Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects / Efectos Protectores y Mecanismos de la Decocción de Huangqi Contra los Efectos Secundarios Inducidos por la Radiación

SUMMARY: The 12C6+ heavy ion beam irradiation can cause bystander effects. The inflammatory cytokines, endocrine hormones and apoptotic proteins may be involved in 12C6+ irradiation-induced bystander effects. This study characterized the protective effects and mechanisms of Huangqi decoction (HQD) against 12C6+ radiation induced bystander effects. Wistar rats were randomly divided into control, 12C6+ heavy ion irradiation model, and high-dose/medium-dose/low-dose HQD groups. HE staining assessed the pathological changes of brain and kidney. Peripheral blood chemical indicators as well as inflammatory factors and endocrine hormones were detected. Apoptosis was measured with TUNEL. Proliferating cell nuclear antigen (PCNA) expression was determined with real-time PCR and Western blot.Irradiation induced pathological damage to the brain and kidney tissues. After irradiation, the numbers of white blood cells (WBC) and monocyte, and the expression of interleukin (IL)-2, corticotropin-releasing hormone (CRH) and PCNA decreased. The damage was accompanied by increased expression of IL-1β, IL-6, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) as well as increased neuronal apoptosis. These effects were indicative of radiation-induced bystander effects. Administration of HQD attenuated the pathological damage to brain and kidney tissues, and increased the numbers of WBC, neutrophils, lymphocyte and monocytes, as well as the expression of IL-2, CRH and PCNA. It also decreased the expression of IL-1β, IL-6, CORT and ACTH as well as neuronal apoptosis. HQD exhibits protective effects against 12C6+ radiation-induced bystander effects. The underlying mechanism may involve the promotion of the production of peripheral blood cells, inhibition of inflammatory factors and apoptosis, and regulation of endocrine hormones.

La irradiación con haz de iones pesados 12C6+ puede provocar efectos secundarios. Las citoquinas inflamatorias, las hormonas endocrinas y las proteínas apoptóticas pueden estar involucradas en los efectos secundarios inducidos por la irradiación 12C6+. Este estudio caracterizó los efectos y mecanismos protectores de la decocción de Huangqi (HQD) contra los efectos externos inducidos por la radiación 12C6+. Las ratas Wistar se dividieron aleatoriamente en grupos control, modelo de irradiación de iones pesados 12C6+ y grupos de dosis alta/media/baja de HQD. La tinción con HE evaluó los cambios patológicos del cerebro y el riñón. Se detectaron indicadores químicos de sangre periférica, así como factores inflamatorios y hormonas endocrinas. La apoptosis se midió con TUNEL. La expresión del antígeno nuclear de células en proliferación (PCNA) se determinó mediante PCR en tiempo real y transferencia Western blot. La irradiación indujo daños patológicos en los tejidos cerebrales y renales. Después de la irradiación, disminuyó el número de glóbulos blancos (WBC) y monocitos, y la expresión de interleucina (IL)-2, hormona liberadora de corticotropina (CRH) y PCNA. El daño estuvo acompañado por una mayor expresión de IL-1β, IL-6, corticosterona (CORT) y hormona adrenocorticotrópica (ACTH), así como un aumento de la apoptosis neuronal. Estas alteraciones fueron indicativas de efectos inducidos por la radiación. La administración de HQD atenuó el daño patológico a los tejidos cerebrales y renales, y aumentó el número de leucocitos y monocitos, así como la expresión de IL-2, CRH y PCNA. También disminuyó la expresión de IL-1β, IL-6, CORT y ACTH, así como la apoptosis neuronal. HQD exhibe mecanismos protectores contra los efectos externos inducidos por la radiación 12C6+. El mecanismo subyacente puede implicar la promoción de la producción de células sanguíneas periféricas, la inhibición de factores inflamatorios y la apoptosis y la regulación de hormonas endocrinas.

