Expression, Functional Polymorphism, and Diagnostic Values of MIAT rs2331291 and H19 rs217727 Long Non-Coding RNAs in Cerebral Ischemic Stroke Egyptian Patients.

Cerebral ischemic stroke (CIS) is a severe cerebral vascular event. This research aimed to evaluate the role of single-nucleotide polymorphisms (SNPs) of the lncRNAs MIAT rs2331291 and H19 rs217727 and epigenetic methylation in the expression patterns of serum lncRNA H19 in CIS Egyptian patients. It included 80 CIS cases and 40 healthy subjects. Serum MIAT expression levels decreased, whereas serum H19 expression levels increased among CIS compared to controls. For MIAT rs2331291, there were significant differences in the genotypic and allelic frequencies between the CIS and healthy subjects at p = 0.02 and p = 0.0001, respectively. Our findings illustrated a significantly increased MIAT T/T genotype frequency in hypertensive CIS compared to non-hypertensive CIS at p = 0.004. However, H19 rs217727 gene frequency C/C was not significantly higher in non-hypertensive CIS than in hypertensive CIS. The methylation of the H19 gene promoter was significantly higher in CIS patients compared to healthy subjects. The level of MIAT was positively correlated with serum H19 in CIS. Receiver operating characteristics (ROC) analysis revealed that serum MIAT and H19 have a high diagnostic potential for distinguishing CIS subjects from healthy ones. In conclusion, the MIAT-rs2331291 polymorphism might serve as a novel potential indicator of CIS.

Canagliflozin alleviates experimentally induced benign prostate hyperplasia in a rat model: exploring potential mechanisms involving mir-128b/EGFR/EGF and JAK2/STAT3 signaling pathways through in silico and in vivo investigations.

Benign prostatic hyperplasia (BPH) poses a significant health concern amongst elderly males. Canagliflozin (Cana), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has a powerful anti-inflammatory influence. Nevertheless, its role in treating BPH has not been clarified. Therefore, the study aimed to investigate the potential ameliorative effect of Cana on experimentally induced BPH in rats and explore the underlying mechanisms compared to the standard finasteride (Fin). The study employed histological analysis, biochemical assays using ELISA, and western blotting. Animals were categorized into four groups: Control (2.5 ml/kg CMC, orally + 3 ml/kg olive oil, subcutaneous), BPH (3 mg/kg testosterone, subcutaneous + CMC orally), Fin-treated BPH (5 mg/kg, orally), and Cana-treated BPH (5 mg/kg, orally), for 28 days. The BPH group showed obvious BPH manifestations including an increase in prostate weight (PW), prostate index (PI), dihydrotestosterone (DHT) level, and histological aberrations compared to control. Fin and Cana therapy had a comparable impact. Cana treatment significantly reduced PW and PI, besides it improved prostatic biochemical, and histopathological features compared to BPH, consistent with in silico study findings. Cana was associated with downregulation of the androgen axis, increased miR-128b expression, with a lowered expression of epidermal growth factor (EGF) and its receptor. Phosphorylation of STAT3 and its downstream proliferative markers were significantly reduced suggesting apoptotic activity. Cana markedly rescued the BPH-induced upregulation of IL-1ß, and iNOS levels. Altogether, the current study demonstrates that Cana could impede BPH progression, possibly by modulating miR-128b/EGFR/EGF and JAK2/STAT3 pathways and downregulating AR, cyclin D1, and PCNA immunoreactivity.

Donepezil halts acetic acid-induced experimental colitis in rats and its associated cognitive impairment through regulating inflammatory/oxidative/apoptotic cascades: An add-on to its anti-dementia activity.

Ulcerative colitis (UC) is a persistent inflammatory bowel disease (IBD) that is regarded as a risk factor for cognitive impairment. Donepezil (DON), a centrally acting acetylcholinesterase inhibitor (AChEI), is approved for the management of Alzheimer's disease (AD). We aimed to scrutinize the impact of DON on acetic acid (AA)-induced UC in rats and to evaluate its ability to attenuate inflammatory response, oxidative strain, and apoptosis in this model and its associated cognitive deficits. Rats were categorized into: normal, DON, AA, and AA + DON groups. DON (5 mg/kg/day) was administered orally for 14 days either alone or beginning with the day of UC induction. Colitis was evoked by a single transrectal injection of 1 ml of 4 % acetic acid. Results revealed that DON significantly improved the behavioral abnormalities with the mitigation of inflammation, apoptosis, and histopathological changes in the hippocampi of the colitis group. Moreover, DON significantly alleviated the macroscopic and microscopic changes associated with colitis. Interestingly, DON inhibited pro-inflammatory cytokines via suppression of AA-induced activation of nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) in the colon, along with serum IL-1ß. DON inhibited colon lipid peroxidation, restored the antioxidants with a significant amelioration of the degree of neutrophil infiltration, and repressed colitis-induced matrix metalloproteinases-9 (MMP-9) production. Furthermore, DON decreased the Bax/Bcl-2 ratio and caspase-3 protein expressions. Eventually, in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells, DON suppressed nitric oxide (NO) release, demonstrating the ability of DON to significantly curtail inflammation in immune cells. Taken together, DON ameliorated experimental colitis and its linked cognitive dysfunction, possibly via its antioxidant effect and modulation of pro-inflammatory cytokines and apoptosis. Thereby, DON could be a therapeutic nominee for UC and associated neurological disorders.

