Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway.

Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.

Protective effects of Brownea grandiceps (Jacq.) against ϒ-radiation-induced enteritis in rats in relation to its secondary metabolome fingerprint.

Radiation enteritis is the most common complication of radiotherapy in patients with pelvic malignancies. Thus, the radioprotective activity of the total hydro-alcoholic extract (BGE) and the ethyl acetate soluble fraction (EAF) of Brownea grandiceps leaves was evaluated against ϒ-radiation-induced enteritis in rats. (BGE) and (EAF) were characterized using HPLC-PDA-ESI-MS/MS analysis. The total phenolic and flavonoid contents were also quantified. In vivo administration of (BGE) (400 mg/kg) and (EAF) (200 & 400 mg/kg) prevented intestinal injury and maintained the mucosal integrity of irradiated rats through increasing villi length and promoting crypt regeneration. Also, (EAF) showed more potent antioxidant activity than (BGE) through reduction of MDA level and enhancement of GSH content and catalase enzyme activity. (BGE) and (EAF) down-regulated intestinal NF-κB expression leading to diminished expression of downstream inflammatory cytokine TNF-α. Moreover, (EAF) markedly reduced the expression of profibrotic marker TGF-ß1. Seventy-nine compounds were tentatively identified, including flavonoids, proanthocyanidins, polar lipids and phenolic acids. (EAF) showed significantly higher total phenolic and flavonoid contents, as compared to (BGE). Results revealed remarkable radioprotective activity of (BGE) and (EAF), with significantly higher activity for (EAF). The chemical constituents of (BGE) and (EAF) strongly supported their radioprotective activity. To the best of our knowledge, the present study describes for the first time the radioprotective activity of B. grandiceps leaves in relation to its secondary metabolome fingerprint; emphasizing the great promise of B. grandiceps leaves, especially (EAF), to be used as natural radio-protective agent.

Promising drug repurposing approach targeted for cytokine storm implicated in SARS-CoV-2 complications.

A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global pandemic galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis, transmission, and clinical symptoms. Remarkably, the most common complication associated with this disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine storm with new medications is needed to hamper COVID-19 complications where the most prominent strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially those required for testing drug safety and thus may help in reducing the dissemination of this pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their plausible mechanism of action for possible management of severe COVID-19 cases.

Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-ß, Wnt/ß-Catenin and Hippo Pathways.

Radiotherapy is an indispensable cancer treatment approach. However, it is associated with hazardous consequences on multiple organs characterized by insidious worsening severity over time. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) in radiation-induced premature ovarian failure (POF). Exposing female rats to 3.2 Gy whole-body ϒ-rays successfully induced POF. One week later, a single intravenous injection of BM-MSCs (2*106) cells was administered. BM-MSCs perfectly home to the damaged ovaries, enhanced ovarian follicle pool, and preserved the ovarian function manifested by restoring serum estradiol and follicle stimulating hormone levels, besides, rescuing the fertility outcomes of irradiated rats. These events have been associated with inhibiting ovarian apoptosis (Bax/Bcl2, caspase 3) and enhancing proliferation (PCNA). Interestingly, BM-MSCs reversed the inhibition of ovarian FOXO3 expression induced by radiation which resulted in increased primordial follicles stock. Moreover, BM-MSCs recovered the suppressed folliculogenesis process induced by radiation through upregulating FOXO1, GDF-9, and Fst genes expression accompanied by downregulating TGF-ß which enhanced granulosa cells proliferation and secondary follicle development. Mechanistically, BM-MSCs miRNAs epigenetically upregulate Wnt/ß-catenin and Hippo signaling pathways which are implicated in ovarian follicles growth and maturation. Therefore, BM-MSCs presented a ray of hope in the treatment of radiation-associated POF through genetic and epigenetic modulation of the integrated TGF-ß, Wnt/ß-catenin, and Hippo pathways which control apoptosis, proliferation, and differentiation of ovarian follicles.

Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB/TGF-ß/MMP-9 pathways.

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-ß1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-ß1/MMP-9 signaling pathway.

Chemical constituents and gastro-protective potential of Pachira glabra leaves against ethanol-induced gastric ulcer in experimental rat model.

Gastric ulcer is a very common illness that adversely affects a significant number of people all over the globe. Phytochemical investigation of P. glabra leaf alcohol extract (PGLE) resulted in the isolation and Characterization of a new nature compound, quercetin-3- O-α -L-rhamnosyl-(1'''-6'')-(4''- O -acetyl)-ß -D-galactoside (4), in addition to seven known compounds. They are ferulic acid (1), p- coumaric acid (2), quercetin 3-O-α-L-rhamnoside-3'-O-ß-D-glucoside (3), quercetin-3- O-α -L-rhamnosyl-(1'''-6'')-(4''- O -acetyl)- ß -Dgalactoside (4), quercetin-3- O-ß -D-galactoside (5), 7-hydroxy maltol-3-O-ß-D-glucoside (6), maltol-3- O-ß -D-glucoside (7), and methyl coumarate (8) that were first to be isolated from the genus Pachira. PGLE demonstrated in vitro anti-Helicobacter pylori activity. Moreover, the in vivo gastroprotective assessment of PGLE at different dosses, 100, 200, and 400 mg/kg against ethanol induced ulceration revealed a dose-dependent gastroprotection comparable to omeprazole. PGLE attenuated gastric lesions and histopathological changes triggered by ethanol. Interestingly, PGLE exhibited an anti-inflammatory effect through down-regulating the expression of nuclear factor-ĸB and pro-inflammatory enzyme cyclooxygenase-2 in the ulcer group. It also hindered apoptosis through decreasing Bax and increasing Bcl-2 expression hence decreasing Bax/Bcl2 ratio with a subsequent reduction in caspase 3 expression. Collectively, P. glabra is a rich reservoir of various phytochemicals reflecting a promising potential for alleviation of gastric ulcer through the mediation of inflammatory and apoptotic cascades.

Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats.

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.

Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-ß, TGF-ß, and FOXL-2.

Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-ß and FOXL-2 with downregulation of TGF-ß expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females' cancer survivors.

Coenzyme Q10 mitigates ionizing radiation-induced testicular damage in rats through inhibition of oxidative stress and mitochondria-mediated apoptotic cell death.

Radiotherapy is a common treatment modality for cancer patients; however, its use is limited by decreasing the probability of fertility in male cancer survivors. Therefore, this study aimed to define the capability of coenzyme Q10 (CoQ10), a potent stimulator of mitochondrial function, in attenuating ionizing radiation (IR)-induced spermatogenesis impairments. Male Sprague Dawley rats were exposed to a single dose of ϒ-rays (10 Gy) and/or treated with CoQ10 (10 mg/kg, orally, for 2 consecutive weeks). IR mediated irregular seminiferous tubules, which were emerged with typical morphological characteristics of apoptosis, and nuclear condensation, while CoQ10 significantly preserved the testicular structure and maintained spermatogenesis, which was displayed by higher levels of serum estradiol and testosterone. CoQ10 remarkably augmented sperm count, motility, and viability while diminished the rate of sperm-defects relatively to their counterparts after IR exposure. CoQ10 modulations in reproductive parameters were underpinned by attenuating IR-induced oxidative stress as evidenced by decreasing lipid peroxidation and increasing the antioxidant enzymes glutathione peroxidase and glutathione-s-transferase activities, and glutathione level. Supporting the involvement of CoQ10 in the anti-apoptotic response, the reduced mRNA expression levels of p53, Puma, and Bax accompanied by the increased Bcl-2 mRNA expression were observed. Subsequently, CoQ10 ameliorated the mitochondria dependent apoptotic pathway through diminishing Bax/Bcl-2 ratio, caspase-3 protein expression, and DNA fragmentation in testes of irradiated rats. Taken together, our findings showed that CoQ10 conserved against IR-induced steroidogenesis disruption through subsiding mitochondria-mediated oxidative stress injury in germinal cells.

Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects.

Chemotherapeutic platinum-containing drugs are widely used to treat a variety of cancer types; however, they cause ovarian failure and infertility. The aim of this study is to investigate the molecular mechanism underlying the potential protective effect of resveratrol against cisplatin-induced ovarian damage in a rat model. Female rats were given either cisplatin (6 mg/kg, i.p., once per week for two consecutive weeks) and/or resveratrol (10 mg/kg, orally for 17 days). Follicular development, ovarian function markers, as well as apoptotic and inflammatory markers were assessed 24 h after the last resveratrol dose. Resveratrol ameliorated the marked follicular loss and the significant reduction in anti-Müllerian hormone (AMH) level triggered by cisplatin. Mechanistically, cisplatin elicited a potent inflammatory response in ovarian tissue as evidenced by the elevated expression of tumor necrosis factor, nuclear factor kappa-B, and proinflammatory enzymes. Co-treatment with resveratrol inhibited the elevation in inflammatory mediators induced by cisplatin. Further, cisplatin switched on the apoptotic machinery in ovarian tissues via increasing the expression of both cytochrome c and caspase-3 which was reversed upon resveratrol co-treatment. Resveratrol also counteracts the upregulating poly(ADP-ribose) polymerase expression which could attribute to the inflammatory and apoptotic effects of cisplatin. Resveratrol protects the ovary from cisplatin-induced toxicity through preventing the loss of the AMH-secreting granulosa cells, diminishing PARP-1 expression, and downregulating the inflammatory and apoptotic events implicated in cisplatin toxicity.

Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: Emphasis on TGF-ß/MAPKs signaling pathway.

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-ß protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-ß/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.

Sodium selenite improves folliculogenesis in radiation-induced ovarian failure: a mechanistic approach.

Radiotherapy is a major factor contributing to female infertility by inducing premature ovarian failure (POF). Therefore, the need for an effective radioprotective agent is evident. The present study investigated the mechanism of potential radioprotective effect of sodium selenite on radiation-induced ovarian failure and whether sodium selenite can stimulate in-vivo follicular development in experimental rats. Immature female Sprague-Dawely rats were either exposed to gamma-radiation (3.2 Gy, LD(20)), once and/or treated with sodium selenite (0.5 mg/kg), once daily for one week before irradiation. Follicular and oocyte development, apoptotic markers, proliferation marker as well as oxidative stress markers were assessed 24-h after irradiation. In addition, fertility assessment was performed after female rats became completely mature at two months of age. Sodium selenite significantly enhanced follicular development as compared to the irradiated group. Sodium selenite significantly reversed the oxidative stress effects of radiation that was evidenced by increasing in lipid peroxide level and decreasing in glutathione level, and glutathione peroxidase (GPx) activity. Assessment of apoptosis and cell proliferation markers revealed that caspase 3 and cytochrome c expressions markedly-increased, whereas, PCNA expression markedly-decreased in the irradiated group; in contrast, sodium selenite treatment prevented these alterations. Histopathological examination further confirmed the radioprotective efficacy of sodium selenite and its in-vivo effect on ovarian follicles' maturation. In conclusion, sodium selenite showed a radioprotective effect and improved folliculogenesis through increasing ovarian granulosa cells proliferation, estradiol and FSH secretion, and GPx activity, whilst decreasing lipid peroxidation and oxidative stress, leading to inhibition of the apoptosis pathway through decreasing the expressions of caspase 3 and cytochrome c.