Investigation of the protective effect of boric acid against hepatotoxic and nephrotoxic injury induced by acrylamide in rats / Investigación del efecto protector del ácido bórico contra lesiones hepatotóxicas y nefrotóxicas inducidas por acrilamida en ratas

SUMMARY: To investigate if the administration of boric acid (BA) would exert any protective effect against possible nephrotoxicity and hepatotoxicity induced by the exposure to acrylamide (ACR) in rats. In our study, we used a total of 28 rats that were divided into four equal groups. Group 1: the control group which was not treated with any procedure. Group 2: the ACR group that was administered ACR 50 mg/kg/day via intraperitoneal (i.p) route for 14 days. Group 3: the BA group that was administered BA 200 mg/kg/ day via gavage via peroral (p.o) route for 14 days. Group 4: the ACR+BA group that was administered BA simultaneously with ACR. Total antioxidant and oxidant (TAS/TOS) capacities were measured in all groups at the end of the experiment. In addition, the specimens obtained were evaluated with histopathological examination. Studies showed that the ACR and ACr+BA groups were not significantly different in terms of hepatic TAS level while the TOS level was higher in the ACR group than the ACR+BA group. The groups did not show any significant difference regarding renal TAS and TOS levels. In the histopathological examination of the hepatic tissue, the histopathological injury score of the ACR group was significantly higher than those of the other groups whereas it was significantly lower in the ACR+BA group than the ACR group. Our study concluded that Boric acid had a protective effect against acrylamide- induced hepatotoxicity, but not against nephrotoxicity.

El objetivo de este estudio fue investigar si la administración de ácido bórico (BA) ejercería algún efecto protector frente a la posible nefrotoxicidad y hepatotoxicidad inducida por la exposición a acrilamida (ACR) en ratas. En nuestro estudio, utilizamos un total de 28 ratas que se dividieron en cuatro grupos iguales. Grupo 1: grupo control que no fue tratado. Grupo 2: grupo ACR al que se le administró ACR 50 mg/kg/día por vía intraperitoneal (i.p) durante 14 días. Grupo 3: grupo BA al que se le administró BA 200 mg/kg/día por sonda por vía peroral (p.o) durante 14 días. Grupo 4: grupo ACR+BA al que se administró BA simultáneamente con ACR. Las capacidades antioxidantes y oxidantes totales (TAS/TOS) se midieron en todos los grupos al final del experimento. Además, los especímenes obtenidos fueron evaluados con examen histopatológico. Los estudios demostraron que los grupos ACR y ACr+BA no fueron significativamente diferentes en términos del nivel hepático de TAS, mientras que el nivel de TOS fue mayor en el grupo ACR que en el grupo ACR+BA. Los grupos no mostraron ninguna diferencia significativa con respecto a los niveles renales de TAS y TOS. En el examen histopatológico del tejido hepático, la puntuación de lesión histopatológica del grupo ACR fue significativamente mayor que la de los otros grupos, mientras que fue significativamente menor en el grupo ACR+BA que en el grupo ACR. Nuestro estudio concluyó que el ácido bórico tiene un efecto protector contra la hepatotoxicidad inducida por acrilamida, pero no contra la nefrotoxicidad.

Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.

BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.

Fluorometholone inhibits high glucose-induced cellular senescence in human retinal endothelial cells.

Diabetic retinopathy (DR) is a common diabetic complication that severely impacts the life quality of diabetic patients. Recently, cellular senescence in human retinal endothelial cells (HRECs) induced by high glucose has been linked to the pathogenesis of DR. Fluorometholone (FML) is a glucocorticoid drug applied in the treatment of inflammatory and allergic disorders of the eye. The objective of the present study is to investigate the protective function of FML on high glucose-induced cellular senescence in HRECs. The in vitro injury model was established by stimulating HRECs with 30 mm glucose. After evaluating the cytotoxicity of FML in HRECs, 0.05% and 0.1% FML were used as the optimal concentration in the entire experiment. It was found that the excessive released inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) in HRECs induced by high glucose were significantly suppressed by FML, accompanied by the inhibitory effects on the expression levels of vascular endothelial growth factor (VEGF) and tissue factor (TF). Declined telomerase activity and enhanced senescence-associated ß-galactosidase (SA-ß-gal) activity were found in high glucose-challenged HRECs, which were dramatically alleviated by FML, accompanied by the inactivation of the p53/p21 and retinoblastoma (Rb) signaling. Interestingly, FML ameliorated high glucose-induced dephosphorylation of Akt. Lastly, the protective effects of FML against high glucose-induced cellular senescence in HRECs were abolished by the co-treatment of the PI3K/Akt signaling inhibitor LY294002, suggesting the involvement of this pathway. Taken together, these data revealed that FML-inhibited high glucose-induced cellular senescence mediated by Akt in HERCs, suggesting a novel molecular mechanism of FML.

