Nebivolol ameliorates sepsis-evoked kidney dysfunction by targeting oxidative stress and TGF-ß/Smad/p53 pathway.

Sepsis is a potential fetal organ destruction brought on through an overzealous immunologic reaction to infection, causing severe inflammation, septic shock, and damage to different organs. Although there has been progress in the identification and controlling of clinical sepsis, the fatality rates are still significant. This study, for the first time, intended to examine the possible ameliorative impact of Nebivolol, a ß1-adrenergic antagonist antihypertensive drug, against nephrotoxicity resulted from cecal ligation and puncture (CLP)-induced sepsis in rats, on molecular basis. Sixty male Wistar albino rats were chosen. Oxidative stress indicators and biochemical markers of kidney activity were evaluated. Inflammatory mediators, fibrosis- and apoptosis-related proteins and gene expressions were investigated. Moreover, renal histopathological investigation was performed. CLP-induced nephrotoxicity characterized by markedly elevated serum levels of creatinine, blood urea nitrogen, uric acid, and renal malondialdhyde. On the other hand, it decreased serum total protein level, renal superoxide dismutase activity and reduced glutathione level. Additionally, it significantly elevated the renal inflammatory mediators (tumor necrosis factor-alpha, ilnerlukin (IL)-6, and IL-1ß) and Caspase-3 protein, reduced IL-10 level, amplified the expression of transforming growth factor-beta 1 (TGF-ß1), p-Smad2/3 and alpha-smooth-muscle actin proteins, downregulated the B cell lymphoma-2 (Bcl-2) gene and elevated the transcription of Bcl-2-associated X-protein (Bax), p53 and Nuclear factor-kappa B (NF-κB) genes. Furtheremor, kidney tissues exhibited significant histopathological changes with CLP. On the contrary, Nebivolol significantly improved all these biochemical changes and enhanced the histopathological alterations obtained by CLP. This research showed, for the first time, that Nebivolol effectively mitigated the CLP-induced kidney dysfunction via its antioxidant, antifibrotic and anti-apoptotic activity through modulation of oxidative stress, TGF-ß/NF-κB and TGF-ß/Smad/p53 signaling pathways.

Modified Citrus Pectin (MCP) Confers a Renoprotective Effect on Early-Stage Nephropathy in Type-2 Diabetic Mice.

Diabetic nephropathy (DN) is a significant global health concern with a high morbidity rate. Accumulating evidence reveals that Galectin-3 (Gal-3), a ß-galactoside-binding lectin, is a biomarker in kidney diseases. Our study aimed to assess the advantageous impacts of modified citrus pectin (MCP) as an alternative therapeutic strategy for the initial and ongoing progression of DN in mice with type 2 diabetes mellitus (T2DM). The animal model has been split into four groups: control group, T2DM group (mice received intraperitoneal injections of nicotinamide (NA) and streptozotocin (STZ), T2DM+MCP group (mice received 100 mg/kg/day MCP following T2DM induction), and MCP group (mice received 100 mg/kg/day). After 4 weeks, kidney weight, blood glucose level, serum kidney function tests, histopathological structure alterations, oxidative stress, inflammation, apoptosis, and fibrosis parameters were determined in renal tissues. Our findings demonstrated that MCP treatment reduced blood glucose levels, renal histological damage, and restored kidney weight and kidney function tests. Additionally, MCP reduced malondialdehyde level and restored glutathione level, and catalase activity. MCP demonstrated a notable reduction in inflammatory and apoptosis mediators TNF-α, iNOS, TGF-ßRII and caspase-3. Overall, MCP could alleviate renal injury in an experimental model of DN by suppressing renal oxidative stress, inflammation, fibrosis, and apoptosis mediators.

Dapoxetine prevents neuronal damage and improves functional outcomes in a model of ischemic stroke through the modulation of inflammation and oxidative stress.

Stroke is a medical emergency that is associated with substantial mortality and functional disability in adults. The most popular class of antidepressants, selective serotonin reuptake inhibitors SSRIs, have recently been shown in studies to have positive effects on post-stroke motor and cognitive function. Thus, we hypothesized that dapoxetine (DAP), a short-acting SSRI, would be effective against cerebral ischemia/reperfusion injury. Adult male Wister rats (200-250 g) were subjected to a sham operation or bilateral common carotid artery occlusion (BCCAO) for 30 min followed by 24 h of reperfusion to induce global cerebral ischemia/reperfusion (I/R) injury. Rats were treated with vehicle or DAP (30 or 60 mg/kg, i.p.) 1 h before BCCAO. The neurobehavioral performance of rats was assessed. The infarct volume, histopathological changes, oxidative stress parameters, and apoptotic and inflammatory mediators were determined in the brain tissues of euthanized rats. Our results confirmed that DAP significantly ameliorated cerebral I/R-induced neurobehavioral deficits, reduced cerebral infarct volume, and histopathological damage. Moreover, DAP pretreatment reduced lipid peroxidation, caspase-3, and inflammatory mediators (TNF-α and iNOS) compared to I/R-injured rats. Thus, DAP pretreatment potentially improves neurological function, and cerebral damage in cerebral ischemic rats may be partly related to the reduction in the inflammatory response, preservation of oxidative balance, and suppression of cell apoptosis in brain tissues.

