Involvement of the SIRT1-NLRP3 pathway in the inflammatory response.

The silent information regulator 2 homolog 1-NACHT, LRR and PYD domains-containing protein 3 (SIRT1-NLRP3) pathway has a crucial role in regulation of the inflammatory response, and is closely related to the occurrence and development of several inflammation-related diseases. NLRP3 is activated to produce the NLRP3 inflammasome, which leads to activation of caspase-1 and cleavage of pro-interleukin (IL)-1ß and pro-IL-18 to their active forms: IL-1ß and IL-18, respectively. They are proinflammatory cytokines which then cause an inflammatory response.SIRT1 can inhibit this inflammatory response through nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B pathways. This review article focuses mainly on how the SIRT1-NLRP3 pathway influences the inflammatory response and its relationship with melatonin, traumatic brain injury, neuroinflammation, depression, atherosclerosis, and liver damage. Video Abstract.

Exploration of the underlying mechanisms of isoniazid/rifampicin-induced liver injury in mice using an integrated proteomics and metabolomics approach.

The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass-based untargeted metabolomics and label-free quantitative proteomics approach was used to clarify the mechanism of INH/RIF-induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7 or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for mass spectrum-based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.

The evaluation of hepatoprotective effects of flavonoids from Scorzonera austriaca Wild against CCl4-induced acute liver injury in vitro and in vivo.

Scorzonera austriaca Wild is a traditional herbal medicine; however, little is known with regard to the effect of flavonoids from S. austriaca (FSA) on liver injury induced by Carbon tetrachloride (CCl4), especially the mechanism remains unknown. Therefore, our paper was designed to investigate the hepatoprotective effect of FSA against CCl4-induced acute liver injury in vitro and in vivo, with focus on its potential mechanism. The purity of FSA prepared by using polyporous resin column chromatography could reach 94.5%, and seven flavonoid compounds in FSA were identified by using LC-ESI-MS analysis. In vivo results showed that FSA markedly decreased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and malonaldehyde (MDA) and increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Furthermore, in vivo and in vitro results confirmed that FSA could inhibit inflammatory response, as evidenced by decreasing the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) through inactivating toll-like receptor-4/nuclear factor-κB (TLR4/NF-κB) signaling pathway. FSA activated autophagy by increasing the ratio of LC3B-II/I and decreasing the protein level of p62 so as to exert its hepatoprotective effect. In general, these evidences suggested that FSA is likely to serve as a potential material for the drugs against chemical hepatic injury.

Ginsenoside Rg3 attenuates cisplatin-induced kidney injury through inhibition of apoptosis and autophagy-inhibited NLRP3.

The NOD-like receptor family pyrin domain-containing (NLRP3) inflammasomes is centrally implicated in cisplatin (CP)-induced kidney injury. Autophagy is critical for inhibiting production of NLRP3 protein that effectively reduces the inflammatory response. Ginsenoside Rg3 (SY), an active component extracted from ginseng, is reported to protect against CP-induced nephrotoxicity. However, the mechanisms underlying renoprotection by SY have not been established to date. Our results indicate that SY attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability, decreased the proportion of late apoptotic cells, elevated mitochondrial membrane potential, and ameliorated histopathological damage of the kidney. SY ameliorated CP-induced human renal tubular (HK-2) cells and kidney injury through upregulation of LC3II/I and beclin-1, inhibition of p62, NLRP3, ASC, caspase-1, and interleukin-1ß. However, blockade of autophagy by 3-methyladenine reversed the suppression of SY on NLRP3 inflammasome activation and the protection of SY on HK-2 cells. Our collective results support the utility of SY as a therapeutic agent that effectively protects against CP-induced kidney injury by activating the autophagy-mediated NLRP3 inhibition pathway.

Huaiqihuang (HQH) granule alleviates cyclophosphamide-induced nephrotoxicity via suppressing the MAPK/NF-κB pathway and NLRP3 inflammasome activation.

CONTEXT: Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. OBJECTIVE: This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. MATERIALS AND METHODS: Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. RESULTS: Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. CONCLUSIONS: HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

Calycosin ameliorates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and inflammation via the sirtuin 1-NOD-like receptor protein 3 pathway.

