APOE genotype, eicosapentaenoic acid (EPA) supplementation and n-3 highly unsaturated fatty acid (HUFA) levels in patients with multiple colorectal polyps: A secondary analysis of the seAFOod polyp prevention trial.

INTRODUCTION: We examined the relationship between Apolipoprotein E (APOE) genotype and n-3 highly unsaturated fatty acid (HUFA) levels in participants of the seAFOod trial, who were undergoing colonoscopy surveillance after removal of colorectal polyps. METHODS: Baseline and on-treatment (eicosapentaenoic acid [EPA] 2 g daily or placebo for 6 months) levels of n-3 HUFAs, and plasma 18-hydroxyeicosapentaenoic acid (HEPE), were analysed according to APOE genotype (based on polymorphisms rs429358 and rs7412) in 584 participants. RESULTS: Before treatment, APOE2/2 individuals had lower levels, and APOE4/4 participants had higher levels, of n-3 HUFAs, including EPA, than APOE3/3 counterparts (P < 0.01 for the APOE2/2 versus APOE4/4 comparison). After EPA supplementation, n-3 HUFA levels were not significantly different when stratified by APOE genotype, although APOE4 carriers displayed lower plasma 18-HEPE levels than individuals without an APOE4 allele (P = 0.002). CONCLUSIONS: APOE genotype is associated with differential n-3 HUFA and 18-HEPE levels in individuals with multiple colorectal polyps.

Walnut Kernel Oil and Defatted Extracts Enhance Mesenchymal Stem Cell Stemness and Delay Senescence.

Decreased stemness and increased cellular senescence impair the ability of mesenchymal stem cells (MSCs) to renew themselves, change into different cell types, and contribute to regenerative medicine. There is an urgent need to discover new compounds that can boost MSCs' stemness and delay senescence. Therefore, this study aimed to investigate the impact of walnut kernel oil (WKO) and defatted (WKD) extracts on bone marrow (BM)-MSC stemness and senescence. Premature senescence and inflammation were induced in BM-MSCs using H2O2 and LPS, respectively. Phytochemical constituents of WKO and WKD extracts were detected by HPLC. The stemness (proliferation and migration), senescence-related markers (p53, p21, SIRT1, and AMPK), oxidative stress/antioxidant markers, inflammatory cytokines, and cell cycle of BM-MSCs were measured by MTT assay, qPCR, ELISA, and flow cytometry. WKO and WKD extracts improved rat BM-MSC stemness, as evidenced by (1) increased cell viability, (2) decreased apoptosis (low levels of Bax and caspase3 and high levels of Bcl2), (3) upregulated MMP9 and downregulated TIMP1 expression, and (4) cell cycle arrest in the G0/G1 phase and declined cell number in the S and G2/M phases. Additionally, WKO and WKD extracts reduced rat BM-MSC senescence, as indicated by (1) decreased p53 and p21 expression, (2) upregulated expression and levels of SIRT1 and AMPK, (3) reduced levels of ROS and improved antioxidant activity (higher activity of CAT, SOD, and GPx and upregulated expression of NrF2 and HO-1), and (4) declined levels of TNFα, IL1ß, and NF-κB. When compared to the WKO extract, the WKD extract had a greater impact on the induction of stemness and reduction of senescence of BM-MSCs due to its stronger antioxidant activity, which could be attributed to its higher levels of flavonoids and phenolic compounds, as detected by HPLC analysis. WKO and WKD extracts enhance rat BM-MSC stemness and protect them from senescence, suggesting their potential use as enhancers to increase MSCs' therapeutic efficacy.

Comparative effects of finasteride and laser-irradiated silver nanoparticles on testicular function and histology in testosterone induced benign prostatic hyperplasia in rats.

