Association of long noncoding RNA H19 rs2839698 C/T with hepatitis B virus infection and hepatocellular carcinoma risk.

The intricate pathogenesis of the hepatitis B virus (HBV) and its progression to hepatocellular carcinoma (HCC) have not yet been fully elucidated. H19 is one of the earliest imprinted long noncoding RNAs (lncRNAs) associated with liver pathobiology. This study investigated the association of H19 single nucleotide polymorphisms (SNPs) rs2839698 C/T and rs217727 C/T with HBV and HBV-related HCC and their correlation with H19 expression level. A total of 230 subjects were enrolled in this study including 100 HBV-infected patients, 30 HBV-related HCC patients, and 100 apparently healthy controls. TaqMan genotyping human assays were utilized to assess allelic discrimination for H19 SNPs. H19 expression was assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Our findings showed that H19 rs2839698 was linked to a higher incidence of HBV infection and HBV-related HCC. Individuals who bear the CT genotype of rs2839698 were more susceptible to HBV infection (OR = 3.05; 95% CI 1.714-5.457; p < 0.001). Those harboring the TT genotype were more prone to develop HCC (OR = 2.625; 95% CI 1.037-6.64; p = 0.038). Our data revealed that rs2839698 could function as a promising predictor of HCC risk. Furthermore, H19 was significantly downregulated in HBV (p < 0.01) and HCC (p < 0.01) patients versus the control group. Significant upregulation of H19 in HCC patients with cirrhosis (p < 0.001) was detected. Altogether, this is considered the first prospective case-control study to address the implication of the genetic variations of H19 SNPs in HBV and HBV-related HCC in Egyptian patients.

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.

Diagnostic and prognostic value of the RUNXOR/RUNX1 axis in multiple sclerosis.

The runt-related transcription factor-1 (RUNX1) gene with its lncRNA RUNXOR are recently becoming a research focus in various diseases, specifically immune-related diseases as they are implicated in multiple pathways. Interestingly, their role in multiple sclerosis (MS) remains unstudied. The present study explored the role of RUNXOR/RUNX1 in the development and progression of MS and investigated their possible mechanism of action. We measured the serum expression levels of lncRNA RUNXOR, as well as RUNX1, microtubule associated protein 2 (MAP2), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNAs in 30 healthy controls and 120 MS patients subdivided into 4 groups: 30 clinically isolated syndrome patients, 30 relapsing-remitting MS (RRMS) patients in relapse, 30 RRMS patients in remission and 30 secondary progressive MS patients. Additionally, we measured the serum protein levels of RUNX1, MAP2, NGF, BDNF and interleukin-10 (IL-10). All measured RNA expression levels were markedly downregulated and, consequently, the protein levels of RUNX1, MAP2, NGF, BDNF and IL-10 were significantly decreased in MS patients compared to healthy controls. Moreover, the levels of the measured parameters varied significantly within the MS groups. According to receiver-operating-characteristic (ROC) curve and logistic regression analyses, lncRNA RUNXOR, RUNX1 mRNA and its protein levels were predictors of disease progression, in addition to RUNX1 mRNA exhibiting a diagnostic potential. Altogether, this study suggests the implication of the RUNXOR-RUNX1 axis in MS development, progression, and increased MS-related disability, and highlights the potential utility of the studied parameters as promising diagnostic/prognostic biomarkers for MS.

Potential therapeutic effects of antagonizing adenosine A2A receptor, curcumin and niacin in rotenone-induced Parkinson's disease mice model.

Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.

Impact of betanin against paracetamol and diclofenac induced hepato-renal damage in rats.