Resveratrol mitigates diclofenac-induced hepatorenal toxicity in rats via modulation of miR-144/Nrf2/GSH axis.

Despite the extensive therapeutic uses of diclofenac, it may cause several adverse effects, including hepatorenal injury. The antioxidant and anti-inflammatory properties of resveratrol, a polyphenolic compound, make the agent effective in ameliorating a variety of drug-induced injuries. This study investigated the potential beneficial effects of resveratrol on diclofenac-induced hepatorenal toxicity and explored the role of miR-144 and its relationship to oxidative stress and inflammation triggered by diclofenac. Rats were divided into four groups: control; diclofenac group received diclofenac (10 mg/kg/day, intraperitoneal [ip]) for 7 days; prevention group received resveratrol concomitantly with diclofenac for 7 days; and the treatment group received diclofenac for 7 days followed by resveratrol (20 mg/kg/day, per oral) for another 7 days. Diclofenac administration induced a significant increase in serum hepatorenal biomarkers and histopathological aberrations. In addition, diclofenac upregulated miR-144 while reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels and glutathione (GSH) content. Moreover, diclofenac induced tissue inflammation and apoptosis as evidenced by increased protein expression of nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and caspase-3. Intriguingly, resveratrol prevention or treatment significantly mitigated the toxic effects of diclofenac as manifested by normalization of the hepatorenal functions and amelioration of the histopathological changes. Resveratrol also triggered miR-144 downregulation with Nrf2 upregulation. Consequently, resveratrol showed hepatorenal antioxidant, anti-inflammatory, and antiapoptotic activities as manifested by improvement in the antioxidant markers along with a decline in NF-κB, TNF-α, and caspase-3 expressions. In conclusion, this study demonstrates a potential therapeutic role of resveratrol in mitigating diclofenac-induced hepatorenal insult, possibly via modulating miR-144/Nrf2/GSH axis.

Immunomodulatory effect of diallyl sulfide on experimentally-induced benign prostate hyperplasia via the suppression of CD4+T/IL-17 and TGF-ß1/ERK pathways.

Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate common in older men. Diallyl sulfide (DAS), a major component of garlic, has been reported to possess antioxidant, anti-inflammatory, and antiproliferative effects. However, the underlying protective immunomodulatory mechanism of DAS on BPH remains vague. Herein, experimental BPH was induced in rats by daily subcutaneous injection of testosterone propionate (TP) (3 mg/kg, s.c.) for 4 weeks. In parallel, finasteride (Fin) (5 mg/kg, p.o) or DAS (50 mg/kg, p.o.) was administered orally during BPH induction. TP-induced histological alterations and the immune-inflammatory cascade. On the other hand, DAS or Fin administration alleviated all abnormalities induced testosterone. Fin and DAS administration markedly reduced prostate weight by 53% with Fin, and by 60% with DAS. Moreover, serum testosterone and DHT were reduced by 55% and 52%, respectively, with Fin and by 68% and 75%, respectively, with DAS, in concordance with decreased protein expression of androgen receptor (AR), and prostate-specific antigen (PSA). Furthermore, both regime lessen immune-inflammatory milieu, as evidenced by decrease CD4+ T-cells protein expression and associated inflammatory cytokines. Concomitantly, Fin and DAS exhibited marked mitigation in insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-ß1), and phosphorylated extracellular signal-regulated kinase (ERK1/2) signaling. Besides alleviating oxidative stress by 53% and 68% in prostatic MDA and by 27% and 7% in prostatic iNOS with Fin and DAS, respectively. In conclusion, this work highlighted a potential therapeutic approach of DAS as a dietary preventive agent against BPH via its anti-inflammatory and immunomodulatory effect along with suppression of the ERK pathway.

Aberrations of miR-126-3p, miR-181a and sirtuin1 network mediate Di-(2-ethylhexyl) phthalate-induced testicular damage in rats: The protective role of hesperidin.