5-Lipoxygenase Inhibition Protects Retinal Pigment Epithelium from Sodium Iodate-Induced Ferroptosis and Prevents Retinal Degeneration.

Excessive reactive oxygen species (ROS) contribute to damage of retinal cells and the development of retinal diseases including age-related macular degeneration (AMD). ROS result in increased metabolites of lipoxygenases (LOXs), which react with ROS to induce lipid peroxidation and may lead to ferroptosis. In this study, the effect of 5-LOX inhibition on alleviating ROS-induced cell death was evaluated using sodium iodate (NaIO3) in the retinal pigment epithelium (RPE) cell line ARPE-19 and a mouse model investigating oxidative stress in AMD. We demonstrated that NaIO3 induced cell death in the RPE cells through mechanisms including ferroptosis. Inhibition of 5-LOX with specific inhibitor, Zileuton, or siRNA knockdown of ALXO5 mitigated NaIO3-induced lipid peroxidation, mitochondrial damage, DNA impairment, and cell death in ARPE-19 cells. Additionally, in the mouse model, pretreatment with Zileuton reduced the NaIO3-induced lipid peroxidation of RPE cells, cell death in the photoreceptor layer of the retina, inflammatory responses, and degeneration of both the neuroretina and RPE monolayer cells. Our results suggest that 5-LOX plays a crucial role in ROS-induced cell death in the RPE and that regulating 5-LOX activity could be a useful approach to control ROS and ferroptosis-induced damage, which promote degeneration in retinal diseases.

Protective effect of rosuvastatin pretreatment against acute myocardial injury by regulating Nrf2, Bcl-2/Bax, iNOS, and TNF-α expressions affecting oxidative/nitrosative stress and inflammation.

Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.

Zingerone Inhibits the Neutrophil Extracellular Trap Formation and Protects against Sepsis via Nrf2-Mediated ROS Inhibition.

Neutrophils release chromatin and antimicrobial proteins to trap and kill microbes, which is termed as neutrophil extracellular trap (NET) formation. NETs play a pivotal role in host defense against infection. However, emerging evidence indicated that NETs also contribute to an exaggerated inflammatory response and organic injuries in sepsis. Zingerone, a natural compound extracted from Zingiber officinale, exerts antioxidant, anti-inflammatory, and antioncogenic properties. In this study, we found that treatment with zingerone reduced organ injury and improved the outcome in a cecal ligation puncture- (CLP-) induced polymicrobial sepsis model. Administration of zingerone also alleviates reactive oxygen species (ROS) accumulation and systematic inflammation in septic mice and inhibits neutrophil extracellular traps (NETs) formation in vivo and in vitro. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) with its specific antagonist significantly counteracted the suppressive effects of zingerone on ROS and NETs and retarded the protective role of zingerone against sepsis-associated organ injury. In addition, exposure to zingerone does not affect phagocytic activity of neutrophils in vitro and bacterial dissemination in vivo. Above all, our results indicate that zingerone treatment obviously attenuates NET formation and inflammatory response via Nrf2-mediated ROS inhibition, thus providing a novel therapeutic strategy against sepsis-induced injury.

Silymarin protects the rats against paraquat-induced acute kidney injury via Nrf2.