Context: Paracetamol (PAR) and diclofenac (DF) are the most popular consumed analgesics and anti-inflammatory medications.Objective: This study aimed to explore the protective effect of betanin (Bet) against PAR or DF induced hepato-renal damage in rats.Methods: Rats were randomly divided into five groups: Normal control (NC) group rats were given saline only. PAR group rats received PAR (400 mg/kg). PAR/Bet treated group rats administered PAR (400 mg/kg) plus Bet (25 mg/kg). DF group rats received DF (10 mg/kg). DF/Bet treated group rats administered DF (10 mg/kg) plus Bet (25 mg/kg). All drugs were given by gavage for 28 consecutive days.Results: PAR and DF administration in high dose and long-time induced liver and kidney injury, disrupted serum lipid profile, enhanced serum levels of inflammatory and oxidative stress markers, triggered DNA fragmentation and caused drastic changes in the histopathological pictures of the two organs. Bet supplementation succeeded to ameliorate most of the biochemical changes and protected DNA from damage as obtained from comet assay. Histological features in H&E taken to different groups also mirrors this findings.Conclusion: Bet exerted a potential anti-inflammatory and antioxidant effect against hepato-renal damage induced by PAR or DF overconsumption.

Protective effects of betanin against paracetamol and diclofenac induced neurotoxicity and endocrine disruption in rats.

Context: Overconsumption of paracetamol (PAR) and diclofenac (DF) have been reported to induce neurotoxicity and endocrine disruption. Objective: The current study was designed to explore the protective potential of betanin against PAR and DF inducing neurotoxicity and endocrine disruption in a rat model. Material and Methods: Forty rats were equally divided into five groups: group I served as control, group II received PAR (400 mg/kg), group III received PAR plus betanin (25 mg/kg), group IV received DF (10 mg/kg) and group V received DF plus betanin orally for 28 consecutive days. Thyroid axis hormones, sex hormone, neurotransmitters, paraoxonase-1, hemeoxygenase-1 and nuclear factor-2 were measured by ELISA. While, the oxidative stress markers were colorimetrically estimated. Moreover, DNA damage and histopathological picture of the brains were investigated. Results: A marked reduction in thyroid axis hormones, brain neurotransmitters and serum testosterone as well as enhanced oxidative stress and brain DNA damage accompanied by drastic changes in the brain histopathological picture were recorded in the challenged PAR and DF groups. Betanin supplementation ameliorated most of the biochemical and histopathological changes induced by PAR or DF. Conclusion: The study suggests betanin of potential protective effects against neurotoxicity and endocrine disruption induced by PAR and DF overconsumption.

Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model.

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.

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.

RNA methylation machinery and m6A target genes as circulating biomarkers of ulcerative colitis and Crohn's disease: Correlation with disease activity, location, and inflammatory cytokines.

Accurate diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), the main subtypes of inflammatory bowel disease (IBD), has been challenging due to the constraints of the current techniques. N6-methyl adenosine (m6A) regulators have evolved as key players in IBD pathogenesis; however, their relation to its clinical setting is largely unexplored. This study investigated the potential of selected RNA methylation machinery and m6A target genes as serum biomarkers of UC and CD, their predictive and discriminating capabilities, and their correlations with laboratory data, interleukin (IL)-6, interferon-γ, disease activity scores, and pathological features. Fifty UC and 45 CD patients, along with 30 healthy volunteers were enlisted. The mRNA expression levels of the m6A writers methyltransferase-like 3 (METTL3) and Wilms-tumor associated protein (WTAP), and the reader YTH domain family, member 1 (YTHDF1), along with the m6A candidate genes sex determining region Y-box 2 (SOX2), hexokinase 2 (HK2), and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) were upregulated in UC patients, whereas only METTL3, HK2, and UBE2L3 were upregulated in CD patients versus controls. Serum WTAP (AUC = 0.94, 95 %CI = 0.874-1.006) and HK2 (AUC = 0.911, 95 %CI = 0.843-0.980) expression levels showed excellent diagnostic accuracy for UC, METTL3 showed excellent diagnostic accuracy for CD (AUC = 0.91, 95 %CI = 0.828-0.992), meanwhile, WTAP showed excellent discriminative power between the two diseases (AUC = 0.91, 95 %CI = 0.849-0.979). Multivariate logistic analysis unveiled the association of METTL3 and UBE2L3 expression with the risk of CD and UC diagnosis, respectively, controlled by age and sex as confounders. Remarkable correlations were recorded between the gene expression of studied m6A regulators and targets in both diseases. Among UC patients, serum METTL3 and WTAP were correlated with UC extent/type, while WTAP was correlated with IL-6. Among CD patients, serum METTL3 and HK2 were correlated with CD activity index (CDAI) and CD location. In conclusion, m6A regulators and target genes are distinctly expressed in UC and CD clinical samples, correlate with disease activity and extent/location, and could serve as a novel approach to empower the diagnosis and stratification of IBD subtypes.

Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats.

Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor-ß1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs.

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson's Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy.

Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1ß levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.

Modulation of p38 MAPK and Nrf2/HO-1/NLRP3 inflammasome signaling and pyroptosis outline the anti-neuroinflammatory and remyelinating characters of Clemastine in EAE rat model.

There is vast evidence for the effect of NOD-like receptor protein-3 (NLRP3) inflammasome on multiple sclerosis (MS) pathogenesis. Clemastine (CLM) targets NLRP3 in hypoxic brain injury and promotes oligodendrocyte differentiation. However, no previous study pointed to the link of CLM with inflammasome components in MS. Herein, the study aimed to verify the action of CLM on NLRP3 signaling in experimental autoimmune encephalomyelitis (EAE) as an MS rat model. Homogenate of spinal cord with complete Freund's adjuvant was administered on days 0 and 7 to induce EAE. Rats received either CLM (5 mg/kg/day; p.o.) or MCC950 (2.5 mg/kg/day; i.p) for 15 days starting from the first immunization day. In EAEs' brains, NLRP3 pathway components; total and phosphorylated p38 mitogen-activated protein kinase (MAPK), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukins 1ß and -18 along with pyroptotic marker; gasdermin D (GSDMD) were upregulated. These were accompanied with diminished nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and total antioxidant capacity levels. CLM improved these perturbations as well as signs of MS; weight loss, clinical scores, and motor disorders observed in the open field, hanging wire and rotarod tests. Histopathological examinations revealed improvement in H&E abnormalities and axonal demyelination as shown by luxol fast blue stain in lumbar sections of spinal cord. These CLM's actions were studied in comparison to MCC950 as a well-established selective blocker of the NLRP3 inflammasome. Conclusively, CLM has a protective role against neuroinflammation and demyelination in EAE via its anti-inflammatory and anti-pyroptotic actions.

Protective and therapeutic effects of Argyreia speciosa against ethanol-induced gastric ulcer in rats.

The protective and therapeutic effects of Argyreia speciosa Sweet (Convolvulaceae) against ethanol-induced gastric ulcer in rats were evaluated. Ethanolic and water extracts of the aerial plant parts (200 mg/kg body weight) were orally administered daily for seven days prior to or after ulceration with one oral dose of 1 mL absolute ethanol on 24-h empty stomachs. Rats were divided into eleven groups. Group 1 served as control. To groups 2 and 3 each extract was administered. Groups 4 to 6 received each extract or ranitidine (100 mg/kg body weight) prior to ulcer induction. Groups 7 to 9 received each extract or ranitidine post ulcer induction. Groups 10 and 11 were gastric ulcerative rats after one hour and one week of ethanol induction. The evaluation was done through measuring ulcer indices: stomach acidity and volume, lesion counts, mucus, and prostaglandin E2 contents. Oxidative stress marker, i. e. malondialdehyde, glutathione, and superoxide dismutase, were estimated. Certain marker enzymes for different cell organelles, i. e. succinate and lactate dehydrogenases, glucose-6-phosphatase, acid phosphatase, and 5'-nucleotidase, were evaluated. The work was extended to determine the collagen content and the histopathological assessment of the stomach. Gastric ulcer exhibited a significant elevation of the ulcer index, antioxidant levels, collagen content, and the marker enzymes. The water extract attenuated these increments and was more potent as a protective agent, while the ethanol extract exhibited stronger therapeutic potency. In conclusion, A. speciosa acted as antiulcer agent. More detailed studies are required to identify the compounds responsible for the pharmacological effect.