The limitation of doxorubicin (DOX), which is widely used for the treatment of solid tumors and hematologic malignancies, is a vital problem in clinical application. The most serious of limit factors is cardiotoxicity. Calycosin (CA), an isoflavonoid that is the major active component in Radix astragali, has been reported in many bioactivities including antitumor, anti-inflammatory, and cardioprotection. The aim of the study was to investigate the effects and mechanisms of CA on DOX-induced cardiotoxicity in vitro and in vivo. CA increased H9c2 cell viability and reduced apoptosis induced by DOX via Bcl-2, Bax, and the PI3K-Akt signaling pathway. Moreover, CA prevented DOX-induced oxidative stress in cells by decreasing the generation of reactive oxygen species. Similarly, oxidative stress was inhibited by CA through the increased activities of antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase and decreased the levels of aspartate aminotransferase, lactate dehydrogenase, and malondialdehyde in vivo. Furthermore, the levels of sirtuin 1 (Sirt1)-NOD-like receptor protein 3 (NLRP3) and related proteins were ameliorated by CA in cells and in mice hearts. When H9c2 cells were treated by Ex527 (Sirt1 inhibitor), the effect of CA on expressions of NLRP3 and thioredoxin-interacting protein was suppressed. In conclusion, the results suggested that CA might be a cotreatment with DOX to ameliorate cardiotoxicity by Sirt1-NLRP3 pathway.

XingNaoJing injection ameliorates cerebral ischaemia/reperfusion injury via SIRT1-mediated inflammatory response inhibition.

Context: XingNaoJing injection (XNJ), extracted from a traditional compound Chinese medicine Angong niuhuang pill, is well known for treating stroke in the clinic, but the specific effects and mechanisms remain unclear.Objective: We investigated the mechanistic basis for the protective effect of XNJ on cerebral ischaemia/reperfusion (I/R) injury.Materials and methods: Five groups of 10 SD rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. XNJ at 10 and 15 mL/kg was intraperitoneally administered 24 h before ischaemia and at the onset of reperfusion respectively. The silent information regulator 1 (SIRT1) inhibitor EX527 was intracerebroventricularly injected 0.5 h before reperfusion. Cerebral infarction size, neurological scores, morphological changes, and expression levels of inflammatory mediators and SIRT1 were measured. Furthermore, human brain microvascular endothelial cells (HBMECs) were subjected to 3 h oxygen and glucose deprivation (OGD) followed by 24 h reoxygenation to mimic cerebral I/R in vitro. EX527 pre-treatment occurred 1 h before OGD. SIRT1 and inflammatory mediator levels were analyzed.Results: Both XNJ doses significantly decreased cerebral infarct area (40.11% vs. 19.66% and 9.87%) and improved neurological scores and morphological changes. Inflammatory mediator levels were remarkably decreased in both model systems after XNJ treatment. XNJ also enhanced SIRT1 expression. Notably, the SIRT1 inhibitor EX527 attenuated the XNJ-mediated decrease in inflammation in vivo and in vitro.Conclusions: XNJ improved cerebral I/R injury through inhibiting the inflammatory response via the SIRT1 pathway, which may be a useful target in treating cerebral I/R injury.

Quercetin protected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway.

Isoniazid (INH) is one of the most commonly used antituberculosis drugs, but its clinical applications have been limited by severe hepatic toxicity. Quercetin (Que), a natural flavonoid, has been proved to have many medicinal properties. This study aimed to clarify the possible protective effects of Que against INH-induced hepatotoxicity using HepG2 cells. Our results indicated that Que significantly increased cell viability, superoxide dismutase, and GSH levels, while decreased alanine aminotransferase/aspartate aminotransferase levels. Besides, Que significantly abrogated INH-induced cell apoptosis by upregulating the expression levels of Bcl-2 and decreasing the levels of Bax, cleaved caspase-3, and cleaved caspase-9. Furthermore, Que obviously reversed the inhibition of INH on Sirtuin 1 (SIRT1) expression and extracellular signal-regulated kinase (ERK) phosphorylation. Next, the SIRT1 inhibitor EX527 blocked the enhancement of Que upon ERK phosphorylation. Notably, EX527 partially abolished the beneficial effects of Que. In brief, our results provided the first evidence that Que protected against INH-induced HepG2 cells by regulating the SIRT1/ERK pathway.

Salvianolic acid inhibits the effects of high glucose on vascular endothelial dysfunction by modulating the Sirt1-eNOS pathway.

Salvianolic acid (SA) is known for improving blood circulation, scavenging hydroxyl radicals, and preventing platelet aggregation. The research explored whether SA can protect against cardiovascular disease induced by high glucose conditions. Our results indicate that SA significantly increases cells viability and nitric oxide levels while decreasing reactive oxygen species generation. SA upregulated the expression levels of Bcl-2 and decreased the levels of Bax, cleaved caspase-3, and cleaved caspase-9. Furthermore, the expression levels of Sirtuin 1 (Sirt1) and p-endothelial nitric oxide synthase (eNOS) were markedly increased in response to SA treatment. Moreover, exposure of human umbilical vein endothelial cells to Ex527 resulted in reducing expression of p-eNOS. However, the beneficial effects of SA were abolished partially when Ex527 was added. These findings suggest that SA can be used as a potential therapeutic to protect against high glucose-induced endothelial injury by modulating Sirt1-eNOS pathway.

