Quercetin and vitamin E attenuate diabetes-induced testicular anomaly in Wistar rats via the mitochondrial-mediated apoptotic pathway

Oluwatoyin Osinimega Ojo, Olufunso Olabode Olorunsogo

Andrologia . 2021 Jul 18;e14185. doi: 10.1111/and.14185. Online ahead of print.

Abstract

The role of quercetin and vitamin E treatment against streptozotocin (STZ)-induced testicular abnormalities in diabetic rats and the possible mechanism of action they use for protection were investigated. Diabetes was induced by STZ (45 mg/kg i.p. once) and blood glucose was determined. Plasmatic insulin, testosterone, luteinising hormone and follicle-stimulating hormone (FSH) were determined by ELISA. Levels of cytochrome c, caspase 3 and caspase 9 were evaluated by immunohistochemistry, while lesions were viewed by histology. Insulin played a role in testicular protection against male infertility through modulation of luteinising hormone (LH). This consequently increased Leydig and Sertoli cells and maturation of germ cells with the attached epididymis having abundant spermatozoa. The study showed a positive correlation in the levels of LH, FSH and testosterone; it was further established that all treatments normalised diabetes-induced alterations. Treatment with quercetin and vitamin E resulted in 34% decrease of apoptogenic cytochrome c release. This protected the testes against excessive apoptosis by decreasing caspase 3 and caspase 9 activation by up to 30 and 28% respectively (p < .05). Histology also showed that treatment prevented testicular cell death. The findings show that quercetin/vitamin E possess free radical scavenging properties that protected against testicular damage in diabetes. This suggests the possibility of pharmaco-therapeutic intervention.

Qian Hu, Yifan Zhang, Huiling Lou, Zexian Ou, Jin Liu, Wentao Duan, Hao Wang, Yuanlong Ge, Junxia Min, Fudi Wang, Zhenyu Ju

Cell Death Dis . 2021 Jul 15;12(7):706. doi: 10.1038/s41419-021-04008-9.

Abstract

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.

Hala M Helal, Wael M Samy, Elbadawy A Kamoun, Esmail M El-Fakharany, Doaa A Abdelmonsif, Rania G Aly, Sana M Mortada, Marwa A Sallam

Int J Nanomedicine . 2021 Jul 14;16:4781-4803. doi: 10.2147/IJN.S317409. eCollection 2021.

Abstract

Background: Tacrolimus (TAC) is a powerful immunosuppressive agent whose therapeutic applicability is confined owing to its systemic side effects.

Objective: Herein, we harnessed a natural polymer based bioconjugate composed of maltodextrin and α-tocopherol (MD-α-TOC) to encapsulate TAC as an attempt to overcome its biological limitations while enhancing its therapeutic anti-rheumatic efficacy.

Methods: The designed TAC loaded maltodextrin-α-tocopherol nano-micelles (TAC@MD-α-TOC) were assessed for their physical properties, safety, toxicological behavior, their ability to combat arthritis and assist bone/cartilage formation.

Results: In vitro cell viability assay revealed enhanced safety profile of optimized TAC@MD-α-TOC with 1.6- to 2-fold increase in Vero cells viability compared with free TAC. Subacute toxicity study demonstrated a diminished nephro- and hepato-toxicity accompanied with optimized TAC@MD-α-TOC. TAC@MD-α-TOC also showed significantly enhanced anti-arthritic activity compared with free TAC, as reflected by improved clinical scores and decreased IL-6 and TNF-α levels in serum and synovial fluids. Unique bone formation criteria were proved with TAC@MD-α-TOC by elevated serum and synovial fluid levels of osteocalcin and osteopontin mRNA and proteins expression. Chondrogenic differentiation abilities of TAC@MD-α-TOC were proved by increased serum and synovial fluid levels of SOX9 mRNA and protein expression.

Conclusion: Overall, our designed bioconjugate micelles offered an excellent approach for improved TAC safety profile with enhanced anti-arthritic activity and unique bone formation characteristics.

Darío R Gómez-Linton, Arturo Navarro-Ocaña, Angélica Román-Guerrero, Silvestre Alavez, Luis Pinzón-López, José A Mendoza-Espinoza, Laura J Pérez-Flores

J Food Sci Technol . 2021 Jul;58(7):2579-2588. doi: 10.1007/s13197-020-04764-0. Epub 2020 Oct 2.