BACKGROUND: Paraquat (PQ) poisoning induces severe acute kidney injury and causes extremely high rate of death. In this study, we aimed to investigate the protective effects of silymarin on PQ-induced acute kidney injury and explore the underlying mechanisms. METHODS: A rat model was established through intraperitoneal injection of PQ. Rats were administrated with saline or silymarin for 3 days. Then, survival rate, physiological parameters, and renal injury score were evaluated. The apoptosis and oxidative stress in kidney tissues were determined through hematoxylin and eosin staining, quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assays. RESULTS: Silymarin administration could significantly increase the survival rate of PQ-poisoned rats. It was found that silymarin treatment improved renal function, decreased injury score in kidney tissues, and inhibited the apoptosis and oxidative stress in PQ-induced acute kidney injury through the activating the signaling pathway of Nrf2 and promoting its nuclear translocation. CONCLUSION: Silymarin exhibited a protective effect against PQ-induced kidney injury, suggesting that treatment with this flavonoid could be a potential therapeutic agent for the treatment of acute kidney injury.

Protective effects of bioactive peptides in foxtail millet protein hydrolysates against experimental colitis in mice.

It is of great significance to develop a dietary intervention strategy to prevent inflammatory bowel disease (IBD). A millet-rich diet can ameliorate IBD, but the active ingredients and mechanisms remain to be studied. Our results showed that the oral administration of foxtail millet protein hydrolysates (FMPH) reduced the disease activity index (DAI) score and improved the colon symptoms of dextran sulfate sodium (DSS)-induced colitis mice. FMPH reduced the serum LPS level, increased intestinal ZO-1 and occludin expression, inhibited NF-κB phosphorylation, and reduced the levels of TNF-α and IL-6. Further, FMPH inhibited Th17 cell differentiation, and inhibited inflammasome activation and IL-1ß expression through the NLRP3/ASC/caspase-1 pathway. The results on Caco-2 cells confirmed the role of FMPH on tight junction and inflammasomes activation. A total of 2620 peptides were identified in FMPH by UPLC-MS/MS, of which 22 peptides were predicted as potential biopeptides, and the key sequences were LPF, ANP, PY, YW, and IPP. This study supports the effect of a diet rich in millet on the improvement of IBD and provides a scientific basis for the use of millet protein as a functional food to improve intestinal inflammation.

SGLT2 inhibitors therapy protects glucotoxicity-induced ß-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress.

Progressive loss of pancreatic ß-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and ß-cell exhaustion. However, loss of ß-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional ß-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in ß-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring ß-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of ß-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives ß-cell failure in diabetes, ii) recovery of ß-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent ß-cell failure when used in early stages of diabetes, but not when loss of ß-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of ß-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.

Functional EL-HN Fragment as a Potent Candidate Vaccine for the Prevention of Botulinum Neurotoxin Serotype E.

Clostridium botulinum produces botulinum neurotoxin (BoNT), which is the most toxic known protein and the causative agent of human botulism. BoNTs have similar structures and functions, comprising three functional domains: catalytic domain (L), translocation domain (HN), and receptor-binding domain (Hc). In the present study, BoNT/E was selected as a model toxin to further explore the immunological significance of each domain. The EL-HN fragment (L and HN domains of BoNT/E) retained the enzymatic activity without in vivo neurotoxicity. Extensive investigations showed EL-HN functional fragment had the highest protective efficacy and contained some functional neutralizing epitopes. Further experiments demonstrated the EL-HN provided a superior protective effect compared with the EHc or EHc and EL-HN combination. Thus, the EL-HN played an important role in immune protection against BoNT/E and could provide an excellent platform for the design of botulinum vaccines and neutralizing antibodies. The EL-HN has the potential to replace EHc or toxoid as the optimal immunogen for the botulinum vaccine.

Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.

Effect of an Extract from the Egyptian Sea Cucumber, Bohadschia marmorata, on Methotrexate-Induced Hepatorenal Toxicity in Male Mice.