Dioscorea bulbifera L. delays the excretion of doxorubicin and aggravates doxorubicin-induced cardiotoxicity and nephrotoxicity by inhibiting the expression of P-glycoprotein in mice liver and kidney.

We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues. Our results demonstrated that, after co-administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys.

Autophagy inhibition-enhanced assembly of the NLRP3 inflammasome is associated with cisplatin-induced acute injury to the liver and kidneys in rats.

The nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has a key role in the inflammatory response. We found that cisplatin (7.5, 15 mg/kg, IV) could induce acute injury to the liver and kidneys of rats. Western blot and immunohistochemical analyses showed that expression of NLRP3, caspase-1 and interleukin-1ß was upregulated significantly in a dose-dependent manner after cisplatin exposure. Autophagy could inhibit NLRP3 expression and assembly of the NLRP3 inflammasome. Expression of light chain 3 II/I and p62 suggested that autophagy was inhibited during injury to the liver and kidneys. These data suggested that cisplatin might activate NLRP3 by inhibiting autophagy in the liver and kidneys of rats.

Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury via the SIRT1/FXR Pathway in Rats and HepG2 Cells.

To explore the role of the abnormal expression of the bile salt export pump (BSEP) and multidrug resistance protein 2 (MRP2) in isoniazid (INH)-induced liver injury, we assessed the liver injury induced by INH in rats and HepG2 cells in vitro. The regulatory pathways via Sirtuin 1 (SIRT1) and farnesoid X receptor (FXR) were also determined. Rat liver injury was assessed by histopathological and biochemical analysis and HepG2 cytotoxicity was assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The levels of protein were determined by Western blot. The results indicated that INH could induce hepatotoxicity in vivo and in vitro in a dose dependent manner. The liver index and serum biochemical analysis, especially the levels of total bile acids (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL), were significantly increased in rats. The INH hepatotoxicity was severe in the high dose group, and occurred alongside the down-regulation of BSEP and MRP2 in vivo and in vitro, leading to the accumulation of toxic substrates in the hepatocytes. The SIRT1/FXR pathway was identified as being important for the down-regulation of transporters. In summary, our study indicated that the down-regulation of BSEP and MRP2 represents one mechanism of INH-induced liver injury and the down-regulation of SIRT1/FXR may be a key regulator. This will inform the development of novel therapies and enable the prevention of INH-induced liver injury.

Antioxidation of Cerium Oxide Nanoparticles to Several Series of Oxidative Damage Related to Type II Diabetes Mellitus In Vitro.

BACKGROUND It is well known that cerium oxide nanoparticles (CeNPs) have intense antioxidant activity. The antioxidant property of CeNPs are widely used in different areas of research, but little is known about the oxidative damage of Cu2+ associated with Type II diabetes mellitus (T2DM). MATERIAL AND METHODS In our research, the function of CeNPs was tested for its protection of ß-cells from the damage of Cu2+ or H2O2. We detected hydroxyl radicals using terephthalic acid assay, hydrogen peroxide using Amplex Ultra Red assay, and cell viability using MTT reduction. RESULTS We found that CeNPs can persistently inhibit Cu2+/H2O2 evoked hydroxyl radicals and hydrogen peroxide in oxidative stress of ß-cells. CONCLUSIONS CeNPs will be useful in developing strategies for the prevention of T2DM.

Potential role of irisin in digestive system diseases.

Digestive system diseases (DSD) are very complex conditions that severely threaten human health. Therefore, there is an urgent need to develop new pharmacological treatment strategies. Irisin, a myokine discovered in 2012, is produced by fibronectin type III domain-containing protein 5 (FNDC5), which is a transmembrane protein. Irisin is involved in promoting the browning of white adipose tissue, the regulation of energy metabolism, and the improvement of insulin resistance. Irisin is also an essential mediator of the inflammatory response, oxidative stress, and cell apoptosis. Recent studies have proved that irisin concentration is altered in DSD and exerts pivotal effects on the initiation, progression, and prognosis of these diseases through various mechanisms. Therefore, studying the expression and function of irisin may have great significance for the diagnosis and treatment of DSD. Here, we focus on irisin and explore the multiple molecular pathways targeted by irisin therapy. This review indicates that irisin can serve as a diagnostic marker or potential therapeutic agent for DSD. DATA AVAILABILITY: Not applicable.

