Effectiveness of cannabidiol (CBD) on histopathological changes and gene expression in hepatocellular carcinoma (HCC) model in male rats: the role of Hedgehog (Hh) signaling pathway.

The third most prevalent malignancy to cause mortality is hepatocellular carcinoma (HCC). The Hedgehog (Hh) signaling pathway is activated by binding to the transmembrane receptor Patched-1 (PTCH-1), which depresses the transmembrane G protein-coupled receptor Smoothened (SMO). This study was performed to examine the preventative and therapeutic effects of cannabidiol in adult rats exposed to diethyl nitrosamine (DENA)-induced HCC.A total of 50 male rats were divided into five groups of 10 rats each. Group I was the control group. Group II received intraperitoneal (IP) injections of DENA for 14 weeks. Group III included rats that received cannabidiol (CBD) orally (3-30 mg/kg) for 2 weeks and DENA injections for 14 weeks. Group IV rats received oral CBD for 2 weeks before 14 weeks of DENA injections. Group V included rats that received CBD orally for 2 weeks after their last injection of DENA. Measurements were made for alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and alpha fetoprotein (AFP). Following total RNA extraction, Smo, Hhip, Ptch-1, and Gli-1 expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR). A histopathological analysis of liver tissues was performed.The liver enzymes, oxidant-antioxidant state, morphological, and molecular parameters of the adult male rat model of DENA-induced HCC showed a beneficial improvement after CBD administration. In conclusion, by focusing on the Hh signaling system, administration of CBD showed a beneficial improvement in the liver enzymes, oxidant-antioxidant status, morphological, and molecular parameters in the DENA-induced HCC in adult male rats.

Tubular mitochondrial pyruvate carrier disruption elicits redox adaptations that protect from acute kidney injury.

OBJECTIVE: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. METHODS: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. RESULTS: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. CONCLUSIONS: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.

Tooth color change and tolerability evaluation of a hydrogen peroxide whitening strip compared to a strip, paste, and rinse regimen containing plant-based oils and Dead Sea salt.

PURPOSE: To assess tooth color changes and tolerability with use of a hydrogen peroxide whitening strip compared to a regimen of a strip, rinse and paste for tooth whitening. METHODS: This was a single-center, parallel-group, double-blind, randomized controlled clinical trial. Qualified generally healthy adult participants were assigned to one of two treatment groups. The test group included peroxide-free strips, a fluoride-free whitening toothpaste, and a whitening mouthwash (all Lumineux Oral Essentials); all test products contain plant-based oils (coconut, sage, and lemon peel) and Dead Sea salt. The control group included hydrogen peroxide whitening strips (Crest 3DWhitestrips Classic White) and a sodium fluoride non-whitening toothpaste (Crest). Both groups used a soft manual toothbrush (Oral-B). Strips (for both groups) and rinse (for test group) were used once daily. Changes in tooth color were assessed objectively and quantitatively by digital image analysis after 7, 10 and 14 treatments. RESULTS: 50 participants were enrolled and randomized to treatment and 48 completed the trial. Participants had an average age of 40.8 years (range 18 to 62 years) and 64% were female. At the end of treatment, the test group did not provide statistically significant changes in yellowness (b*) or lightness (L*) from baseline (P≥ 0.411), whereas the control group demonstrated a statistically significant mean yellowness reduction (SD) of 1.55 (0.703) and a mean lightness improvement (SD) of 1.57 (1.141) compared to baseline (P< 0.001 for both). The control group also provided statistically significantly greater mean yellowness reductions and mean lightness improvements compared to the test group at all time points (P< 0.002). Products in both groups were well tolerated, with minor oral irritation and tooth sensitivity representing the most common findings during treatment. CLINICAL SIGNIFICANCE: The Crest Whitestrips control whitening strip provided significant tooth whitening efficacy, whereas the Lumineux Oral Essentials test regimen containing plant-based oils and Dead Sea salt did not. This evidence is important for dental professionals to consider when making recommendations for patients seeking at-home whitening treatments.

Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.

RATIONALE: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. OBJECTIVE: The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidant/antioxidant status, and Aß plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aß1-40. METHODS: Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5 µl phosphate-buffered saline), AG (50 mg/kg; P.O., as PCO vehicle), PCO (50 mg/kg; P.O.), AD model (ICV injection of 5 µl Aß), AD + AG (50 mg/kg; P.O.), and AD + PCO (50 mg/kg; P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aß plaques, were examined. RESULTS: The results showed that injection of Aß reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aß plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aß-infused rats. CONCLUSIONS: The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidant/antioxidant status, and inhibition of Aß plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Air Pollution and Pediatric Respiratory Hospitalizations: Effect Modification by Particle Constituents and Oxidative Potential.

Rationale: Outdoor particulate and gaseous air pollutants impair respiratory health in children, and these associations may be influenced by particle composition. Objectives: To examine whether associations between short-term variations in fine particulate air pollution, oxidant gases, and respiratory hospitalizations in children are modified by particle constituents (metals and sulfur) or oxidative potential. Methods: We conducted a case-crossover study of 10,500 children (0-17 years of age) across Canada. Daily fine particle mass concentrations and oxidant gases (nitrogen dioxide and ozone) were collected from ground monitors. Monthly estimates of fine particle constituents (metals and sulfur) and oxidative potential were also measured. Conditional logistic regression models were used to estimate associations between air pollutants and respiratory hospitalizations, above and below median values for particle constituents and oxidative potential. Measurements and Main Results: Lag-1 fine particulate matter mass concentrations were not associated with respiratory hospitalizations (odds ratio and 95% confidence interval per 10 µg/m3 increase in fine particulate matter: 1.004 [0.955-1.056]) in analyses ignoring particle constituents and oxidative potential. However, when models were examined above or below median metals, sulfur, and oxidative potential, positive associations were observed above the median. For example, the odds ratio and 95% confidence interval per 10 µg/m3 increase in fine particulate matter were 1.084 (1.007-1.167) when copper was above the median and 0.970 (0.929-1.014) when copper was below the median. Similar trends were observed for oxidant gases. Conclusions: Stronger associations were observed between outdoor fine particles, oxidant gases, and respiratory hospitalizations in children when metals, sulfur, and particle oxidative potential were elevated.

Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts.

Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer. The present studies tested the hypothesis that pro-energetics creatine monohydrate (Cr) and nicotinamide (NAM) can protect normal dermal human fibroblasts (DHF) against experimentally induced senescence. To that end, we used an experimental model of senescence in which primary DHF are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity, p21 protein expression, and senescence associated secretory phenotype cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with Cr or NAM protects DHF from the H2O2-induced cell senescence. Treatment with pro-energetics post-H2O2 had no effect. Moreover, these agents also inhibited reactive oxygen species generation from H2O2 treatment. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes.

Protective Mechanism of Berberine on Human Retinal Pigment Epithelial Cells against Apoptosis Induced by Hydrogen Peroxide via the Stimulation of Autophagy.

Age-related macular degeneration (AMD) is a major cause of severe and irreversible vision loss with limited effective therapies. Diminished autophagy and increased oxidative damage caused by ROS in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of AMD, and strategies aimed at enhancing autophagy are likely to protect these cells from oxidative damage. We have previously shown that berberine (BBR), an isoquinoline alkaloid isolated from Chinese herbs, was able to protect human RPE cells from H2O2-induced oxidative damage through AMPK activation. However, the precise mechanisms behind this protective effect remain unclear. Given the essential role of AMPK in autophagy activation, we postulated that BBR may confer protection against H2O2-induced oxidative damage by stimulating AMPK-dependent autophagy. Our results showed that BBR was able to induce autophagy in D407 cells, whereas autophagy inhibitor PIKIII or silencing of LC3B blocked the protective effect of BBR. Further analysis showed that BBR activated the AMPK/mTOR/ULK1 signaling pathways and that both pharmacological and genetic inhibitions of the AMPK pathway abolished the autophagy-stimulating effect of BBR. Similar results were obtained in primary cultured human RPE cells. Taken together, these results demonstrate that BBR is able to stimulate autophagy in D407 cells via the activation of AMPK pathway and that its protective effect against H2O2-induced oxidative damage relies on its autophagy-modulatory effect. Our findings also provide evidence to support the potential application of BBR in preventing and treating AMD.