BACKGROUND: The sea cucumber, Bohadschia marmorata, is a marine echinoderm consumed and used as a medication. Extract of this species displays a broad spectrum of bioactivity, such as antifungal, antibacterial, immunomodulatory, and cytotoxic properties. This investigation explored sea cucumber extract for hepatorenal protection against the toxicity of methotrexate (MTX). METHODS: Four groups of mice were divided into G1: control, G2: MTX treated, G3: B. marmorata extract-treated daily for 14 days, and G4: B. marmorata extract and MTX treated. RESULTS AND CONCLUSIONS: Biochemical analysis and histopathological examination of liver tissue showed that administration of MTX increased serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), lowered levels of serum albumin, total protein, Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Administration of B. marmorata extract to MTX- injected mice significantly reversed the increase in serum levels of liver enzymes and induced a significant elevation in serum albumin and total protein levels. SOD, CAT, and GSH levels returned to nearly normal levels. Histopathological examination indicated fewer signs of toxicity in liver and kidney tissues of mice treated with both extract and MTX compared to MTX treatment alone. An extract of B. marmorata will protect mice from hepatorenal toxicity induced by MTX.

Tissue Kallikrein Protects Rat Prostate against the Inflammatory Damage in a Chronic Autoimmune Prostatitis Model via Restoring Endothelial Function in a Bradykinin Receptor B2-Dependent Way.

OBJECTIVE: The aim of this study was to investigate whether tissue kallikrein (KLK1) can protect the prostate from inflammatory damage and the mechanism involved in it. METHODS: A total of 50 male Wistar rats were used in this study. Initially, 20 rats were sacrificed to obtain the prostate antigen to induce experimental autoimmune prostatitis (EAP), and the remaining 30 rats were randomly divided into 5 experimental groups (normal control group (NC group), NC+KLK1 group (NCK group), EAP group, EAP+KLK1 group (EAPK group), and EAP+KLK1+HOE140 group (EAPKH group); n = 6). It should be explained that KLK1 mainly exerts its biological effects through bradykinin, and HOE140 is a potent and selective bradykinin receptor B2 (BDKRB2) antagonist. EAP was induced by intradermal injection of 15 mg/ml prostate antigen and complete Freund's adjuvant on days 0, 14, and 28. KLK1 was injected via tail vein at a dose of 1.5 × 10-3 PAN U/kg once a day, and HOE140 was administered by intraperitoneal injection at 20 µg/kg once every two days. Rats were sacrificed on day 42. The RNA and protein of the rat prostate were extracted to analyze the expression differences of KLK1, as well as the inflammation-, fibrosis-, and oxidative stress-related genes. The inflammatory cell infiltration and microvessel density of the prostate were also analyzed by pathological examination. In addition, pathological analysis was performed on prostate samples from patients undergoing benign prostate hyperplasia (BPH) surgery. RESULTS: The expression of KLK1 in the prostate decreased in the EAP group as well as BPH patients with obvious inflammation. KLK1 administration significantly inhibited inflammatory cell infiltration and reduced the production of inflammatory cytokines in the EAPK group. Prostate samples from the EAP group showed increased infiltration of T cells and macrophages, as well as gland atrophy, hypoxia, fibrosis, and angiogenesis. KLK1 administration upregulated endothelial nitric oxide synthase (eNOS) expression and suppressed oxidative stress, as well as transforming growth factor ß1 (TGF-ß) signaling pathways and the proangiogenic vascular endothelial growth factor (VEGF) in the EAPK group. However, in the EAPKH group in which HOE140 blocked BDKRB2, the beneficial effects of KLK1 were all cancelled. In addition, KLK1 intervention in normal rats had no obvious side effects. CONCLUSION: The KLK1 expression is inhibited in the inflamed prostates of humans and rats. Exogenous KLK1 restored endothelial function via a BDKRB2-dependent way and then played a role in improving microcirculation and exerted anti-inflammatory, antifibrotic, and antioxidative stress effects in the rat chronic-inflamed prostate.