Integration of metabolomics and proteomics analysis to explore the mechanism of neurotoxicity induced by receipt of isoniazid and rifampicin in mice.

Isoniazid (INH) and rifampicin (RIF) are co-administered in tuberculosis treatment but can cause neurotoxicity, and the mechanism is not known. To explore this mechanism, we employed an integrated approach using metabolomics analysis (MA) and proteomics analysis (PA). Male mice were divided into three groups and administered vehicle (control group), or co-administered INH (120 mg/kg) and RIF (240 mg/kg), for 7 or 14 days. Mice brains were collected for mass spectrometry-based PA and MA plus lipidomics analysis. Measurement of brain levels of malondialdehyde and superoxide dismutase revealed time-dependent brain injury after exposure to INH+RIF for 7 and 14 days. Also, 422 proteins, 35 metabolites, and 21 lipids were dysregulated and identified. MA demonstrated "purine metabolism," "phenylalanine, tyrosine and tryptophan biosynthesis," "biosynthesis of unsaturated fatty acids," "phenylalanine metabolism," and "arginine biosynthesis" to be disturbed significantly. PA demonstrated pathways such as "lipids," "amino acids," and "energy metabolism" to be disrupted. Peroxisome proliferator-activated receptor (PPAR) pathways were changed in energy metabolism, which led to the neurotoxicity induced by INH+RIF. Immunohistochemical analyses of PPARs in mice brains verified that PPAR-α and -γ expression was downregulated. PPAR-α and -γ activation might be a key target for alleviating INH+RIF-induced neurotoxicity.

The identification of key metabolites and mechanisms during isoniazid/rifampicin-induced neurotoxicity and hepatotoxicity in a mouse model by HPLC-TOF/MS-based untargeted urine metabolomics.

The co-administration of isoniazid (INH) and rifampicin (RIF) is associated with hepatotoxicity and neurotoxicity. To systematically investigate the mechanisms of hepatotoxicity and neurotoxicity induced by INH/RIF, we used high performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics to analyze urine from a mouse model and screened a range of urinary biomarkers. Mice were orally co-administered with INH (120 mg/kg) and RIF (240 mg/kg) and urine samples were collected on days 0, 7, 14 and 21. Hepatotoxicity and neurotoxicity were assessed by samples of liver, brain and kidney tissue which were harvested for histological analysis. Toxicity analysis revealed that INH/RIF caused hepatotoxicity and neurotoxicity in a time-dependent manner; compared with day 0, the levels of 35, 82 and 86 urinary metabolites were significantly different on days 7, 14 and 21, respectively. Analysis showed that by day 21, exposure to INH+RIF had caused disruption in vitamin B6 metabolism; the biosynthesis of unsaturated fatty acids; tyrosine, taurine, hypotaurine metabolism; the synthesis of ubiquinone and other terpenoid-quinones; and the metabolism of tryptophan, nicotinate and nicotinamide. Nicotinic acid, nicotinuric acid and kynurenic acid were identified as sensitive urinary biomarkers that may be useful for the diagnosis and evaluation of toxicity.

The SIRT1-HMGB1 axis: Therapeutic potential to ameliorate inflammatory responses and tumor occurrence.

Inflammation is a common complication of many chronic diseases. It includes inflammation of the parenchyma and vascular systems. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, which can directly participate in the suppression of inflammation. It can also regulate the activity of other proteins. Among them, high mobility group box 1 (HMGB1) signaling can be inhibited by deacetylating four lysine residues (55, 88, 90, and 177) in quiescent endothelial cells. HMGB1 is a ubiquitous nuclear protein, once translocated outside the cell, which can interact with various target cell receptors including the receptor for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, and TLR4 and stimulates the release of pro-inflammatory cyto-/chemokines. And SIRT1 has been reported to inhibit the activity of HMGB1. Both are related to the occurrence and development of inflammation and associated diseases but show an antagonistic relationship in controlling inflammation. Therefore, in this review, we introduce how this signaling axis regulates the emergence of inflammation-related responses and tumor occurrence, providing a new experimental perspective for future inflammation research. In addition, it explores diverse upstream regulators and some natural/synthetic activators of SIRT1 as a possible treatment for inflammatory responses and tumor occurrence which may encourage the development of new anti-inflammatory drugs. Meanwhile, this review also introduces the potential molecular mechanism of the SIRT1-HMGB1 pathway to improve inflammation, suggesting that SIRT1 and HMGB1 proteins may be potential targets for treating inflammation.

Untargeted metabolomics analysis of omeprazole-enhanced chemosensitivity to cisplatin in mice with non-small cell lung cancer.

