Oleander attenuates hepatic inflammation in a TLR4-independent manner and by favorable modulation of hepatocellular global metabolome that supports cytoprotection.

ETHNOPHARMACOLOGICAL RELEVANCE: Nerium oleander is used to treat liver-associated chronic metabolic diseases in traditional medicinal systems across the globe. The hepatoprotective effects of oleander are mentioned in Indian and Chinese traditional medicinal literature. AIM OF THE STUDY: The present study aimed to investigate the cellular mechanisms behind the hepatoprotective effects of a non-toxic dose of oleander (NO). MATERIALS AND METHODS: The hepatoprotective effects of NO were tested against lipopolysaccharide (LPS)-treated HepG2 cells. Oxidative stress response was studied using cellular enzymatic assays, and gene expression was analyzed using qRT-PCR. HepG2 cells were pretreated with TAK-242 (pharmacological inhibitor of TLR4) to decipher the anti-inflammatory mechanisms of NO. Cell-free metabolites were analyzed using GCMS and were subjected to pathway enrichment analysis. RESULTS: NO reduced systemic inflammation, serum lipid peroxidation byproducts, and glucose without affecting serum transaminase levels and hepatic histopathological features. NO attenuated the inflammation-induced loss of antioxidant enzyme activities and mRNA expressions of toll-like receptor-4 (TLR4)/nuclear factor κß (NFκß)-dependent inflammatory genes. In TAK-242 pretreated cells, LPS was unable to induce inflammatory and oxidative responses. However, NO treatment in TAK-242 pretreated cells with LPS stimulation further reduced the signs of inflammation and improved hepatoprotective activities. A comparative analysis of the intracellular global metabolome from HepG2 cells with and without NO treatment indicated NO-mediated favorable modulation of intracellular metabolic pathways that support cytoprotective activities. CONCLUSION: NO protects HepG2 cells from LPS-induced oxidative and inflammatory injury. The hepatoprotective effects of NO are mediated by a TLR4-independent process and through a favorable modulation of the intracellular global metabolome that supports cytoprotection.

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection.

BACKGROUND: Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). METHODS: We treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML. RESULTS: The combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs. CONCLUSIONS: Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling.

Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

Integration of molecular docking, molecular dynamics and network pharmacology to explore the multi-target pharmacology of fenugreek against diabetes.

Fenugreek is an ancient herb that has been used for centuries to treat diabetes. However, how the fenugreek-derived chemical compounds work in treating diabetes remains unclarified. Herein, we integrate molecular docking and network pharmacology to elucidate the active constituents and potential mechanisms of fenugreek against diabetes. First, 19 active compounds from fenugreek and 71 key diabetes-related targets were identified through network pharmacology analysis. Then, molecular docking and simulations results suggest diosgenin, luteolin and quercetin against diabetes via regulation of the genes ESR1, CAV1, VEGFA, TP53, CAT, AKT1, IL6 and IL1. These compounds and genes may be key factors of fenugreek in treating diabetes. Cells results demonstrate that fenugreek has good biological safety and can effectively improve the glucose consumption of IR-HepG2 cells. Pathway enrichment analysis revealed that the anti-diabetic effect of fenugreek was regulated by the AGE-RAGE and NF-κB signalling pathways. It is mainly associated with anti-oxidative stress, anti-inflammatory response and ß-cell protection. Our study identified the active constituents and potential signalling pathways involved in the anti-diabetic effect of fenugreek. These findings provide a theoretical basis for understanding the mechanism of the anti-diabetic effect of fenugreek. Finally, this study may help for developing anti-diabetic dietary supplements or drugs based on fenugreek.

Biological Activity and Component Analyses of Chamaecyparis obtusa Leaf Extract: Evaluation of Antiwrinkle and Cell Protection Effects in UVA-Irradiated Cells.