Renoprotective Effect of Intraoperative Dexmedetomidine in Renal Transplantation.

BACKGROUND: Renal dysfunction after kidney transplantation may be influenced by many reasons. This study was designed to evaluate whether the administration of dexmedetomidine (Dex) could ameliorate renal function and prognosis after kidney transplantation. METHODS: A total of 65 patients were divided into Dex group (n = 33) and Con group (Con, n = 32). Dex group intravenously received an initial loading dose of 0.6 µg/kg Dex for 15 min before anaesthesia induction, followed by a rate of 0.4 µg/kg/h until 30 min after kidney reperfusion. By contrast, Con group received saline. The concentration of urinary kidney injury molecule-1 (KIM-1), serum creatinine (Cr), blood urea, urine output, ß2 microglobulin (ß2-MG), Cystatin C (CysC), and estimated glomerular filtration rate (eGFR) was recorded and compared between two groups during the course of the hospitalization or follow-up. Mean arterial pressure (MAP) and heart rate (HR), vasoactive drugs, and anaesthetics were recorded during the operation. Pain degree was evaluated using a visual analogue scale (VAS) after operation. Delayed graft function (DGF), graft loss, length of hospital stay, and mortality were compared between groups. RESULTS: The concentration of KIM-1 in Dex group was lower than Con group at 2 h (P = 0.018), 24 h (P = 0.013), 48 h (P < 0.01), and 72 h (P < 0.01) after reperfusion. MAP of Dex group after tracheal intubation (P = 0.012) and incision (P = 0.018) and HR after intubation (P = 0.021) were lower than that of Con group. The dosage of sufentanil during operation in Dex group was less than Con group (P = 0.039). Patients that used atropine in Dex group were more than Con group (P = 0.027). Patients who received Dex presented with lower VAS scores at 6 h (P = 0.01) and 12 h (P = 0.002) after operation. Concentration of serum Cr and blood urea had no significant differences between groups before operation and on postoperative day 1 to 6. Urine output was recorded for 6 days after operation and had no differences between groups. Also, no differences were identified between two groups in urea, Cr, ß2-MG, CysC, and eGFR in the first 3 months after operation. Incidence of DGF after operation was detected no difference between groups, while length of hospital stay in Dex group was less than Con group (P = 0.012). CONCLUSION: Dex can decrease kidney injury marker level, attenuate perioperative stress, relieve the dosage of sufentanil and postoperative pain, and reduce length of hospital stay. However, Dex is not associated with changes in prognosis in the first 3 months after transplantation.

Inhibition of PAD4-mediated NET formation by cl-amidine prevents diabetes development in nonobese diabetic mice.

Many evidences indicated that neutrophil extracellular traps (NETs) play pathogenic roles in type 1 diabetes (T1D). Peptidylarginine deiminases 4 (PAD4) has been proved to be indispensable for generation of NETs. In the current study, we investigated whether oral administration of cl-amidine, an effective inhibitor of PAD4, protects non-obese diabetic (NOD) mice from T1D development. Female NOD mice were orally administrated with cl-amidine (5 µg/g body weight) from the age of 8 weeks up to 16 weeks. It showed that cl-amidine inhibit NET formation in vitro and in vivo. The onset of T1D was delayed nearly 8 weeks and the incidence of disease was significantly decreased in cl-amidine treated mice compared with the control group. Moreover, cl-amidine decreased the serum levels of anti-citrullinated peptide antibody (ACPA) and anti-neutrophil cytoplasmic antibodies (ANCA) in NOD mice. Also, it decreased generation of T1D autoantibodies such as glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase-related islet antigen-2 antibody (IA2A) and zinc transporter 8 antibody (ZnT8A), which were strongly correlated with the reduced serum PAD4 and MPO-DNA levels. Furthermore, cl-amidine administration inhibited pancreatic inflammation and increased frequency of regulatory T cells in pancreatic lymph nodes (PLNs). In addition, cl-amidine improved gut barrier dysfunction and decreased the serum level of lipopolysaccharide (LPS), which was positively correlated with the NETs markers (PAD4 and MPO-DNA) and T1D autoantibody IA2A. In conclusion, our data showed that orally delivery of cl-amidine effectively prevent T1D development and suggested inhibition of PAD4-dependent NET formation as a potential way of clinical treatment in T1D.