Abstract

Achiote (Bixa orellana) is highly appreciated as a condiment and as the main source of bixin and tocotrienols, both having antioxidant properties. To explore the possibility of maximizing the antioxidant activity of achiote seed extracts using clean methodologies, the use of sonication and green solvents were tested. Ethyl lactate, isopropyl acetate, and ethanol combined with probe sonication produced the best results, obtaining similar bixin contents but higher δ-tocotrienol contents, as well as significantly higher in vitro and in vivo antioxidant activity compared with the maceration method extract, requiring low energy and saving time and solvents. The probe-sonicated achiote extract with the highest δ-tocotrienol content was better at increasing the Caenorhabditis elegans resistance to oxidative stress than the extract obtained through maceration. This is the first report about the effect of sonication combined with green solvents on the bixin and δ-tocotrienol content in achiote seed extracts and its relevance on the in vitro and in vivo antioxidant activity.

Sara Mohamed Naguib Abdel Hafez, Eman Elbassuoni, Walaa Yehia Abdelzaher, Nermeen N Welson, Gaber El-Saber Batiha, Khalid J Alzahrani, Fatma Alzhraa Fouad Abdelbaky

Biomed Pharmacother . 2021 Jul;139:111637. doi: 10.1016/j.biopha.2021.111637. Epub 2021 May 6.

Abstract

Methotrexate (MXT) is a chemotherapeutic drug that has been used in a wide range of clinical practices. Unfortunately, the administration of MXT during pregnancy may induce abortion, fetal deformities, and intrauterine growth retardation. Vitamin E is an antioxidant agent that can ameliorate free radical damage. The current work aimed to shed more light on the possible protective effect of vitamin E against MXT induced placental toxicity and to determine the possible mechanisms; biochemically, histologically, and immunohistochemically. Four groups were used: control pregnant, Vitamin E (VIT E) pregnant, Methotrexate (MXT) pregnant, and Vitamin E Methotrexate (VIT E-MXT) pregnant. The placental tissues were processed for light, immunohistochemical, and electron microscopic study. Other samples were obtained for biochemical study; the placental oxidant/antioxidant status was evaluated. The results showed that MXT caused various placental morphological changes in the form of distorted chorionic projection with an accumulation of hemosiderin granules in the trophoblastic cells. Maternal blood vessels showed a homogenous acidophilic material Edema of the extra-embryonic fetal membranes was noticed. A significant decreased in placental weight as well as increase in the oxidative and inflammatory markers were detected. Increased COX2 and decreased eNOS expressions were observed in the MXT group if compared to the control group. VIT E significantly restored the normal histological and immunohistochemical appearance, placental weight, and oxidant/antioxidant balance. It could be concluded the biochemical, morphological, and morphometric findings suggested that vitamin E coadministration is promising in attenuating the placental toxic effect of methotrexate. In this study, VIT E decreased the inflammatory and oxidative stress effect of methotrexate on the placental tissue by enhancing the level of eNOS.

Esdras Façanha de Carvalho, Maitê Bertotti, Cesar Augusto Migliorati, André Caroli Rocha

J Oral Maxillofac Surg . 2021 Jul 8;S0278-2391(21)00655-8. doi: 10.1016/j.joms.2021.06.036. Online ahead of print.

Abstract

Several treatment protocols for medication-related osteonecrosis of the jaw (MRONJ) have been published. Despite the efficacy of surgical therapy of approximately 90% as primary therapy, the role of other agents, such as drug administration, should not be underestimated. Based on previous experience with osteoradionecrosis, the association of pentoxifylline and tocopherol has shown encouraging results in MRONJ patients. Despite the need for long-term use of the combination, compliance has been good. However, studies in breast cancer patients revealed that pentoxifylline can require dose reduction or discontinuation due to nausea and epigastric pain. Cilostazol has been used as a substitute for pentoxifylline in peripheral artery disease. Herein we report a case in which cilostazol replaced pentoxifylline at a dose of 100mg, 2 times/day with tocopherol 500UI, 2 times/day, in a 77-year-old female patient that could not tolerate pentoxifylline for the management of MRONJ. After an uneventful 22 months of follow-up, a cone-beam computed tomography revealed complete bone formation and no signs of recurrence. Cilostazol may be a useful and safe alternative to pentoxifylline as part of MRONJ management protocols.

Farah D R Al-Baiaty, Aziana Ismail, Zarina Abdul Latiff, Khairul Najmi Muhammad Nawawi, Raja Affendi Raja Ali, Norfilza Mohd Mokhtar

Front Pediatr . 2021 Jul 8;9:667247. doi: 10.3389/fped.2021.667247. eCollection 2021.