Background and Objectives: Chamaecyparis obtusa (C. obtuse) extract has been used as a folk medicinal remedy in East Asian countries to alleviate inflammation and prevent allergies. Active oxygen causes skin aging and leads to skin cell and tissue damage. Extensive research has been conducted to control active oxygen generation to prevent skin aging. We evaluated the antioxidant activity and antiwrinkle effect of C. obtusa extract to determine its potential as a cosmetic material. Materials and Methods: The antioxidant activity of a 70% ethanol extract of C. obtusa (COE 70) and a water extract of C. obtusa (COW) was determined using 2,2-diphenyl-1-picrylhydrazy (DPPH) scavenging, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) scavenging, superoxide dismutase-like activity, xanthine oxidase inhibition, and ferric-reducing antioxidant power assays. The effective concentration of the extracts was determined using the methyl thiazolyl tetrazolium assay to evaluate their toxicity. The effects of COE 70 on the production of matrix metalloproteinases (MMPs) and procollagen, and expression of activated cytokines, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), in UVA-irradiated fibroblasts were determined using quantitative real-time PCR. Additionally, quercitrin, amentoflavone, hinokiflavone, and myricetin concentrations in COE 70 were determined using high-pressure high-performance liquid chromatography. Results: COE 70 had higher polyphenol and flavonoid concentrations than COW and exhibited an excellent antioxidant effect. COE 70 suppressed UVA-induced fibroblast death by 21.3% at 25 µg/mL. It also increased MMP-1, MMP-3, TNF-α, and IL-6 mRNA levels at 5-25 µg/mL compared with those in control UVA-irradiated fibroblasts. Moreover, mRNA levels of collagen type I and superoxide dismutase significantly increased, indicating the antiwrinkle and anti-inflammatory effects of the extract. Among the COE 70 components, quercitrin concentration was the highest; hence, quercitrin could be an active ingredient. Conclusions: COE 70 could be used as a natural antioxidant and antiwrinkle agent.

Pharmacological and Nutraceutical Activation of Rejuvenation, Geroprotection and Cytoprotection: Proofs of Concept.

Aging is a process associated with life [...].

Effectiveness of beetroot extract in SH-SY5Y neuronal cell protection against Fumonisin B1, Ochratoxin A and its combination.

Fumonisin B1 (FB1) and ochratoxin A (OTA) are fungal metabolites of worldwide concern because of their effect on human and animal health, as both have been classified by IARC as possible carcinogens (Group 2B). Beetroot is a source of dietary fiber, folic acid, and vitamin C, and some studies have demonstrated their antioxidant activity. Therefore, this work presents the cytoprotective effect of beetroot extract (BRE) on a neuroblastoma cell line (SH-SY5Y cells) exposed to FB1, OTA, and its combination. Cytotoxicity was studied by the MTT ([3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, for 24 h and 48 h. Simultaneous treatment and pre-treatment strategies were tested with 1:512-1:2 and 1:0 dilutions of BRE, with a concentration range from 0.4 to 100 µM of FB1 and from 0.19 to 50 µM of OTA. IC50 values of 5.8 µM and 9.1 µM at 24 h and 48 h, respectively were obtained for OTA while no cytotoxic effect was detected at the concentrations tested for FB1. Cytoprotection with increased viability was obtained when the simultaneous BRE + OTA strategy was performed. Finally, better protection was observed in the pretreatment strategy in which cells were exposed 24 h previously to BRE, compared to that shown in the simultaneous assay.

Novel anti-aging herbal formulation Jing Si displays pleiotropic effects against aging associated disorders.