AIMS: The objective of this study was to compare the effects of finasteride, a medication used to treat benign prostatic hyperplasia (BPH), and laser irradiated silver nanoparticles (AgNPs), a potential candidate for BPH therapy (Sanchez-Salas, 2017; Marghani et al., 2022) [1,2], on the sex hormone profiles, sperm quality, steroidogenesis, testicular oxidative stress, and histomorphology changes in BPH rats. MATERIALS AND METHODS: BPH was induced in male Sprague-Dawley (SD) rats via intramuscular (i.m.) injection of 5 mg/kg BW testosterone propionate (TP) for 14 days. Once the BPH model was induced, rats were divided into four groups (n = 6) as follows: the control group; the BPH group; the BPH/Fina group, which received 5 mg/kg BW finasteride by oral gavage daily for 14 days; and the BPH/AgNPs group, which received a daily intraperitoneal (i.p.) injection of 50 mg/kg BW AgNPs, followed by 5min of exposure to a 532 nm NIR laser in the prostatic area for the constitutive 14 days. KEY FINDINGS: On day 14, the BPH rats had a significant increase in prostate specific antigen (PSA), dihydrotestosterone, and prostate weights, while testicular weights and sperm quality were significantly lower than in the control rats. On day 28, laser irradiated AgNps treated BPH rats showed improved sex hormone balance, testicular weights, sperm quality, steroidogenesis, and an ameliorative effect on testicular histopathology compared to finasteride. SIGNIFICANCE: Surprisingly, these findings suggest that laser irradiated AgNPs can be used as an alternative therapy to finasteride for the treatment of BPH without causing negative effects on the testes.

The combined effect of zinc oxide nanoparticles and milrinone on acute renal ischemia/reperfusion injury in rats: Potential underlying mechanisms.

AIM: To investigate the efficacy of zinc oxide nanoparticles (ZnO-NPs) and/or milrinone (MIL) on renal ischemia/reperfusion injury (I/RI) in rats and their possible underlying mechanisms. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley albino rats were randomly assigned into six equal-sized groups (n = 8): normal control, sham-operated, I/R group (45 min/24 h), ZnO-NPs group (10 mg/kg i.p.), MIL group (0.5 mg/kg i.p.), and ZnO-NPs + MIL group in the same previous doses. KEY FINDINGS: In comparison to the I/R-operated group, administration of either ZnO-NPs or MIL significantly decreased serum creatinine and urea concentrations, and renal vascular permeability (p < 0.05). The oxidative stress was significantly declined, as evidenced by increased GPx, CAT, and SOD activities and decreased MDA and NO concentrations. Renal expressions of TNF-α, NF-κB, KIM-1, NGAL, and caspase-3 decreased significantly, while Nrf2 increased significantly. Histopathology investigation revealed improvement with minimal renal lesions and fibrosis after ZnO-NPs or MIL treatments. The combined treatments synergistically improved the studied parameters more than either treatment alone. These findings were validated by molecular modeling, which revealed that MIL inhibited TNF-α, NF-kB, caspase-3, KIM-1 and NGAL. SIGNIFICANCE: Both ZnO-NPs and MIL exerted cytoprotective effects against acute renal I/RI, and a combination of both was found to be even more effective. This renoprotective effect is suggested to be mediated through activation of Nrf2 and the prevention of the NF-κB activation-induced oxidative stress and inflammation, which may strengthen the potential role of ZnO-NPs or MIL in renal I/RI protection during surgical procedures.

Thiamethoxam evoked neural oxido-inflammatory stress in male rats through modulation of Nrf2/NF-kB/iNOS signaling and inflammatory cytokines: Neuroprotective effect of Silymarin.