Evaluation of Natural Bioactive-Derived Punicalagin Niosomes in Skin-Aging Processes Accelerated by Oxidant and Ultraviolet Radiation.

INTRODUCTION: Skin aging is a normal process that might be accelerated or delayed by altering the balance between antioxidants and free radicals due to increase in the exposure to reactive oxygen species (ROS) into skin cells via UV radiation. Antioxidants can neutralize the harmful effects of ROS, and secondary plant metabolites might help protect against UV radiation. METHODS: In this study, punicalagin was extracted from pomegranate, and concentrations of total polyphenolics and flavonoids were determined, and antioxidant activities were measured. Punicalagin was loaded onto niosomes, and its morphology and release were studied. An in vitro study was performed on human fibroblast cell line HFB4 cells with aging induced by H2O2 and UV radiation. Cell cycle arrest was studied, and different genes (MMP3, Col1A1, Timp3, and TERT) involved in the skin aging process were selected to measure punicalagin's effect. RESULTS: Punicalagin succeeded in reducing the growth arrest of HFB4 cells, activated production of the Col1A1 and Timp3 genes, maintained collagen level, and lowered MMP3. Punicalagin increased human TERT concentration in skin cells. DISCUSSION: Punicalagin is promising as a natural antioxidant to protect human skin from aging.

Klotho inhibits H2 O2 -induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression.

Periodontitis, a human chronic inflammatory disease, has affected the lives of millions of individuals. Periodontal ligament stem cells (PDLSCs), derived from the periodontal ligament, exhibit tissue specificity and impaired differentiation ability and are closely associated with tissue regeneration in periodontitis. Klotho, a single-pass transmembrane protein, has been reported to positively affect H2 O2 -induced oxidative stress and inflammation in PDLSCs. The ultimate damage of oxidative stress stimulation in PDLSCs was cell apoptosis, which was also the major lesion in periodontitis. Thus, the present study aimed to figure out the effect of klotho on H2 O2 -injured PDLSCs and its underlying mechanism to provide new therapeutic targets in periodontitis. The expression of klotho and uncoupling protein 2 (UCP2) was investigated in the gingival tissues, gingival crevicular fluid (GCF), and periodontal ligament stem cells (PDLSCs) in patients with chronic periodontitis. Then, under klotho treatment, oxidative stress was evaluated by measuring SOD and GSH-PX levels. Cell apoptosis and cell necrosis were also detected by measuring the cell death-relevant proteins, including Caspase-3, BAX, Bcl, MLKL, RIP1, and RIP3. Finally, a rescue assay was performed by inhibiting the expression of UCP2. The results showed that klotho and UCP2 were downregulated in patients with chronic periodontitis. In addition, klotho upregulated the production of UCP2 in H2 O2 -treated PDLSCs. Klotho inhibited H2 O2 -induced oxidative stress and cellular loss in PDLSCs, moreover, the rescue assay suggested that UCP2 knockdown suppressed the effects of klotho on PDLSCs. In conclusion, this study showed that klotho inhibits H2 O2 -induced oxidative stress and apoptosis in PDLSCs by regulating UCP2 expression. This novel discovery might provide a potential target for chronic periodontitis treatment.

Cystine reduces tight junction permeability and intestinal inflammation induced by oxidative stress in Caco-2 cells.