Common characteristics of aging include reduced somatic stem cell number, susceptibility to cardiac injuries, metabolic imbalances and increased risk for oncogenesis. In this study, Pleiotropic anti-aging effects of a decoction Jing Si herbal drink (JS) containing eight Traditional Chinese Medicine based herbs, with known effects against aging related disorders was evaluated. Adipose derived mesenchymal stem cells (ADMSCs) from 16 week old adult and 24 month old aging WKY rats were evaluated for the age-related changes in stem cell homeostasis. Effects of JS on self-renewal, klotho and Telomerase Reverse Transcriptase expression DNA damage response were determined by immunofluorescence staining. The effects were confirmed in senescence induced human ADMSCs and in addition, the potential of JS to maintain telomere length was evaluated by qPCR analysis in ADMSCs challenged for long term with doxorubicin. Further, the effects of JS on doxorubicin-induced hypertrophic effect and DNA damage in H9c2 cardiac cells; MPP+-induced damages in SH-SY5Y neuron cells were investigated. In addition, effects of JS in maintaining metabolic regulation, in terms of blood glucose regulation in type-II diabetes mice model, and their potential to suppress malignancy in different cancer cells were ascertained. The results show that JS maintains stem cell homeostasis and provides cytoprotection. In addition JS regulates blood glucose metabolism, enhances autophagic clearances in neurons and suppresses cancer growth and migration. The results show that JS acts on multiple targets and provides a cumulative protective effect against various age-associated disorders and therefore it is a candidate pleiotropic agent for healthy aging.

Evaluation of cell protection by Psephellus pyrrhoblepharus (Boiss.) Wagenitz extracts in MPP+-induced dopaminergic cell damage.

Neurodegenerative diseases affect millions of people. Major reasons behind the onset and progression of these diseases are still under investigation. Therefore, any approach that would treat/prevent progression is important. In this study, we aimed to investigate the potential protective effects of Psephellus pyrrhoblepharus (Boiss.) Wagenitz extracts in MPP+-induced dopaminergic cell damage and compare the effectiveness of different extracts (methanol:water (1:1), chloroform and n-hexane). The cells were pretreated with four different concentrations (10, 50, 100, and 200 µg/ml) of methanol:water (1:1), chloroform and n-hexane extracts of P. pyrrhoblepharus following MPP+ treatment for 12 or 24 h. The changes in cell viability were determined using the MTT assay. Additionally, antioxidant activities and total phenolic/flavonoid contents of the extracts were determined with radical scavenging capacity, Folin-Ciocalteu and aluminum chloride assays, respectively. The extracts at selected concentrations were found to be protective in a dose-dependent manner at 12 and 24 h. Nevertheless, the methanol extract of the plant showed the highest protection both at 100 and 200 µg/ml (115.13%±3.98, 121.87%±1.66; p < 0.05) against dopaminergic damage at 24 h. The results showed that selected concentrations were not toxic and did not affect cell proliferation rate. Besides, the chloroform extract was found to have higher antioxidant activity than the other extracts (p < 0.05). The total phenolic and total flavonoid contents were found consistent with antioxidant activities. Our findings support the neuroprotective and antioxidant potential of P. pyrrhoblepharus. However, further studies on identifying the presence of chemicals in P. pyrrhoblepharus extracts which are responsible for protection should be carried out to confirm their therapeutic potential.

Butyrate supplementation to pregnant mice elicits cytoprotection against colonic injury in the offspring.

BACKGROUND: Maternal diet during pregnancy can impact progeny health and disease by influencing the offspring's gut microbiome and immune development. Gut microbial metabolism generates butyrate, a short-chain fatty acid that benefits intestinal health. Here we assess the effects of antenatal butyrate on the offspring's gastrointestinal health. We hypothesized that antenatal butyrate supplementation will induce protection against colitis in the offspring. METHODS: C57BL/6 mice received butyrate during pregnancy and a series of experiments were performed on their offspring. RNA sequencing was performed on colonic tissue of 3-week-old offspring. Six-8-week-old offspring were subjected to dextran sulfate sodium-induced colitis. Fecal microbiome analysis was performed on the 6-8-week-old offspring. RESULTS: Antenatal butyrate supplementation dampened transcript enrichment of inflammation-associated colonic genes and prevented colonic injury in the offspring. Antenatal butyrate increased the offspring's stool microbiome diversity and expanded the prevalence of specific gut microbes. CONCLUSIONS: Antenatal butyrate supplementation resulted in downregulation of genes in the offspring's colon that function in inflammatory signaling. In addition, antenatal butyrate supplementation was associated with protection against colitis and an expanded fecal microbiome taxonomic diversity in the offspring. IMPACT: Dietary butyrate supplementation to pregnant mice led to downregulation of colonic genes involved in inflammatory signaling and cholesterol synthesis, changes in the fecal microbiome composition of the offspring, and protection against experimentally induced colitis in the offspring. These data support the mounting evidence that the maternal diet during pregnancy has enduring effects on the offspring's long-term health and disease risk. Although further investigations are needed to identify the mechanism of butyrate's effects on fetal gut development, the current study substantiates the approach of dietary intervention during pregnancy to optimize the long-term gastrointestinal health of the offspring.