Recently, oxidative stress was implicated in the environmental contaminant Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity, however the mechanism is unclear. We investigated the role of oxidative stress-responsive microRNAs in DEHP-induced aberrations and the protective effect of the citrus flavonoid, hesperidin (HSP). Male Wistar rats were randomly allocated into four groups as vehicle-treated control, DEHP-alone group (500 mg/kg/day) for 30 days, and HSP (25 or 50 mg/kg) for 60 days; testicular damage was triggered by oral administration of DEHP (500 mg/kg/day) after thirty days of oral administration of HSP (25 or 50 mg/kg). DEHP administration reduced testis weight coefficient, serum testosterone, testicular 3ß-hydroxysteroid dehydrogenase and antioxidant enzyme activities, and elevated serum fatty acid-binding protein-9, testicular malondialdehyde, and Bax/Bcl2 ratio. Aberrant testicular miR-126-3p and miR-181a expression was observed, along with decreased expression of sirtuin1 (SIRT1) and its targets; nuclear factor-erythroid 2-related factor2, haeme oxygenase-1, and superoxide dismutase2. HSP administration significantly ameliorated these changes and restored testicular function in a dose-dependent manner. We highlight a novel role of oxidative stress-miR-126/miR-181a-SIRT1 network in mediating DEHP-induced changes which were reversed by the antioxidant HSP.

Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/ß-catenin signalling pathways.

3-Nitropropionic acid (3-NP) induces a spectrum of Huntington's disease (HD)-like neuropathologies in the rat striatum. The present study aimed to demonstrate the neuroprotective effect of lercanidipine (LER) in rats with 3-NP-induced neurotoxicity, address the possible additional protective effect of combined treatment with bone marrow-derived mesenchymal stem cells (BM-MSCs) and LER, and investigate the possible involvement of the Ca2+/calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) and Wnt/ß-catenin signalling pathways. Rats were injected with 3-NP (10 mg/kg/day, i.p.) for two weeks and were divided into four subgroups; the first served as the control HD group, the second received a daily dose of LER (0.5 mg/kg, i.p.), the third received a single injection of BM-MSCs (1 x 106/rat, i.v.) and the last received a combination of both BM-MSCs and LER. The combined therapy improved motor and behaviour performance. Meanwhile, this treatment led to a marked reduction in striatal cytosolic Ca2+, CaN, tumour necrosis factor-alpha, and NFATc4 expression and the Bax/Bcl2 ratio. Combined therapy also increased striatal brain-derived neurotrophic factor, FOXP3, Wnt, and ß-catenin protein expression. Furthermore, haematoxylin-eosin and Nissl staining revealed an amelioration of striatum tissue injury with the combined treatment. In conclusion, the current study provides evidence for a neuroprotective effect of LER and/or BM-MSCs in 3-NP-induced neurotoxicity in rats. Interestingly, combined LER/BM-MSC therapy was superior to cell therapy alone in inhibiting 3-NP-induced neurological insults via modulation of the Ca2+/CaN/NFATc4 and Wnt/ß-catenin signalling pathways. LER/BM-MSC combined therapy may represent a feasible approach for improving the beneficial effects of stem cell therapy in HD.

Venlafaxine Mitigates Depressive-Like Behavior in Ovariectomized Rats by Activating the EPO/EPOR/JAK2 Signaling Pathway and Increasing the Serum Estradiol Level.

Reduced estradiol levels are associated with depression in women during the transition to and after menopause. A considerable number of studies focusing on the theme of treating depression through the activation of erythropoietin (EPO)-induced signaling pathways have been published. Venlafaxine is an approved antidepressant drug that inhibits both serotonin and norepinephrine transporters. The aim of the present study was to investigate the effects of venlafaxine on the depressive-like behaviors and serum estradiol levels in female rats following ovariectomy (OVX) and the possible roles of EPO-induced signaling pathways. Venlafaxine (10 mg/kg/day) was orally administered to OVX rats over a period of 4 weeks using two different treatment regimens: either starting 24 h or 2 weeks after OVX. Venlafaxine showed a superior efficacy in inducing antidepressant-like effects after an acute treatment (24 h post-OVX) than after the delayed treatment (2 weeks post-OVX) and was characterized by a decreased immobility time in the forced swimming test. In parallel, venlafaxine induced EPO and EPO receptor mRNA expression and increased levels of phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 5, and phospho-extracellular signal-regulated kinase 1/2 in the hippocampus of OVX rats. Meanwhile, rats exhibited a marked reduction in the hippocampal Bax/Bcl2 ratio, caspase-3 activity, and tumor necrosis factor alpha levels after venlafaxine treatment. Venlafaxine also increased the hippocampal brain-derived neurotrophic factor and serum estradiol levels. Based on these findings, venlafaxine exerts a neuroprotective effect on OVX rats that is at least partially attributed to the activation of EPO/EPOR/JAK2 signaling pathways, anti-apoptotic activities, anti-inflammatory activities, and neurotrophic activities, as well as an increase in serum estradiol level. Graphical Abstract ᅟ.

Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: A pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation.

Multiple sclerosis is a chronic inflammatory demyelinating central nervous system disorder leading to serious neurological deficits. Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently showed neuroprotective properties against neurodegenerative diseases. This study investigated the possible neuroprotective effect of linagliptin against cuprizone-induced demyelination in mice and its potential early-remyelinating properties. C57Bl/6 mice were fed chow containing 0.7% cuprizone for 1 week, followed by 3 weeks of a 0.2% cuprizone diet. Linagliptin (10 mg/kg/day, p.o.) was given for 3 weeks starting from the second week. Linagliptin treatment improved behavioural and motor abnormalities induced by cuprizone, as demonstrated by open field, rotarod and grip strength tests. In parallel, linagliptin lessened the demyelination through enhancing Olig2 gene expression, as shown by increased myelin basic protein, myelin proteolipid protein levels and Luxol fast blue-staining intensity. Linagliptin attenuated cuprizone-induced oxidative stress by decreasing brain thiobarbituric acid reactive substances along with restoring reduced glutathione levels. Linagliptin exerted an anti-inflammatory effect by reducing brain tumor necrosis factor-alpha. Interestingly, linagliptin diminished phosphorylated JAK2, phosphorylated STAT3 and NF-κB p65 protein expression while up-regulating phosphorylated AMP-activated protein kinase (p-AMPK) protein and SIRT1 gene expression levels. In conclusion, linagliptin exerted a neuroprotective effect in mice with cuprizone-induced demyelination possibly by modulating AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathways.

Association of rs6983267 at 8q24, HULC rs7763881 polymorphisms and serum lncRNAs CCAT2 and HULC with colorectal cancer in Egyptian patients.

The impact of HULC rs7763881 on colorectal cancer (CRC) susceptibility is not yet known. Also, the biological function of the cancer-related rs6983267 remains unclear. We investigated the association of these SNPs with the risk of CRC and adenomatous polyps (AP), their correlation with CCAT2 and HULC expression, and the potential of serum CCAT2 and HULC as biomarkers for CRC. 120 CRC patients, 30 AP patients, and 96 healthy controls were included. Genotyping and serum lncRNAs were assayed by qPCR. Studied SNPs were not associated with AP susceptibility. rs6983267 GG was associated with increased CRC risk, whereas rs7763881 AC was protective. rs7763881 and rs6983267 CT haplotype was protective. Serum CCAT2 and HULC were upregulated in CRC and AP patients versus controls and discriminated these groups by ROC analysis. rs6983267 GG and rs7763881 AA patients demonstrated higher serum CCAT2 and HULC compared with GT/TT and AC, respectively. rs6983267 and serum HULC predicted CRC diagnosis among non-CRC groups (AP + controls) by multivariate analysis. Studied SNPs or serum long noncoding RNAs weren't correlated with nodal or distant metastasis. In conclusion, rs6983267 and rs7763881 are potential genetic markers of CRC predisposition and correlate with serum CCAT2 and HULC, two novel potential non-invasive diagnostic biomarkers for CRC.

Could Caffeic Acid Phenethyl Ester Expand the Antitumor Effect of Tamoxifen in Breast Carcinoma?

Despite tamoxifen (TAM) is beneficial in treating a significant proportion of patients with breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis, with a plethora of important biological actions including anticancer activity. This study aimed to explore the cytotoxicity, the type of drugs interaction as well as the apoptotic and autophagic pathways of the combined treatment of TAM and CAPE in MCF-7 cells. Their antitumor activity and effect on survival of mice bearing Ehrlich tumor were also analyzed. The results showed synergistic cytotoxic effects, manifested by significant activation of apoptotic machinery, along with downregulation of protein levels of Bcl-2 and beclin-1, upon using the combination regimen. However, the ratio between microtubule-associated protein light chain 3-II and -I was not altered. Moreover, a decrease in vascular endothelial growth factor level was detected. Similarly, TAM + CAPE increased the life span of tumor-bearing animals and caused a marked regression in their tumor size and weight compared with those treated with either TAM or CAPE alone. In conclusion, CAPE relatively improved the anticancer activity of TAM in both in vitro and in vivo models via its apoptotic and angiostatic potentials.

Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells.

Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.