Intestinal oxidative stress produces pro-inflammatory cytokines, which increase tight junction (TJ) permeability, leading to intestinal and systemic inflammation. Cystine (Cys2) is a substrate of glutathione (GSH) and inhibits inflammation, however, it is unclear whether Cys2 locally improves intestinal barrier dysfunction. Thus, we investigated the local effects of Cys2 on oxidative stress-induced TJ permeability and intestinal inflammatory responses. Caco-2 cells were cultured in a Cys2-supplemented medium for 24 h and then treated with H2O2 for 2 h. We assessed TJ permeability by measuring transepithelial electrical resistance and the paracellular flux of fluorescein isothiocyanate-dextran 4 kDa. We measured the concentration of Cys2 and GSH after Cys2 pretreatment. The mRNA expression of pro-inflammatory cytokines was assessed. In addition, the levels of TJ proteins were assessed by measuring the expression of TJ proteins in the whole cells and the ratio of TJ proteins in the detergent-insoluble fractions to soluble fractions (IS/S ratio). Cys2 treatment reduced H2O2-induced TJ permeability. Cys2 did not change the expression of TJ proteins in the whole cells, however, suppressed the IS/S ratio of claudin-4. Intercellular levels of Cys2 and GSH significantly increased in cells treated with Cys2. Cys2 treatment suppressed the mRNA expression of pro-inflammatory cytokines, and the mRNA levels were significantly correlated with TJ permeability. In conclusion, Cys2 treatment locally reduced oxidative stress-induced intestinal barrier dysfunction possively due to the mitigation of claudin-4 dislocalization. Furthermore, the effect of Cys2 on the improvement of intestinal barrier function is related to the local suppression of oxidative stress-induced pro-inflammatory responses.

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol.

3-hydroxytyrosol (HT) is the main phenolic compound found in olive oil with known antioxidant, anti-inflammatory, and antimicrobial properties in several dermatological conditions, both when taken in the form of olive oil or pure in cosmeceutical formulations. To date, its direct effect on the wound healing process and the molecular mechanisms involved have not yet been elucidated. Thus, in the present study, we aimed to explore its effects in vitro in epidermal keratinocyte cultures focusing on the molecular mechanism implied. HT was able to induce keratinocyte proliferation in the low micromolar range, increasing the expression of cyclin dependent kinases fundamental for cell cycle progression such as CDK2 and CDK6. Furthermore, it increased cell migration through the activation of tissue remodeling factors such as matrix metalloproteinase-9 (MMP-9) protein. Then, we evaluated whether HT also showed antioxidant activity at this concentration range, protecting from H2O2-induced cytotoxicity. The HT prevented the activation of ATM serine/threonine kinase (ATM), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2), and p53, reducing the number of apoptotic cells. Our study highlighted novel pharmacological properties of HT, providing the first evidence of its capability to induce keratinocyte migration and proliferation required for healing processes and re-epithelialization.

Queen loss increases worker survival in leaf-cutting ants under paraquat-induced oxidative stress.

Longevity is traded off with fecundity in most solitary species, but the two traits are positively linked in social insects. In ants, the most fecund individuals (queens and kings) live longer than the non-reproductive individuals, the workers. In many species, workers may become fertile following queen loss, and recent evidence suggests that worker fecundity extends worker lifespan. We postulated that this effect is in part owing to improved resilience to oxidative stress, and tested this hypothesis in three Myrmicine ants: Temnothorax rugatulus, and the leaf-cutting ants Atta colombica and Acromyrmex echinatior. We removed the queen from colonies to induce worker reproduction and subjected workers to oxidative stress. Oxidative stress drastically reduced survival, but this effect was less pronounced in leaf-cutting ant workers from queenless nests. We also found that, irrespective of oxidative stress, outside workers died earlier than inside workers did, likely because they were older. Since At. colombica workers cannot produce fertile offspring, our results indicate that direct reproduction is not necessary to extend the lives of queenless workers. Our findings suggest that workers are less resilient to oxidative stress in the presence of the queen, and raise questions on the proximate and ultimate mechanisms underlying socially mediated variation in worker lifespan. This article is part of the theme issue 'Ageing and sociality: why, when and how does sociality change ageing patterns?'

Reproductive activation in honeybee (Apis mellifera) workers protects against abiotic and biotic stress.