Ergothioneine: A Stress Vitamin with Antiaging, Vascular, and Neuroprotective Roles?

Significance: Ergothioneine (ET) is an unusual sulfur-containing amino acid derived from histidine, acquired predominantly from food. Its depletion is associated with deleterious consequences in response to stress stimuli in cell culture models, prompting us to classify it as a vitamin in 2010, which was later supported by in vivo studies. ET is obtained from a variety of foods and is taken up by a selective transporter. ET possesses antioxidant and anti-inflammatory properties that confer cytoprotection. ET crosses the blood-brain barrier and has been reported to have beneficial effects in the brain. In this study, we discuss the cytoprotective and neuroprotective properties of ET, which may be harnessed for combating neurodegeneration and decline during aging. Recent Advances: The designation of ET as a stress vitamin is gaining momentum, opening a new field of investigation involving small molecules that are essential for optimal physiological functioning and maintenance of health span. Critical Issues: Although ET was discovered more than a century ago, its physiological functions are still being elucidated, especially in the brain. As ET is present in most foods, toxicity associated with its deprivation has been difficult to assess. Future Directions: Using genetically engineered cells and mice, it may now be possible to elucidate roles of ET. This coupled with advances in genomics and metabolomics may lead to identification of ET function. As ET is a stable antioxidant with anti-inflammatory properties, whose levels decline during aging, supplementing ET in the diet or consuming an ET-rich diet may prove beneficial. Antioxid. Redox Signal. 36, 1306-1317.

Aloperine protects beta-cells against streptozocin-induced injury to attenuate diabetes by targeting NOS1.

Type 1 diabetes (T1D) is a metabolic dysfunction characterized by the selective destruction of islet ß-cells, with oxidative stress playing an essential role in the manifestation of this disease state. Aloperine (ALO) represents the main active alkaloid extracted from the traditional Chinese herbal Sophora alopecuroides L. and features outstanding antioxidative properties. In this study, T1D was induced by a single high dose streptozotocin (STZ, 150 mg/kg, intraperitoneal) in mice. Diabetic animals were intragastrically administered ALO at a dose of 50 mg/kg/day. Notably, treatment of ALO (50 mg/kg/day) for seven consecutive days could observably reverse the onset of diabetes induced by STZ accompanied by weight gain, lower blood glucose levels, and relief of ß-cells damage. Our in vitro study further demonstrated that ALO protected ß-cells from STZ/hydrogen peroxide-induced oxidative damage as manifested by increased expression of MnSOD and CAT. Furthermore, a network pharmacology study revealed that NOS1 represented the main target of ALO. Mechanistic studies subsequently showed that treatment of ALO increased the expression of NOS1, whereas NOS2 was decreased. Moreover, a docking study carried out suggested that ALO could fit into the binding pocket of human NOS1 and molecular dynamics simulation further validated this docking event. Collectively, the administration of ALO prior to diabetes could be a viable approach to the prevention of ß-cell injury. This study may offer a novel potential herbal medicine against T1D and may further help improve the understanding of the underlying molecular mechanisms of ALO-mediated protection against oxidative stress.

Triggers for the Nrf2/ARE Signaling Pathway and Its Nutritional Regulation: Potential Therapeutic Applications of Ulcerative Colitis.