Empagliflozin alleviates endoplasmic reticulum stress and augments autophagy in rotenone-induced Parkinson's disease in rats: Targeting the GRP78/PERK/eIF2α/CHOP pathway and miR-211-5p.

Empagliflozin, a selective sodium-glucose co-transporter-2 inhibitor, has been demonstrated to provide additional non-glycemic benefits, including neuroprotection. Endoplasmic reticulum (ER) stress is a key player in neurodegeneration and occurs at the crossroads of other pathologic mechanisms; however, its role in the pathogenesis of Parkinson's disease (PD) is still elusive. miR-211-5p regulates neuronal differentiation and viability and was predicted to target CHOP, a downstream effector in the ER stress pathway. For the first time, this study investigated the possible neuroprotective effect of empagliflozin in a rotenone-induced rat model of PD from the perspective of ER stress. Rotenone (1.5 mg/kg) was administered subcutaneously every other day for 3 weeks. Meanwhile, the treated group received empagliflozin 10 mg/kg/day orally for 15 consecutive days post-PD induction. On the molecular level, the ER stress pathway components; GRP78, total and phosphorylated PERK, eIF2α and CHOP, along with miR-211-5p expression were upregulated in the striatum of rotenone-injected rats. Concurrently, the untreated rats showed elevated striatal α-synuclein levels along with diminished autophagy and the proteasome system as evidenced by reduced beclin-1 protein and ELF2/NERF mRNA expression levels. The rotenone-induced striatal oxidative stress and neuroinflammation were expressed by reduced catalase activity and elevated interleukin (IL)-1ß levels. miR-211-5p was positively correlated with PERK/eIF2α/CHOP, IL-1ß and α-synuclein, while negatively correlated with ELF2/NERF, beclin-1 and catalase activity. Empagliflozin treatment showed a restorative effect on all biochemical alterations and improved the motor function of rats tested by open field, grip strength and footprint gait analysis. In the histopathological examination, empagliflozin increased the intact neuron count and attenuated astrogliosis and microgliosis by reducing the glial fibrillary acidic protein and ionized calcium-binding adaptor protein 1 immunostaining. Conclusively, these results emphasize the neurotherapeutic impact of empagliflozin in PD by moderating the GRP78/PERK/eIF2α/CHOP ER stress pathway, downregulating miR-211-5p, resolving oxidative stress, lessening astrocyte/microglial activation and neuroinflammation, along with augmenting autophagy.

Cromolyn chitosan nanoparticles reverse the DNA methylation of RASSF1A and p16 genes and mitigate DNMT1 and METTL3 expression in breast cancer cell line and tumor xenograft model in mice.

BACKGROUND: Developing epigenetic drugs for breast cancer (BC) remains a novel therapeutic approach. Cromolyn is a mast cell stabilizer emerging as an anticancer drug; its encapsulation in chitosan nanoparticles (CSNPs) improves its effect and bioavailability. However, its effect on DNA and RNA methylation machineries has not been previously tackled. METHODS: The possible anticancer effect of cromolyn CSNPs and its potential as an epigenetic drug was investigated in vitro using MCF-7 human BC cell line and in vivo using Ehrlich ascites carcinoma-xenograft model in mice symbolizing murine mammary adenocarcinoma. Mice were injected with a single dose of Ehrlich ascites carcinoma cells subcutaneously for the induction of tumor mass, and then randomized into three groups: control, cromolyn CSNPs (equivalent to 5 mg cromolyn/kg, i.p.) and plain CSNPs twice/week for 2 weeks. RESULTS: Cromolyn CSNPs showed prominent anticancer effect in MCF-7 cells by reducing the cell viability percent and enhancing DNA damage in the comet assay demonstrating its apoptotic actions. Mechanistically, cromolyn CSNPs influenced potential epigenetic processes through mitigating DNA methyltransferase 1 (DNMT1) expression, reversing the hypermethylation pattern of the tumor suppressor RASSF1A and p16 genes and attenuating the expression of the RNA N6-methyladenosine writer, methyltransferase-like 3 (METTL3). Cromolyn CSNPs diminished ERK1/2 phosphorylation, a possible arm influencing DNMT1 expression. In vivo, cromolyn CSNPs lessened the tumor volume and halted DNMT1 and METTL3 expression in Ehrlich carcinoma mice. CONCLUSIONS: Cromolyn CSNPs have the premise as an epigenetic drug through inhibiting ERK1/2 phosphorylation/DNMT1/DNA methylation and possibly impacting the RNA methylation machinery via mitigating METTL3 expression.

Effects of caffeic acid phenethyl ester on endotoxin-induced cardiac stress in rats: a possible mechanism of protection.

Endotoxins (lipopolysaccharides; LPS) are known to cause multiple organ failure, including myocardial dysfunction. The present study aimed to investigate the mechanism of caffeic acid phenethyl ester (CAPE) protection against LPS-induced cardiac stress. Rats were allocated into three groups; group 1 served as a normal control group, group 2 (LPS) received a single intraperitoneal injection of LPS (10 mg/kg), group 3 (LPS + CAPE) was injected intraperitoneally with CAPE (10 mg/kg/day; solubilized in saline containing 20% tween 20) throughout a period of 10 days prior to LPS injection. Rats were maintained 4 h before sacrifice. Caffeic acid phenethyl ester pretreatment normalized LPS-enhanced activities of serum creatine kinase (CK) and lactate dehydrogenase (LDH) as well as glutathione peroxidase (GPx), and myeloperoxidase (MPO) in cardiac tissue. A significant reduction of the elevated levels of serum tumor necrosis factor-alpha (TNF-α) as well as serum and cardiac nitrite/nitrate (NOx) ) was achieved after CAPE pretreatment. CAPE also restored malondialdelyde (MDA), reduced glutathione (GSH), and cytosolic calcium (Ca2+ ) levels in the heart. A marked induction of cardiac heme oxygenase-1 (HO-1) protein level was detected in CAPE-pretreated group. Whereas, LPS-induced reduction of adenosine triphosphate (ATP) and phosphocreatine (PCr) levels was insignificantly changed. Conclusively, the early treatment with CAPE maintained antioxidant defences, reduced oxidative injury, cytokine damage, and inflammation but did not markedly improve energy status in cardiac tissue. The beneficial effect of CAPE might be mediated, at least in part, by the superinduction of HO-1.

The relative efficacy of aminoguanidine and pentoxifylline in modulating endotoxin-induced cardiac stress.

This study investigates the effect of aminoguanidine (AG), a selective inducible nitric oxide synthase (iNOS) inhibitor, and pentoxifylline (PTX), a tumour necrosis factor-alpha (TNF-α) inhibitor, on lipopolysaccharide (LPS)-induced cardiac stress. Rats were divided into four groups: group I served as a control, group II (LPS) received a single intraperitoneal injection of LPS (10 mg·kg(-1) ), group III (LPS+AG) and group IV (LPS+PTX) were injected with either AG (100 mg·kg(-1) ) or PTX (150 mg·kg(-1) ) intraperitoneally 10 days prior to LPS administration. Normalization of cardiac levels of nitrite/nitrate (NO(X) ), malondialdehyde (MDA), glutathione (GSH), heme oxygenase-1 (HO-1), glutathione peroxidase (GPx) and Na(+) , K(+) -ATPase activities was evident in the AG group. Both AG and PTX decreased the elevated serum TNF-α levels, the activities of lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac myeloperoxidase (MPO). The levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and phosphocreatine (PCr) were enhanced following AG and PTX pretreatments. Calcium (Ca(2+) ) levels were altered, and the histopathological observations supported the described results. Conclusively, the study highlights the cardioprotective potential of AG and PTX with superior results from AG. These findings reveal the relative contribution of nitric oxide and TNF-α to oxidative stress and energy failure during endotoxemia.

Association of CARD10 rs6000782 and TNF rs1799724 variants with paediatric-onset autoimmune hepatitis.

Although the pathogenesis of paediatric-onset autoimmune hepatitis (pAIH) remains incompletely understood, genetic variants and environmental factors are known to be involved. Caspase recruitment domain family member 10 (CARD10) is a scaffold protein that participates in a complex pathway activating nuclear factor kappa-B (NFκB) and tumour necrosis factor alpha (TNF-α). This study aimed to investigate the association of CARD10 rs6000782 (g.37928186A > C) and TNF gene promoter rs1799724 (c.-1037C > T) variants with pAIH susceptibility in a cohort of Egyptian children. The research was also extended to assess the relationship of these variants with levels of NFκB-p65 and TNF-α. Fifty-six pAIH patients and 44 age- and sex-matched healthy controls were included. Variant genotyping was performed by polymerase chain reaction (PCR). Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls. Serum levels of NFκB-p65 and TNF-α were higher in pAIH differentiating both groups. Moreover, the recessive model of rs6000782 revealed a significant association with the levels of both NFκB-p65 and TNF-α. In conclusion, rs6000782 and rs1799724 variants are potential genetic risk factors for pAIH predisposition, with the former affecting NFκB-p65 and TNF-α levels. Overall, the inflammatory cascade was associated with the degree of liver cell destruction. Clinically, screening and genetic counselling are recommended for relatives of pAIH patients.

Melatonin and/or rowatinex attenuate streptozotocin-induced diabetic renal injury in rats.

The study aimed to explore the prophylactic effect of melatonin, rowatinex; a naturally occurring renal drug, and its combination on diabetic nephropathy in type 2 diabetic rats. Diabetes was induced by intraperitoneal injection of a single dose of streptozotocin (50 mg/g body weight). Three days before diabetes induction, rats were daily treated with melatonin, rowatinex and their combination continuously for 8 weeks. Evaluation was done through measuring blood urea nitrogen (BUN), serum uric acid, serum creatinine, urine creatinine, creatinine clearance, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), total antioxidant capacity (TAC), kidney injury molecule-1 (KIM-1), heat shock protein-70 (HSP-70), caspase-3, transforming growth factor ß1 (TGFß1), DNA degradation by the comet assay and total protein contents. Histopathologic study was also done for the kidney and the pancreas. Drastic changes in all measured parameters of the diabetic rats were observed. Treatment with melatonin and rowatinex showed amelioration to variable degrees. In conclusion, melatonin showed the most potent effect on protecting rats from deleterious action of diabetic nephropathy followed by its combination with rowatinex.

Genetic variation in microRNA-100 (miR-100) rs1834306 T/C associated with Hepatitis B virus (HBV) infection: Correlation with expression level.

Circulating microRNAs (miRNAs) have a vital role in Hepatitis B virus (HBV) diagnosis and therapeutics. miR-100 was reported to be associated with various aspects of HBV biology. This study focused on a miR-100 Single Nucleotide Polymorphism (SNP) (rs1834306 T/C) and its contribution to an individual's susceptibility and prognosis of HBV infection. The effect of SNP on miR-100 expression will be also evaluated. Two hundred subjects: 100 HBV infected patients and 100 age-and-sex-matched healthy individuals served as a control group. SNP detection was performed using polymerase chain reaction technique with sequence-specific primers (PCR-SSP) method and miR-100 expression through quantitative real-time PCR (qRT-PCR). Our result showed a significant up-regulation of miR-100 expression in HBV patients versus the control group (P < .01). A positive correlation was found between viral load and elevation in miR-100 expression (r = 0.508; P < .01). Concerning miR-100 expression in different genotypes/alleles, TC genotype and T allele in coincides with a significantly elevated expression level of miR-100 (P < .001) in HBV patients than in controls. Best of our knowledge, it is the first observational prospective case-control study concerned with miR-100 (rs1834306 T/C) SNP in the Egyptian population. However, the small size of this preliminary work required more prospective investigations to confirm our data.