Social insect reproductives exhibit exceptional longevity instead of the classic trade-off between somatic maintenance and reproduction. Even normally sterile workers experience a significant increase in life expectancy when they assume a reproductive role. The mechanisms that enable the positive relation between the antagonistic demands of reproduction and somatic maintenance are unclear. To isolate the effect of reproductive activation, honeybee workers were induced to activate their ovaries. These reproductively activated workers were compared to controls for survival and gene expression patterns after exposure to Israeli Acute Paralysis Virus or the oxidative stressor paraquat. Reproductive activation increased survival, indicating better immunity and oxidative stress resistance. After qPCR analysis confirmed our experimental treatments at the physiological level, whole transcriptome analysis revealed that paraquat treatment significantly changed the expression of 1277 genes in the control workers but only two genes in reproductively activated workers, indicating that reproductive activation preemptively protects against oxidative stress. Significant overlap between genes that were upregulated by reproductive activation and in response to paraquat included prominent members of signalling pathways and anti-oxidants known to affect ageing. Thus, while our results confirm a central role of vitellogenin, they also point to other mechanisms to explain the molecular basis of the lack of a cost of reproduction and the exceptional longevity of social insect reproductives. Thus, socially induced reproductive activation preemptively protects honeybee workers against stressors, explaining their longevity. This article is part of the theme issue 'Ageing and sociality: why, when and how does sociality change ageing patterns?'

Hydrogen peroxide-induced oxidative stress impairs redox status and damages aerobic metabolism of breast muscle in broilers.

Oxidative stress has always been a hot topic in poultry science. However, studies concerning the effects of redox status and glucose metabolism induced by hydrogen peroxide (H2O2) in the breast muscle of broilers have been rarely reported. This study was aimed to evaluate the impact of intraperitoneal injection of H2O2 on oxidative damage and glycolysis metabolism of breast muscle in broilers. We also explored the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to provide possible mechanism of the redox imbalance. Briefly, a total of 320 one-day-old Arbor Acres chicks were randomly divided into 5 treatments with 8 replicates of 8 birds each (noninjected control, 0.75% saline-injected, 2.5, 5.0, and 10.0% H2O2-injected treatments). Saline group was intraperitoneally injected with physiological saline (0.75%) and H2O2 groups received an intraperitoneal injection of H2O2. The dosage of the injection was 1.0 mL/kg BW. All birds in the saline and H2O2 groups were injected on days 16 and 37 of the experimental period. At 42 d of age, 40 birds (8 cages per group and one chicken per cage) were selected to be stunned electrically (50 V, alternating current, 400 Hz for 5 s each one), and then immediately slaughtered via exsanguination. The results showed that broilers in the H2O2 injection group linearly exhibited higher contents of reactive oxygen species, carbonyl and malondialdehyde, and lower total antioxidant capacity and glutathione peroxidase activities. With the content of H2O2 increased, the H2O2 groups linearly downregulated the mRNA expressions of GPX, CAT, HMOX1, NQO1, and Nrf2 and its downstream target genes. In addition, H2O2 increased serum activities of creatine kinase and lactate dehydrogenase. Meanwhile, in the pectoral muscle, the glycogen content was linearly decreased, and the lactate content was linearly increased in muscle of broilers injected with H2O2. In addition, the activities of glycolytic enzymes including pyruvate kinase, hexokinase, and lactate dehydrogenase were linearly increased after exposure to H2O2. In conclusion, H2O2 injection could impair antioxidant status and enhance anaerobic metabolism of breast muscle in broilers.

Protective effect of procyanidin A-type dimers against H2O2-induced oxidative stress in prostate DU145 cells through the MAPKs signaling pathway.