Ulcerative colitis (UC), which affects millions of people worldwide, is characterized by extensive colonic injury involving mucosal and submucosal layers of the colon. Nuclear factor E2-related factor 2 (Nrf2) plays a critical role in cellular protection against oxidant-induced stress. Antioxidant response element (ARE) is the binding site recognized by Nrf2 and leads to the expression of phase II detoxifying enzymes and antioxidant proteins. The Nrf2/ARE system is a key factor for preventing and resolving tissue injury and inflammation in disease conditions such as UC. Researchers have proposed that both Keap1-dependent and Keap1-independent cascades contribute positive effects on activation of the Nrf2/ARE pathway. In this review, we summarize the present knowledge on mechanisms controlling the activation process. We will further review nutritional compounds that can modulate activation of the Nrf2/ARE pathway and may be used as potential therapeutic application of UC. These comprehensive data will help us to better understand the Nrf2/ARE signaling pathway and promote its effective application in response to common diseases induced by oxidative stress and inflammation.

Biological and Cytoprotective Effect of Piper kadsura Ohwi against Hydrogen-Peroxide-Induced Oxidative Stress in Human SW1353 Cells.

Oxidative stress plays a role in regulating a variety of physiological functions in living organisms and in the pathogenesis of articular cartilage diseases. Piper kadsura Ohwi is a traditional Chinese medicine that is used as a treatment for rheumatic pain, and the extracts have anti-inflammatory and antioxidant effects. However, there is still no study related to cell protection by P. kadsura. The P. kadsura extracts (PKE) were obtained by microwave-assisted extraction, liquid-liquid extraction, and column chromatography separation. The extracts could effectively scavenge free radicals in the antioxidant test, the EC50 of extracts is approximately the same as vitamin C. PKE decreased the apoptosis of SW1353 cells treated with H2O2 and could upregulate the gene expression of antioxidant enzymes (SOD-2, GPx, and CAT) and the Bcl-2/Bax ratio, as well as regulate PARP, thus conferring resistance to H2O2 attack. PKE protects cells against apoptosis caused by free radicals through the three pathways of JNK, MEK/ERK, and p38 by treatment with MAPK inhibitor. The identified components of PKE were bicyclo [2.2.1] heptan-2-ol-1,7,7-trimethyl-,(1S-endo)-, alpha-humulene, and hydroxychavicol by gas chromatography-mass spectrometry.

Therapeutic potential of beta-caryophyllene against aflatoxin B1-Induced liver toxicity: biochemical and molecular insights in rats.

Aflatoxin B1 (AFB1) is a mycotoxin highly toxic and carcinogenic to humans due to its potential to induce oxidative stress. The Beta-caryophyllene (BCP) have been highlighted for its broad spectrum of pharmacological effects. The present study aimed to investigate the beneficial effects of BCP against the susceptibility of hepatic and renal tissues to AFB1 toxicity, in biochemical parameters to assess organ function, tissue oxidation, and the immunocontent of oxidative and inflammatory proteins. Male Wistar rats was exposed to AFB1 (250 µg/kg, i.g.) and/or BCP (100 mg/kg, i.p.) for 14 successive days. It was found that exposure to AFB1 did not change the measured renal toxicity parameters. Also, AFB1 increased liver injury biomarkers (gamma glutamyl transferase and alkaline phosphatase) and reduced levels of non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol), however did not cause changes in the lipid peroxidation levels. Moreover, AFB1 interfered in oxidative pathway regulated by Kelch-like ECH-associated protein (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2), overacting Glutathione-S-Transferase (GST) activity. Lastly, a main effect of AFB1 on the total interleukin 1 beta (IL-1ß) was observed. Remarkably, the associated treatment of AFB1 + BCP improved altered liver parameters. In addition, BCP and AFB1 + BCP groups showed an increase in the levels of inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß). Thus, these results indicated that BCP has potential protective effect against AFB1 induced hepatotoxicity.