Abstract

Obesity has become a worldwide health concern among the pediatric population. The prevalence of non-alcoholic fatty liver disease (NAFLD) is growing rapidly, alongside the high prevalence of obesity. NAFLD refers to a multifactorial disorder that includes simple steatosis to non-alcoholic steatohepatitis (NASH) with or devoid of fibrosis. NAFLD is regarded as a systemic disorder that influences glucose, lipid, and energy metabolism with hepatic manifestations. A sedentary lifestyle and poor choice of food remain the major contributors to the disease. Prompt and timely diagnosis of NAFLD among overweight children is crucial to prevent the progression of the condition. Yet, there has been no approved pharmacological treatment for NAFLD in adults or children. As indicated by clinical evidence, lifestyle modification plays a vital role as a primary form of therapy for managing and treating NAFLD. Emphasis is on the significance of caloric restriction, particularly macronutrients (fats, carbohydrates, and proteins) in altering the disease consequences. A growing number of studies are now focusing on establishing a link between vitamins and NAFLD. Different types of vitamin supplements have been shown to be effective in treating NAFLD. In this review, we elaborate on the potential role of vitamin E with a high content of tocotrienol as a therapeutic alternative in treating NAFLD in obese children.

Lara Camillo, Elena Grossini, Serena Farruggio, Patrizia Marotta, Laura Cristina Gironi, Elisa Zavattaro, Paola Savoia

Skin Pharmacol Physiol . 2021 Jul 8;1-12. doi: 10.1159/000517204. Online ahead of print.

Abstract

Background: The altered balance between oxidants/antioxidants and inflammation, changes in nitric oxide (NO) release, and mitochondrial function have a role in skin aging through fibroblast modulation. Tocopherol is promising in counteracting the abovementioned events, but the effective mechanism of action needs to be clarified.

Objective: The aim of this study was to examine the effects of α-tocopherol on cell viability/proliferation, NO release, mitochondrial function, oxidants/antioxidants, and inflammation in human dermal fibroblasts (HDF) subjected to oxidative stress.

Methods: HDF were treated with H2O2 in the presence or absence of 1-10 μM α-tocopherol. Cell viability, reactive oxygen species (ROS), NO release, and mitochondrial membrane potential were measured; glutathione (GSH), superoxide dismutase (SOD)-1 and -2, glutathione peroxidase-1 (GPX-1), inducible NO synthase (iNOS), and Ki-67 were evaluated by RT-PCR and immunofluorescence; cell cycle was analyzed using FACS. Pro- and anti-inflammatory cytokine gene expression was analyzed through qRT-PCR.

Results: α-Tocopherol counteracts H2O2, although it remains unclear whether this effect is dose dependent. Improvement of cell viability, mitochondrial membrane potential, Ki-67 expression, and G0/G1 and G2/M phases of the cell cycle was observed. These effects were accompanied by the increase of GSH content and the reduction of SOD-1 and -2, GPX-1, and ROS release. Also, iNOS expression and NO release were inhibited, and pro-inflammatory cytokine gene expression was decreased, confirming the putative role of α-tocopherol against inflammation.

Conclusion: α-Tocopherol exerts protective effects in HDF which underwent oxidative stress by modulating the redox status, inflammation, iNOS-dependent NO release, and mitochondrial function. These observations have a potential role in the prevention and treatment of photoaging-related skin cancers.

Pochuen Shieh, Shu-Shong Hsu, Wei-Zhe Liang

Environ Toxicol . 2021 Jul;36(7):1375-1388. doi: 10.1002/tox.23133. Epub 2021 Apr 5.

Abstract

Fusarium mycotoxins are one of the largest families of mycotoxins. Among these mycotoxins, deoxynivalenol is the most widespread pollutant of grains. However, the mechanism underlying the effect of deoxynivalenol on cytotoxicity in human brain endothelial cells was still unclear. This study examined whether deoxynivalenol induced oxidative stress-associated cytotoxicity in primary human brain endothelial cells (HBEC-5i), and explored whether Vitamin E (VE), a selective antioxidant, had protective effects on deoxynivalenol-treated cells. Deoxynivalenol (10-50 μM) concentration-dependently induced cytotoxicity in HBEC-5i cells. Deoxynivalenol (IC50 = 20 μM) activated mitochondrial apoptotic pathway by modulating antioxidant protein expressions (Nrf2, HO-1 and NQO1). More significantly, pre-treatment with VE (20 μM) attenuated the deoxynivalenol-induced cytotoxicity in this cell model. Together, VE significantly alleviated the apoptotic effects of deoxynivalenol in HBEC-5i cells suggesting that it protected the cells against deoxynivalenol-induced oxidative damage. Our findings provided new insight that VE had the potential to ameliorate neurotoxicity of deoxynivalenol.

Hemavathy Subramaiam, Wan-Loy Chu, Ammu Kutty Radhakrishnan, Srikumar Chakravarthi, Kanga Rani Selvaduray, Yih-Yih Kok

Nutrients . 2021 Jul 6;13(7):2320. doi: 10.3390/nu13072320.

Abstract

Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina, γT3, or a combination of Spirulina and γT3 (Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction (p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina. There was a marked increase (p < 0.05) of CD4/CD127⁺ T-cells and decrease (p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase (p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant (p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.