It has been reported that B-type procyanidins can alleviate oxidative damage of prostatic cells, but there has been limited information on the similar role of A-type procyanidins. This study investigated the protective effect of procyanidin A-type dimers from peanut skin against H2O2-induced oxidative stress damage in prostate cancer DU145 cells. According to the UPLC-Q-TOF-MS/MS analysis and comparison with standards, the fourth fraction of peanut skin procyanidin (PSP-4) was identified as procyanidin A-type dimers, namely, procyanidin A1 and A2. Results revealed that PSP-4 treatment prior H2O2 exposure increased cell activity and attenuated the cell cycle arrest and apoptosis rate. The H2O2-induced increase in intracellular reactive oxygen species (ROS) was remarkably inhibited by PSP-4. PSP-4 treatment enhanced the activity of catalase (CAT) and total super oxide dismutase (T-SOD) and restored glutathione (GSH) content, compared with the H2O2 treatment. Furthermore, the results indicated that PSP-4 protected DU145 cells by attenuating phosphorylation of the mitogen-activated protein kinases (MAPKs), by increasing the Bcl-2/Bax ratio, and by reducing the activation of caspase-3 and caspase-9 by cascade reactions. This study reveals that procyanidin A-type dimers from peanut skin have the potential function in preventing oxidative stress damage of prostatic cells.

Liraglutide reduces coronary endothelial cells no-reflow damage through activating MAPK/ERK signaling pathway.

Coronary no-reflow damage is caused by endothelial cell damage although little drug is available to intervene in coronary no-reflow. Liraglutide is a kind of anti-diabetic drug and its cardioprotective role has been widely reported. In this study, we explored the role of liraglutide in regulating coronary endothelial cell damage. We used hydrogen peroxide to mimic coronary no-reflow damage in vitro. After exposure to hydrogen peroxide, endothelial cells' viability was significantly reduced, an effect that was followed by an increase in cell apoptosis. Interestingly, liraglutide treatment obviously upregulated endothelial cell viability and thus prevented cell apoptosis. Further, we also found that liraglutide inhibited the activation of caspase-3 in hydrogen peroxide-treated endothelial cells. Besides, cellular metabolism, as reflected by mitochondrial membrane potential, was disrupted by hydrogen peroxide and reversed to normal levels with liraglutide. Further, we found that the ERK pathway is a potential downstream effector of liraglutide. Administration of liraglutide significantly promoted the activation of ERK and this effect may contribute to endothelial cell survival. Altogether, our results illustrated that hydrogen peroxide-mediated endothelial cell damage could be attenuated by liraglutide through modulation of the MAPK/ERK signaling pathway. This finding will pave a novel road for the intervention of coronary no-reflow damage in patients suffering from myocardial infarction.

Hydrogen Peroxide 40% for the Treatment of Seborrheic Keratoses.

OBJECTIVE: Hydrogen peroxide 40% (HP40) was approved by the US Food and Drug Administration for topical treatment of seborrheic keratosis (SK) in December 2017. This article will review phase II and III clinical trials to assess the drug's efficacy, safety, and clinical application. DATA SOURCES: A systematic literature review was performed using the terms "Eskata AND seborrheic keratosis," and "hydrogen peroxide AND seborrheic keratosis" in the OVID MEDLINE, PubMed, Cochrane Library, EMBASE, and Web of Science databases. ClinicalTrials.gov was searched to identify ongoing or nonpublished studies. STUDY SELECTION AND DATA ABSTRACTION: Articles written in English between January 2000 and mid-June 2020 discussing phase II and phase III clinical trials were evaluated. DATA SYNTHESIS: In 2 phase III clinical trials, 4% and 8% of patients treated with HP40 had a Physician Lesion Assessment score of zero for all 4 SKs, respectively, compared with 0% in both vehicle groups at the primary end point of day 106 (P < 0.01; P < 0.0001). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: HP40, although less effective, has a better safety profile than other treatment options. It should be especially considered for treatment of facial SKs, where it is most efficacious and where other treatment modalities, such as cryotherapy, are more challenging. CONCLUSIONS: HP40 is a new, safe alternative treatment for SKs, although it is expensive and only modestly effective, both of which somewhat limit its overall utility. HP40 is a promising topical alternative, particularly for cosmetically sensitive locations, such as the face.