Protective effect of sarsasapogenin in TNBS induced ulcerative colitis in rats associated with downregulation of pro-inflammatory mediators and oxidative stress.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel condition considered by oxido-nitrosative stress and the release of pro-inflammatory cytokines that affects the mucosal lining of the colon. Sarsasapogenin (SG), as an active component, has been found in many plants, and it exhibits potential protective effects, such as anti-inflammatory, antioxidant, anti-psoriasis, anti-arthritis, anti-asthma, anti-depressant and anti-cancer. However, the effects of SG on UC remain unknown. OBJECTIVE: The purpose of this study was to investigate the effects of SG on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced UC in rats. METHOD: Thirty Wistar rats were randomized into five groups: (i) Normal control, (ii) Disease control (TNBS), (iii) Sarsasapogenin (SG) (50 µg/rat), (iv) Fluticasone (FC) (50 µg/rat), (v) Sarsasapogenin + Fluticasone (SG + FC) (25 µg/rat). UC was induced in rats by trans-rectal instillation of TNBS (10 mg/kg). SG, FC and SG + FC were administered for 11 days and on the 8th day colitis was induced. Several molecular, biochemical and histological alterations were evaluated in the colon tissue. All treatment group results were compared to the TNBS group results. RESULT: The study results revealed that treatment of rats with SG and SG + FC combination significantly decreased the colon weight/length ratio, macroscopic inflammation score, lesions score, diarrhea score and adhesion score. Combination treatment in rats significantly reduced the production of biochemical parameters, proinflammatory cytokines, haematological parameters, serum IgE levels and restored the oxidative stress markers. SG and SG + FC treatment also considerably restored the histopathological changes induced by TNBS. CONCLUSION: Thus, SG and SG + FC combination could alter the disease progression and could be a hopeful therapeutic target for the management of UC by reducing its dose in combination with FC to elude the long term adverse effects of FC.

The Nephroprotective Effect of Zizyphus lotus L. (Desf.) Fruits in a Gentamicin-Induced Acute Kidney Injury Model in Rats: A Biochemical and Histopathological Investigation.

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.

Ipomoea staphylina Attenuates Potassium Dichromate-Induced Nephrotoxicity in Wistar Rats via Antioxidant and Antiapoptotic Effects.

Occupational and environmental exposure to chromium compounds leads to nephrotoxicity to humans and animals due to the overproduction of ROS. Our study was aimed to demonstrate the shielding effect of hydroethanolic extract of Ipomoea staphylina (HEIS) bark on male Wistar rats challenged with potassium dichromate (K2Cr2O7). Division of animals was done in 4 groups' viz., normal control, K2Cr2O7 control, K2Cr2O7+HEIS (100 mg/kg), and K2Cr2O7+HEIS (200 mg/kg). Except for the normal control group, other groups were challenged with a single dose (subcutaneous) of K2Cr2O7 (15 mg/kg) and then treated with HEIS (100 and 200 mg/kg) for 1 week. It was observed that animals treated with K2Cr2O7 showed a notable increase in serum creatinine, blood urea, and BUN and dwindles in protein level. These changes were significantly reversed after a 1-week treatment with HEIS (100 and 200 mg/kg). Moreover, HEIS (100 and 200 mg/kg) showed a remarkable improvement in the activity of antioxidant enzymes (GPx, CAT, and SOD) and decreased the levels of TNF-α and IL-1ß in the kidney. Furthermore, treatment with HEIS (100 and 200 mg/kg) notably decreased the activity of caspase-3 and improved the level of HO-1 especially in the K2Cr2O7+ HEIS (200 mg/kg) group. Also, the histopathological study of the kidney supported the protective effects of HEIS. Hence, HEIS bark holds a notable protective effect against K2Cr2O7-induced nephrotoxicity in rats.

Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer.

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.

Potential Effect of Polyphenolic-Rich Fractions of Corn Silk on Protecting Endothelial Cells against High Glucose Damage Using In Vitro and In Vivo Approaches.

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.