Thiamethoxam (TMX), a neonicotinoid insecticide, is a widely used insecticide with neurotoxic potential. Silymarin (SM), a milk thistle-derived flavonoid, is known with its promising biological activities. This study explored the neuroprotective effects of SM against TMX-triggered cortical injury in male rats. Animals were divided into four groups and treated daily either with SM (150 mg/kg), TMX (78.15 mg/kg), or both at the aforementioned doses for 28 days. Our results revealed marked declines in cortical SOD and CAT activities with elevations in MDA, IL-1b and TNF-α levels in TMX-treated rats. Further, TMX induced down-regulation in the gene expressions of Sod, Cat, Gpx, and Nrf-2, with up-regulation in the gene expressions of IL-1b, IL-6, iNOS, TNF-α and NF-kB. Interestingly, pre-treatment with SM provided a notable neuroprotective action against TMX-mediated cortical damage that indicates its promising antioxidant and anti-inflammatory activities. This effect may be mediated by Nrf2/NF-kB/iNOS signalling and suppression of excess free radicals and production of inflammatory cytokines. In brief, SM could be a promising therapeutic agent against TMX-mediated neural complication via its antioxidant and anti-inflammatory properties. PRACTICAL APPLICATIONS: The using of neonicotinoids as thiamethoxam is recently increased and is associated with brain damage. TMX induced excessive oxidative and inflammatory damage. Therefore, new therapeutic approaches are needed to counteract its adverse effects on the nervous system. SM, a flavonoid, is extracted from the seeds and fruits of milk thistle. Due to its potent antioxidative activity, SM have been applied to mitigate the oxidative stress as well as inflammatory disorders. Herein, we examined the potential therapeutic role of SM against TMX-induced brain oxidative stress and inflammation in rats through evaluating oxidative markers, inflammatory response, and histopathological changes in the brain cortical tissue.

Photothermal therapeutic potency of plasmonic silver nanoparticles for apoptosis and anti-angiogenesis in testosterone induced benign prostate hyperplasia in rats.

AIMS: In this study, we used a near-infrared laser (NIR) to increase the potency of silver nanoparticles (AgNPs) to develop a novel, less invasive, and simple photothermal therapy technique for benign prostate hyperplasia (BPH). MATERIALS AND METHODS: The shape, particle size, and zeta-potential of polyvinylpyrrolidone coated-AgNPs (PVP-AgNPs) were determined using transmission electron microscopy (TEM), Zeta-potential, and Particle size analyzer (ELSZ). To induce BPH, thirty-six male Sprague-Dawley (SD) rats were given intramuscular (i.m) injections of testosterone propionate (TP) at 5 mg/kg body weight (b.w)/day suspended in 0.1 ml of olive oil for 14 days. Photothermal therapy with AgNPs-NIR for 14 days was carried out. Prostate size, prostate index (PI), dihydrotestosterone (DHT), prostate-specific antigen (PSA), gross, hepatic, and renal toxicity, as well as antioxidant activity, apoptosis, and angiogenesis markers in prostatic tissues were measured. Histological examinations of prostates and biocompatibility of NIR-AgNPs on vital organs were also performed. KEY FINDINGS: The aggregated spherical AgNPs with a mean size of 50-90 nm and a Zeta potential of -53.22 mV displayed high effectiveness in the NIR (532 nm-1 W) region by decreasing prostate size, PI, DHT, and PSA in BPH rats with no signs of gross, hepatic, or renal damage. As compared to alternative therapies, hyperthermia therapy increased antioxidant activities, induced apoptosis, inhibited angiogenesis, reduced histological alterations in the prostates of BPH rats, and improved biocompatibility of the vital organs. SIGNIFICANCE: The current study demonstrated the effectiveness of plasmonic AgNPs photothermal therapy in the treatment of BPH.

Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies.