6,4'-dihydroxy-7-methoxyflavanone protects against H2O2-induced cellular senescence by inducing SIRT1 and inhibiting phosphatidylinositol 3-kinase/Akt pathway activation.

6, 4'-Dihydroxy-7-methoxyflavanone (DMF) has been shown to possess anti-inflammatory, anti-oxidative, and neuroprotective activities. However, its effect on oxidative stress-induced aging remains undemonstrated. This study aimed at investigating the anti-senescence effect of DMF on hydrogen peroxide (H2O2)-induced premature senescence, and associated molecular mechanisms in human dermal fibroblasts (HDFs). The cells were DMF pretreated with small interfering RNA (siRNAs) of control or sirtuin 1 (SIRT1) before H2O2 exposure, and western blot analysis, senescence-associated ß-galactosidase (SA-ß-gal) activity, cell counting, gene silencing, and SIRT1 activity assay were performed. Pretreatment with DMF inhibited H2O2-induced senescence phenotypes, which showed decreased SA-ß-gal activity and increased cell growth in comparison with H2O2-treated HDFs. Meanwhile, the decreases in ac-p53, p21Cip1/WAF1, and p16Ink4a and the increases in pRb and cyclin D1 were observed. DMF was also found to induce SIRT1 expression and activity level concentration- and time-dependently. Moreover, SIRT1 inhibition abrogated DMF senescence prevention. Additionally, Akt and ERK were activated with different kinetics after H2O2 exposure, and Akt activity inhibition attenuated SA-ß-gal activity augmentation. We also found that DMF inhibited H2O2-induced Akt phosphorylation. This study indicates that DMF effectively protects against oxidative stress-induced premature senescence through SIRT1 expression up-regulation and Akt pathway inhibition in HDFs. These results suggest that DMF can be a potential therapeutic molecule for age-related diseases, or a protective agent against the aging process.

Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice.

Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.

Hydrogen Peroxide Topical Solution, 45% for Common Warts: Phase 2 Efficacy and Safety Trial Results.

BACKGROUND: No FDA-approved prescription therapies are available for common warts. OBJECTIVE: We evaluated a proprietary hydrogen peroxide topical solution, 45% (w/w) (HP45) for treatment of common warts. METHODS: In the phase 2 randomized, double-blind, vehicle-controlled WART-203 trial (NCT03278028), eligible patients aged ≥8 years had 1–6 warts (1 target wart) on the trunk or extremities with a Physician’s Wart Assessment™ (PWA) grade ≥2 (range, 0 [clear] to 3 [wart 3–8 mm in diameter or length]). Patients self-administered HP45 or vehicle twice weekly for 8 weeks and were evaluated through 12 weeks posttreatment (week 20). Efficacy assessments included mean change in target wart PWA grade from baseline at week 8 (primary endpoint) and proportions of patients with target wart clearance. Safety assessments included treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs). RESULTS: A total of 157 patients completed 8 weeks of treatment (HP45, n=79; vehicle, n=78); 151 patients completed the 20-week posttreatment evaluation (HP45, n=75; vehicle, n=76). A significantly greater reduction in mean target wart PWA grade from baseline at week 8 was achieved with HP45 (−0.87) vs vehicle (−0.17; P<0.0001) and maintained at week 20 (−1.00 vs −0.39; P=0.0004). The proportion of patients with target wart clearance at week 8 was significantly greater with HP45 (25.3%) vs vehicle (2.6%; P<0.0001) and remained significantly greater at week 20 (37.3% vs 11.8%; P=0.0002). Forty-seven patients reported 76 TEAEs; most were mild or moderate in severity. Most LSRs were mild and resolved by week 20. In pediatric patients (HP45, n=13; vehicle, n=6), greater reductions in mean target wart PWA grade from baseline were observed with HP45 vs vehicle at weeks 8 (−1.0 vs 0) and 20 (−1.2 vs −0.5). CONCLUSION: These findings support the efficacy and safety of HP45 for the treatment of common warts in patients ≥8 years of age. J Drugs Dermatol. 2020;19(10):969-976. doi:10.36849/JDD.2020.5054.