Drug resistance of tumors remains a major barrier in cisplatin (CDDP)-based chemotherapy. Omeprazole (OME) is often utilized during chemotherapy to alleviate gastrointestinal symptoms. In a previous investigation, we demonstrated a protective effect of OME against CDDP-induced kidney injury. To further establish whether OME could enhance chemosensitivity to CDDP and the underlying mechanisms, an in vivo tumor-bearing mouse model with CDDP-resistant A549 non-small cell lung cancer (A549/CDDP) was established in the current study. A high-performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics approach for tumor tissue and serum was employed to explore the mechanisms underlying the enhanced therapeutic effects of co-administration of CDDP and OME. Notably, tumor weights of mice in the CDDP + OME group were significantly decreased compared with those treated with CDDP alone. HE and TUNEL staining revealed more significant apoptosis of tumor cells in the group co-administered CDDP + OME relative to CDDP alone. Overexpression of multidrug resistance-associated protein 2 in CDDP-resistant tumors was significantly reversed upon treatment with CDDP + OME. PCA score plots of the groups co-treated with CDDP + OME were clearly separated from those treated with CDDP alone in metabolomics analysis for tumor and serum samples, clearly suggesting that co-administration of OME enhances the antitumor effect of CDDP. Subsequently, 10 and 7 metabolites in CDDP + OME group with significant changes in tumor and serum compared with CDDP group, respectively, were identified. Pathway analysis both in tumor and serum samples revealed regulation of the metabolism of purines, several amino acids and riboflavin in enhanced chemotherapy with both OME and CDDP. The collective findings provide beneficial novel insights into drug-drug interactions, which could improve the application of CDDP in clinical practice.

Antioxidant Effect of Tyr-Ala Extracted from Zein on INS-1 Cells and Type 2 Diabetes High-Fat-Diet-Induced Mice.

Type 2 diabetes mellitus (T2DM) is associated with an oxidative milieu that often leads to adverse health problems. Bioactive peptides of zein possess outstanding antioxidant activity; however, their effects on hyperglycemia-related oxidative stress remain elusive. In the present study, the dipeptide Tyr-Ala (YA), a functional peptide with typical health benefits, was applied to alleviate oxidative stress in pancreatic islets under hyperglycemic conditions. By detecting viability, antioxidant ability, and insulin secretion in INS-1 cells, YA showed excellent protection of INS-1 cells from H2O2 oxidative stress, erasing reactive oxygen species (ROS) and promoting insulin secretion. Moreover, by Western blotting, we found that YA can regulate the PI3K/Akt signaling pathway associated with glycometabolism. After establishing a T2DM mice model, we treated mice with YA and measured glucose, insulin, hemoglobin A1C (HbA1c), total cholesterol (TC), triglyceride (TG), and malonaldehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione (GSH) from blood samples. We observed that YA could reduce the production of glucose, insulin, HbA1c, TC, TG, and MDA, in addition to enhancing the activities of SOD and GSH. YA could also repair the function of the kidneys and pancreas of T2DM mice. Along with the decline in fasting blood glucose, the oxidative stress in islets was alleviated in T2DM mice after YA administration. This may improve the health situation of diabetic patients in the future.

Polypharmacy and potentially inappropriate medications among elderly patients in the geriatric department at a single-center in China: A retrospective cross-sectional study.

ABSTRACT: The aging of the population has become a worldwide concern, especially in China. Polypharmacy and potentially inappropriate medications (PIMs) are prominent issues in elderly patients. Therefore, the aim of this study was to investigate the prevalence of polypharmacy and PIMs in older inpatients and further to explore the factors associated with PIM use.A retrospective, single-center, cross-sectional study was conducted. A total of 1200 inpatients aged 65 years or older admitted from January 2015 to December 2015 were included. The prevalence of polypharmacy (5-9 medications) and hyperpolypharmacy (10 or more medications) was calculated. The 2019 American Geriatric Society Beers criteria were applied to assess PIMs use. Multivariate logistic regression was used to determine the independent factors of PIM use, while zero-inflated negative binomial regression was performed to evaluate the relationship between polypharmacy and PIM use.The median age of the study population was 76 years (interquartile range = 71-81). The median number of medications was 9 (interquartile range = 7-12). 91.58% of the patients took 5 or more medications simultaneously, and 30.08% of the patients were subjected to one or more PIMs. Spironolactone, furosemide, and zopiclone were the top 3 most frequently encountered PIMs. Hyperpolypharmacy and older age were identified as independent factors associated with PIM use. The risk of PIMs rises with the number of medications prescribed.Polypharmacy and PIM use were common in our study, and the risk of PIM use correlated with an increase in the number of medications already prescribed.