Triple-negative breast cancers (TNBCs) comprise 10-15% of all breast cancers but with more resistance affinity against chemotherapeutics. Although doxorubicin (DOX) is the recommended first choice, it has observed cardiotoxicity together with apparent drug resistance. The anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition. In this study, we carried out molecular docking studies which revealed the potential blocking of the calmodulin receptor by EMP through its binding with similar crucial amino acids compared to its cocrystallized inhibitor (AAA) as a proposed mechanism of action. Moreover, combination of DOX with EMP showed a slightly lower cytotoxic activity against the MDA-MB-231 cell line (IC50 = 1.700 ± 0.121) compared to DOX alone (IC50 = 1.230 ± 0.131), but it achieved a more characteristic arrest in the growth of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in comparison to the control as determined by cell cycle analysis, and at the same time reached an increase in the total apoptosis percentage from 27.05- to 29.22-fold, compared to DOX alone as indicated by Annexin V-FITC apoptosis assay. Briefly, the aforementioned in vitro studies in addition to PCR of pro- and antiapoptotic genes (mTOR, p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of EMP combination with DOX which can reduce the required therapeutic dose of DOX in TNBC and eventually will decrease its toxic side effects (especially cardiotoxicity), along with decreasing the chemoresistance of TNBC cells to DOX treatment.

Intestinal gene expressions in broiler chickens infected with Escherichia coli and dietary supplemented with probiotic, acidifier and synbiotic.

In this study, we investigated the effects of probiotic, acidifier and synbiotic supplementation on growth performance, mortality rate, intestinal gene expressions, fecal shedding, and organs colonization induced by Escherichia coli in broiler chickens. Six experimental groups were included; negative control group (NC), positive control group (PC), probiotic group (PR), acidifier group (AC), synbiotic group (SY) and colistin sulfate group (CS). Chickens in groups NC and PC were fed a basal diet, while chickens in groups PR, AC, SY, and CS were fed a basal diet containing probiotic, acidifier, synbiotic and colistin sulfate, respectively from the 1st day to the 28th day of age. At 7 days of age, all groups (not NC) were orally challenged with 0.5 ml (1.0 × 109 CFU/ml) E. coli O78. The dietary supplementation of acidifier and synbiotic were sufficient to quell the devastating effects of E. coli infection in broilers. Growth performances represented by body weight gain, feed intake and feed conversion ratio were significantly improved as well as, mortalities were prevented whilst the ileal pro-inflammatory gene expressions (IL-6, IL-8, IL-13, TLR-4, IFN-γ, LITAF, AvBD-2, and AvBD-9) were significantly downregulated and the anti-inflammatory cytokine (IL-10) was significantly increased. In addition, E. coli fecal shedding and organs colonization was significantly diminished. It was concluded that the addition of both acidifier and synbiotic to the diet of broilers infected with E. coli could modulate the intestinal inflammatory responses induced by E. coli infection and minimized the inflammation-induced damage which resulted in improvement in growth performance, prevention of mortalities and reduction of E. coli environmental contamination.

Biochemical and histopathological changes of subacute cadmium intoxication in male rats.

Biochemical and histopathological effects of subacute intoxication of rats with cadmium (Cd) were studied in rats. Twenty adult healthy male albino rats were randomly divided into two duplicate groups (five rats in each cage); (1) control group where rats were provided with standard diet and water ad-libitum, (2) Cd group where rats were subjected to freshly prepared Cd chloride solution (CdCl2) 200 mg/l in drinking water daily for 8 weeks, the whole duration of experiment. Blood samples were obtained after 4 weeks, via retro-orbital bleeding for separation of serum. Five rats were killed, each sacrifice by decapitation for collection of kidneys and heart. Disturbed renal and cardiac functions were achieved after 4 weeks as indicated by the increase of most biochemical parameters measured in the serum, renal, and cardiac tissues. Histopathological examination of kidneys and hearts showed pathological alterations in Cd-intoxicated rats after 4 and 8 weeks with hematoxylin and eosin (H&E) and Masson trichrome stains. It was concluded that subacute exposure of rats to Cd (200 mg/l) in drinking water daily induced glomerular shrinkage, focal renal, and cardiac fibrosis at 4 and 8 weeks.

Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression.