The Possible Protective Role of Dark Chocolate Against Acrylamide Neurotoxicity in Weaning Rats Cerebellum.

Acrylamide (ACR) is selective neurotoxicity, could be found in foods processed by high temperature. This work aimed to evaluate the protective role of the dark chocolate (DC) against cerebellar neurotoxicity induced by subchronic ACR exposure in recently weaned rat pups and to propose it as protective supplement against dietary ACR hazards. Eighteen weaning pups were used in the current study and divided into three groups, six rats in each group; group 1 (control group), group 2 (ACR group), and group 3 (ACR + DC group). The pups were sacrificed after 21 days and the cerebellums were removed for light microscope using H&E stain, ultrastructural study, morphometric analysis of the neurons count, biochemical analysis of oxidant and antioxidant markers and real-time quantitative PCR to evaluate the nuclear receptor subfamily 4, group A, member 2 (Nr4a2) gene expression. Pups with ACR consumption showed signs of neuronal degeneration and reduced Nr4a2 expression. On the other hand, pups with ACR + DC consumption showed relative signs of neuronal restoration and enhanced Nr4a2 expression. In conclusion, DC can be used as effective supplement to decrease the dietary ACR cerebellar neuronal risks.

Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy.

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.

Molecular Docking Studies of Naringenin and its Protective Efficacy against Methotrexate Induced Oxidative Tissue Injury.

BACKGROUND: Although Methotrexate (MTX) possesses a wide clinical spectrum of activity, its toxic side effects on normal cells and drug resistance often hamper its successful outcome. Naringenin (NG) is one of the promising bioactive flavonoids that are extensively found in grapes, citrus fruits, and fruit arils of Pithecellobium dulce. OBJECTIVE: Only a few experimental in vivo studies on the efficacy of NG against chemotherapeutic drugs have been carried out. Aiming to fill this gap, the present study was carried out to characterize and identify its possible therapeutic targets and also to explore its protective efficacy against MTX-induced tissue damage. METHODS: Oxidative stress was induced in mice with MTX (20 mg/kg B.wt), and animals were orally administered with 10 mg/kg B.wt NG for 10 consecutive days. On day 11, all animals were sacrificed, and hematological and serum biochemical parameters were analyzed. The anti-oxidant efficacy of NG against MTX was evaluated by quantifying tissue superoxide dismutase (SOD), glutatione peroxidase (GPx), reduced glutathione (GSH) and catalase along with oxidative stress markers [malondialdehyde (MDA) and nitric oxide (NO)]. Further, the histopathological analysis was performed to confirm the protective efficacy of FPD. In silico docking studies were also performed to exploring anti-oxidant enzyme-based targets. RESULTS: Our results showed that concurrent administration of NG counteracted oxidative stress induced by MTX, as evidenced by increased expression of anti-oxidant markers, decreased expression of renal and hepatotoxicity serum marker enzymes (p <0.05). A molecular docking study was performed using Auto dock vina to understand the mechanism of ligand binding (S-NG and R-NG)with anti-oxidant enzymes. The binding affinity of S-NG with catalase, GPx, ALP, and SGPT was -10.1, -7.1, -7.1, and -7.3 kcal/mol, respectively, whereas for R-NG was -10.8, -7.1, -7.6, and -7.4 kcal/mol, respectively. Further, histopathological analysis affirmed the protective efficacy of NG against MTX-induced hepatic and renal toxicities. CONCLUSION: Treatment with NG significantly reduced MTX-induced pancytopenia, renal, and hepatic toxicity.

NSAIDs, gastrointestinal toxicity and inflammatory bowel disease. / AINE, toxicidad gastrointestinal y enfermedad inflamatoria intestinal.

Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy). NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation.