 by gavage on alternate days for 7 weeks. Microalbuminuria (MALB) and urinary creatinine concentration were detected by a biochemical autoanalyzer. Urine trace element concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and were corrected by urinary creatinine.Results:Throughout the intervention phase, MALB, UACR and urinary creatinine levels in the ZDF group were significantly higher than those in the ZL group, and showed a gradual increase with the prolongation of the intervention time. These changes were reversed in a dose-dependent manner after 1,25(OH)2D3 intervention (P < 0.05). Correspondingly, most of the urinary trace element excretions in the ZDF rats were significantly increased compared with the ZL group, and 1,25(OH)2D3 intervention significantly reduced the urinary copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo) levels in the ZDF rats (P < 0.05), especially in the medium and high dose groups.Conclusion:1,25(OH)2D3 had improvement effects on urinary Cu, Zn, Se, and Mo excretions in ZDF rats, suggesting that it may be related to the reduction of diabetic renal impairment and renal oxidative damage.

Colorectal cancer (CRC) recurrence after surgical resection results in poor clinical outcomes. Long noncoding RNAs (lncRNAs) are emerging new targets for mediating tumorigenesis and immunosuppression within tumor microenvironment. We develop a bio-scaffold encapsulating lncRNA-targeting biomimetic nanosystems for mediating triple immune effects against postoperative CRC recurrence. Liposome (termed as "D")-decorated CRC cells' membrane (CM) envelops a plasmid encoding a short hair-pinned RNA (shRNA) against plasmacytoma variant translocation 1 (Pvt1), forming the shPvt1-CM-D nanosystem. This nanosystem and the chemodrug Oxaliplatin (Oxa) are embedded in a hyaluronic acid and alginate-based bio-scaffold for postoperative implantation. (1) ShPvt1-CM-D-mediated Pvt1 knockdown strengthens Oxa-induced immunogenic cell death (ICD). (2) Such tumor antigens released from enhanced ICD and the CM from shPvt1-CM-D act as dual vaccines of dendritic cells. (3) Pvt1 knockdown by shPvt1-CM-D within granulocytic myeloid-derived suppressor cells (G-MDSCs) ameliorates G-MDSC-mediated immunosuppression. The nanosystem-carrying bio-scaffold significantly suppresses perioperative CRC local recurrence by 97.8% with survival rate (SR) of 62.5%. The bio-scaffold generates robust immune memory responses for completely suppressing tumor ectopic rechallenging and metachronous metastasis (SR: 100%). Additionally, the bio-scaffold reduces synchronously distant metastasis by 70.8%. This work presents a potent nanotechnology-facilitated lncRNA-targeting immunotherapy for postoperative CRC treatments.

Combined with Network Analysis (NA) and in vivo experimental methods, we explored and verified the mechanism of Cepharanthine (CEP) involved in the treatment of acute respiratory distress syndrome (ARDS). Potential targets of CEP were searched using the SwissTargetPrediction database. The pathogenic genes related to ARDS were obtained using the DisGeNET database. A protein-protein interaction network of common target genes of disease-compound was subsequently built and visualised. Functional enrichment analysis was performed through the Enrichr database. Finally, for in vivo experimental verification, we established an oleic acid-induced ARDS rat model, mainly through histological evaluation and the ELISA method to evaluate both the protective effect of CEP on ARDS and its effect on inflammation. A total of 100 genes were found to be CEP targeted genes, while 153 genes were found to be associated with ARDS. The PPI network was used to illustrate the link and purpose of the genes associated with CEP and ARDS, which contained 238 nodes and 2,333 links. GO and KEGG analyses indicated that inflammatory response and its related signalling pathways were closely associated with CEP-mediated ARDS treatment. Thus, a key CEP-gene-pathway-ARDS network was constructed through network analysis, including 152 nodes (5 targets and 6 pathways) and 744 links. The results of in vivo experiments showed that CEP could alleviate histopathological changes and pulmonary edema related to ARDS, in addition to reducing neutrophil infiltration and secretion of inflammatory cytokines, whilst increasing serum contents of ResolvinD1 and ResolvinE1. Thus, these effects enhance the anti-inflammatory responses. Thus, our results show that CEP can treat oleic acid-induced ARDS in rats via ResolvinE1 and ResolvinD1 signalling pathways that promote inflammation resolution, providing a new avenue to explore for the clinical treatment of ARDS.

Total saponins of Panax ginseng (TSPG) have antidepressant effects. However, the underlying antidepressant mechanism of TSPG remains not clear. This study aimed to predict the mechanism of TSPG by bioinformatics analysis and to verify it experimentally. Bioinformatics analysis showed that the antidepressant effects of TSPG may be related to inflammation, and CX3CL1/CX3CR1 may play a key mediating role. Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and TSPG (50 mg/kg/d, 100 mg/kg/d) was administered throughout the modeling period. It was found that TSPG improves depressive behavior and reduces neuropathic damage in the hippocampus in rats. Meanwhile, TSPG decreased mRNA and protein expression of pro-inflammatory cytokines and CX3CL1/CX3CR1 and inhibited P38 and JNK protein phosphorylation in the hippocampus. Rat astrocytes were employed to explore further the potential mechanism of TSPG in regulating CX3CL1/CX3CR1. The results showed that CX3CL1 small interfering RNA (siRNA-CX3CL1) and CX3CR1 inhibitor (JMS-17-2) had similar effects to TSPG, that is, reduced inflammatory response, reactive oxygen species (ROS), and phosphorylation of P38 and JNK proteins, while overexpression of CX3CL1 (pcDNA-CX3CL1) counteracted the above effects of TSPG. It is suggested that the antidepressant effect of TSPG may be achieved through inhibition of CX3CL1/CX3CR1.

BACKGROUND:Hypertensive patients, often characterized by chronic inflammation, are susceptible to diabetes. Evidence suggests that the positive association between serum ferritin (SF) and diabetes was affected by high-sensitivity C-reactive protein (hs-CRP), an inflammation marker. We investigate whether there was an interaction between SF and hs-CRP on diabetes in hypertensive patients. METHODS:We analysed data of 1,735 hypertensive people in this cross-sectional study. Diabetes was diagnosed when fasting blood glucose ≥ 7.0 mmol/L and/or a previous clinical diagnosis of diabetes. Logistic regression models were used to estimate the association of the SF and hs-CRP with diabetes. Multiplicative interaction was evaluated by incorporating a cross-product term for SF and hs-CRP to the logistic regression model. Additive interaction was assessed by calculating the relative excess risk of interaction (RERI) and attributed proportion due to interaction (AP). RESULTS:In the adjusted analysis, SF (highest vs lowest tertile: odds ratio [OR], 1.61; 95 % confidence interval [CI], 1.20-2.16) was positively associated with diabetes. There was no multiplicative interaction between SF and hs-CRP, but evidence of additive interaction in regard to diabetes (RERI: 0.86; 95 % CI: 0.06-1.67). Compared to the patients with low SF (lower two thirds) and low hs-CRP (≤ 2 mg/L), those with high SF (upper one third) and high hs-CRP (> 2 mg/L) had increased OR for diabetes (adjusted OR: 2.33 [1.65-3.30]), with 37.0 % of the effects attributed to the additive interaction (AP: 0.37; 95 % CI: 0.09-0.65). CONCLUSIONS:Within a cross-sectional study consisting of hypertensive patients, co-exposure to high SF and high hs-CRP was synergistically associated with diabetes. Dietary intervention or pharmacological treatment to lowering SF concentration may help to reduce diabetes morbidity in hypertensive patient with chronic inflammation.

Objective: Obesity is now a worldwide disease and is mainly attributable to increased body fat deposition. In a growing number of epidemiological studies, lutein has been revealed to have different degrees of anti-obesity properties, but the potential underlying mechanisms that have been reported are limited. Therefore, we aimed to clarify the protective effects of lutein against excessive lipid accumulation, and we explored the role of SIRT1 and SIRT1-mediated pathways both in abdominal adipose tissue and mature 3T3-L1 cells during lutein administration. Methods: In our design, male Sprague-Dawley rats were fed either control or high-fat diets with or without 25 mg/kg.bw/day lutein for 5 weeks. Additionally, differentiated 3T3-L1 cells were incubated with 40 mu M lutein or 10 mu M Ex527 for 24 h. Results: Lutein supplementation decreased the body weight, abdominal fat index ratio, frequency and mean area of larger adipocytes in HE staining induced by the high-fat diet and then activated the expression of SIRT1 and thus upregulated FoxO1, ATGL, and HSL expression and downregulated SREBP-1, FAS, and ACC expression both in abdominal adipose tissue and differentiated 3T3-L1 cells. However, coincubation with Ex527 and lutein suppressed the activation of SIRT1 and reversed the expression of FoxO1, ATGL, HSL, SREBP-1, FAS, and ACC in comparison to those in the Lut group. Conclusions: Overall, we suggest that the effects of lutein on attenuating excessive lipid accumulation are dependent on the SIRT1-mediated pathway in vivo and in vitro, which indicates that lutein administration may be a potential strategy for preventing excessive lipid accumulation and obesity.

Background: Kai Xin San (KXS) was widely applied for the treatment of depression for thousands of years. However, the underlying antidepressant mechanism of KXS remains not clear. Purpose: This study aimed to investigate whether NLRP3 inflammasome and autophagy are involved in inflammation-induced depression and antidepressant mechanism of KXS. Methods: Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and KXS (3, 5, and 10 g/kg/d) was administrated during the last 2 weeks of CUMS procedure. The effects of KXS on depressive-like behaviors, neuroinflammation, NLRP3 inflammasome activation, and autophagy were investigated in CUMS rats. Rat astrocytes were employed to further explore the potential mechanism of KXS in regulating NLRP3 inflammasome and autophagy. Autophagy inhibitor 3-methyladenine (3-MA, 5 mM) was used in vitro to elucidate the role of autophagy in the antidepressant mechanism of KXS. Results: In vivo, KXS improved depressive-like behaviors of CUMS rats in sucrose preference test, open field test and forced swimming test. Moreover, KXS inhibited the neuroinflammation induced by CUMS and promoted autophagy in prefrontal cortex of rats. The results in vitro further validated the anti-inflammatory and proautohapgic effects of KXS. More importantly, autophagy inhibitor 3-MA diminished the inhibitory effect of KXS on NLRP3 inflammasome activation in rat astrocytes. Conclusion: KXS ameliorated CUMS-induced depressive behaviors in rats and inhibited the NLRP3 inflammasome-mediated inflammation in vivo and in vitro. These effects might be regulated by KXS-induced autophagy.

SIRT1 has been proposed to enhance insulin secretion in β-cell through repressing the expression of uncoupling protein2 (UCP2), but whether ethanol-induced β-cell dysfunction is mediated by the disrupted SIRT1-UCP2 axis remains unknown. This study was conducted to explore the underlying mechanisms by which ethanol resulted in β-cell dysfunction and the potential protective effects of resveratrol in this process. INS-1 cells (rat pancreatic β-cell line) were cultured with ethanol in the presence or absence of resveratrol (2.5, 12.5 μmol/L). The results showed that ethanol exposure reduced glucose-stimulated insulin secretion, ATP production and SIRT1 expression but increased UCP2 expression, while supplementation with resveratrol restored the function of INS-1 cell by upregulating SIRT1 and inhibiting UCP2. Moreover, the critical role of SIRT1-UCP2 axis was further supported by the results that SIRT1 activator SRT1720 reversed ethanol-induced impairment of glucose-stimulated insulin secretion by decreasing UCP2, while SIRT1 inhibitor Ex527 abolished the beneficial effects of resveratrol. Meanwhile, NAD+ booster nicotinamide mononucleotide also counteracted the deleterious effects of ethanol by increasing SIRT1, suggesting the regulation of SIRT1-UCP2 axis may be associated with cellular NAD+/NADH ratio. In conclusion, our observations imply that ethanol induces impaired insulin secretion from INS-1 cell through disrupting SIRT1-UCP2 axis, while resveratrol may reverse this process by augmenting SIRT1 and inhibiting UCP2.

Histone deacetylase (HDAC) inhibitors and DNA alkylators are effective components of combination chemotherapy. The aim of the present study was to investigate the possible mechanism of their synergism by detecting the effect of HDAC inhibitors on the expression levels of drug transporters that export DNA alkylators. It was demonstrated that the HDAC inhibitor sodium butyrate (NaB) induced the differential expression of multidrug resistant ATP-binding cassette (ABC) transporters in lung cancer and colorectal cancer cells. Specifically, NaB increased the mRNA expression levels of ABC subfamily B member 1 (ABCB1), ABCC10 and ABCC12, and protein expression levels of multidrug resistance-1 (MDR1), multidrug resistance-associated protein 7 (MRP7) and MRP9. Moreover, NaB decreased the expression levels of ABCC1, ABCC2 and ABCC3 mRNAs, as well as those of MRP1, MRP2 and MRP3 proteins. The molecular mechanism underlying this process was subsequently investigated. NaB decreased the expression of HDAC4, but not HDAC1, HDAC2 or HDAC3. In addition, NaB promoted histone H3 acetylation and methylation at lysine 9, as well as MDR1 acetylation, suggesting that acetylation and methylation may be involved in NaB-mediated ABC transporter expression. Thus, the present results indicated that the synergism of the HDAC inhibitors with the DNA alkylating agents may due to the inhibitory effect of MRPs by HDAC inhibitors. The findings also suggested the possibility of antagonistic effects following the combined treatment of HDAC inhibitors with MDR1 ligands.

Resveratrol has been found to improve ethanol-induced diabetes. Although pancreatic β-cell senescence-induced β-cell mass loss plays a critical role in the progression of diabetes, the exact mechanism by which resveratrol improves ethanol-triggered β-cell senescence and its role in ethanol-induced diabetes remains unknown. Male Sprague-Dawley rats were fed either control or ethanol liquid diets containing 2.4 g/kg·bw ethanol with or without 100 mg/kg·bw resveratrol for 22 weeks. Resveratrol decreased the ethanol-induced augmentation in senescence-associated β-galactosidase (SA-β-gal)-positive area and attenuated reduction in β-cell mass, which were based on elevated levels of SIRT1 and proliferation marker Ki67 and reduced levels of senescence-associated markers (p-p38MAPK and p16INK4a). Similarly, resveratrol rescued the reduction in NAD+/NADH ratio and SIRT1 and inhibited the upregulation of p-p38MAPK and p16INK4a in ethanol-treated INS-1 cells. Furthermore, supplementation with NAD+ inducer nicotinamide mononucleotide, SIRT1 activator SRT1720 or p38MAPK inhibitor SB203580 effectively reversed ethanol-induced β-cell senescence, while supplementation with SIRT1 inhibitor Ex527 or NAD+ inhibitor FK866 abrogated resveratrol-mediated antisenescence effects in INS-1 cells. Together, our results indicate that resveratrol improves ethanol-triggered β-cell senescence and consequently recovers β-cell mass loss by inhibiting p38MAPK/p16 pathway through an NAD+/SIRT1 dependent pathway.

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes, and the mechanisms are yet to be fully understood. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin-D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)2D3 reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 wk of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)2D3 for 7 wk, age-matched Zucker lean rats served as control. Results showed that ZDF rats treated with 1,25(OH)2D3 had decreased body mass, food intake, water intake, and urine volume. 1,25(OH)2D3 ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)2D3 significantly lowered microalbuminuria, decreased the glomerular basement membrane thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion, and tubular dilatation. Furthermore, 1,25(OH)2D3 attenuated renal oxidative damage, as reflected by the levels of malondialdehyde, reduced glutathione, 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and reactive oxygen species production, and notably inhibited poly(ADP-ribose) polymerase-1 (PARP1), activated sirtuin 1 (SIRT1), and decreased the expression of NADPH oxidase 4 (NOX4). Of interest, the abovementioned proteins could be involved in the antioxidant mechanism of 1,25(OH)2D3 in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)2D3 in diabetic nephropathy that was associated with the PARP1/SIRT1/ NOX4 pathway.