Antioxidants have valuable effects on the process of spermatogenesis, particularly with diabetes mellitus (DM). Therefore, the present study investigated the impact and the intracellular mechanisms by which thymoquinone (TQ) works against diabetes-induced testicular deteriorations in rats. Wistar male rats (n = 60) were randomly allocated into four groups; Control, Diabetic (streptozotocin (STZ)-treated rats where diabetes was induced by intraperitoneal injection of STZ, 65 mg/kg), Diabetic + TQ (diabetic rats treated with TQ (50 mg/kg) orally once daily), and TQ (non-diabetic rats treated with TQ) for 12 weeks. Results revealed that TQ significantly improved the sperm parameters with a reduction in nitric oxide (NO) and malondialdehyde (MDA) levels in testicular tissue. Also, it increased testicular reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity. Interestingly, TQ induced downregulation of testicular inducible nitric oxide synthase (iNOS) and nuclear factor kappa-B (NF-κB) and significantly upregulated the aromatase protein expression levels in testicles in comparison with the diabetic rats. In conclusion, TQ treatment exerted a protective effect against reproductive dysfunction induced by diabetes not only through its powerful antioxidant and hypoglycemic effects but also through its downregulation of testicular iNOS and NF-κB along with upregulation of aromatase expression levels in diabetic rats.

Is extended-field concurrent chemoradiation an option for radiologic negative paraaortic lymph node, locally advanced cervical cancer?

BACKGROUND: The aim was to evaluate whether extended-field concurrent chemoradiation (EF-CCRT) leads to results better than those obtained by standard whole-pelvis concurrent chemoradiation (WP-CCRT) in locally advanced cervical cancer with radiologic negative paraaortic lymph nodes (PALNs). PATIENTS AND METHODS: A total of 102 patients with histopathologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma, and radiologic negative PALN locally advanced cervical cancer, stage IIB-IVA, were accrued between July 2007 and April 2008 and were randomly assigned to WP-CCRT (50 patients) or EF-CCRT (52 patients), followed by high-dose rate brachytherapy. Data regarding the safety profile, response rates, and occurrence of local, PALN, or distant failure were recorded. RESULTS: During a median follow-up time of 60 months (18-66), 74/102 patients completed the treatment protocol and were analyzed. Overall PALN, distant-metastasis control, disease-free survival, and overall survival rates were 97.1%, 86.9%, 80.3%, and 72.4% in EF-CCRT respectively in comparison with WP-CCRT (82.1%,74.7%, 69.1%, and 60.4%), with P-values of 0.02, 0.03, 0.03 and 0.04 respectively. No difference in acute toxicity profile was seen between the groups, and late toxicities were mild and minimal. CONCLUSION: Prophylactic EF-CCRT can be a reasonable option in patients with locally advanced cervical cancer with radiologic positive pelvic lymph nodes and radiologic negative PALN.

Obstructive small bowel metastasis from uterine leiomyosarcoma: a case report.

Background. Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy with an overall poor prognosis. Lungs, bones, and brain are common sites of metastases of uterine leiomyosarcoma. Metastases of uterine leiomyosarcoma to the small bowel are extremely rare, and only four case reports have been published to date. Case presentation. A 55-year-old Saudi woman diagnosed with a case of uterine leiomyosarcoma treated with total abdominal hysterectomy (TAH) and bilateral salpingooophorectomy (BSO) presented in emergency room after sixteen months with acute abdomen. Subsequent work-up showed a jejunal mass for which resection and end-to-end anastomosis were performed. Biopsy confirmed the diagnosis of small bowel metastasis from uterine leiomyosarcoma. Further staging work-up showed wide spread metastasis in lungs and brain. After palliative cranial irradiation, systemic chemotherapy based on single agent doxorubicin was started. Conclusion. Metastatic leiomyosarcoma of small bowel from uterine leiomyosarcoma is a rare entity and is sign of advanced disease. It should be differentiated from primary leiomyosarcoma of small bowel as both are treated with different systemic chemotherapeutic agents.