Curative Effect of AD-MSCs against Cisplatin-Induced Hepatotoxicity in Rats is Potentiated by Azilsartan: Targeting Oxidative Stress, MAPK, and Apoptosis Signaling Pathways.

Despite its clinical value, cisplatin (CISP) is complicated by marked hepatotoxicity via inducing oxidative stress, inflammatory, and apoptotic pathways. This study aims to explore the protective impact of azilsartan (AZIL), an antihypertensive drug, in addition to adipose tissue-derived mesenchymal stem cells (AD-MSCs) on CISP-induced hepatotoxicity. After characterization and labeling of AD-MSCs by PKH26 dye, 54 Wistar male albino rats were randomly divided into nine groups: I (CONT), II (AZIL.H), III (CISP), IV (CISP + AZIL.L), V (CISP + AZIL.H), VI (CISP + AD-MSCs), VII (CISP + AZIL.L + AD-MSCs), VIII (CISP + AZIL.H + AD-MSCs), and IX (CISP + VITA C). Serum alanine aminotransferase (ALT), alanine aminotransferase (AST), and albumin levels were determined. Assessment of reactive oxygen species, malondialdehyde, and glutathione contents, and superoxide dismutase activity and histopathological evaluations were done on hepatic tissue. Quantitative real-time PCR was utilized to estimate the expression of TNF-α and IL-6 genes. Cell homing of labeled AD-MSCs to the liver tissues was investigated. Hepatic expression of JNK1/2, ERK1/2, p38, Bax, Bcl-2, and cleaved caspase-3 proteins was investigated by western blot analysis. CISP elevated serum ALT and AST activities, reduced albumin level, and remarkably changed the hepatic architecture. It increased the expression TNF-α and IL-6 genes, raised the expression of JNK1/2, ERK1/2, p38, Bax, and cleaved caspase-3 proteins, and diminished the Bcl-2 protein. By contrast, treatment of animals with either AZIL or AD-MSCs dramatically reduced the effects of CISP injection. Moreover, treatment with combination therapy (AZIL.L or H + AD-MSCs) considerably mitigated all previously mentioned alterations superior to AZIL or AD-MSCs alone, which might be attributed to the AZIL-enhanced homing ability of AD-MSCs into the injured liver tissue. In conclusion, the present findings demonstrated that AZIL improves the hepatoprotective potential of AD-MSCs against CISP-induced hepatotoxicity by modulating oxidative stress, mitogen-activated protein kinase, and apoptotic pathways.

Interferon-λ3 rs12979860 can regulate inflammatory cytokines production in pulmonary fibrosis.

Pulmonary fibrosis (PF) is the last phase of interstitial lung diseases (ILDs), which are a collection of pulmonary illnesses marked by parenchymal remodeling and scarring. Treatment can only halt the functional decline of the lung, raising the necessity of identifying the basic processes implicated in lung fibrogenesis. The Interferon lambda-3 (IFNL3) gene variant, rs12979860, was determined to be related to an elevated risk of fibrosis in different organs, but the mechanism through which it mediates fibrogenesis is not clear. In the current research, we aim to figure out some of the mechanistic pathways by which IFN-λ3 mediates ILDs. 100 healthy controls and 74 ILD patients were genotyped for IFNL3 rs12979860. Then the mRNA expression of IFNL3 and some other proinflammatory mediators was examined according to genotype in the peripheral blood mononuclear cells (PBMCs) of ILDs patients. The IFNL3 rs12979860 genotype distribution of healthy individuals and ILDs patients was shown to be in Hardy-Weinberg equilibrium (HWE) with a minor allele frequency (MAF) of 0.293 and 0.326, respectively. Furthermore, the CC genotype was demonstrated to be linked to enhanced IFNL3 expression. Also, the CC genotype was linked to an increase in the mRNA expression of TLR4 (P = 0.03) and the inflammatory cytokines IL-1ß and TNF-α (P = 0.01 and 0.04, respectively) and had no effect on the NF-kB level (P = 0.3). From these results, we can deduce that IFN-λ3 may mediate tissue fibrosis via increasing the expression of IFN-λ3 itself and other proinflammatory mediators. This stimulates a self-sustaining loop mechanism which includes a reciprocal production of IFN-λ3, TLR4, IL-1ß, and TNF-α leading to persistent inflammation and fibrosis.

Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway.

Cisplatin (CIS) is a broad-spectrum anti-carcinogen that causes cytotoxic effects both in normal and cancer cells. The purpose of this study was to test whether Hibiscus sabdariffa (HS) extract can reduce CIS-induced hepatotoxicity in rodents and to assess its anticancer activity in vitro. Treatment with HS extract at daily doses of 500 mg/kg before and after a single dose of CIS (10 mg/kg) reduced hepatotoxicity in Wistar male albino rats. HS extract reduced activity of hepatic damage marker enzymes ( i.e. alanine and aspartate aminotransferases), necrosis, and apoptosis in liver tissues of CIS-treated rats. This hepatic protection was associated with reduced oxidative stress in liver tissues. The antioxidant effects of HS were manifested as a normalization of malondialdehyde levels and glutathione levels which were all raised after CIS-induction. In addition, HS treatment resulted in a decrease of catalase, and superoxide dismutase activity. The combined effects of CIS and HS were also studied in two human lung cancer cell lines (A549 and H460). Treatment with HS (20 µg /mL) enhanced the cytotoxic activity of CIS both in A549 and H460 cell lines. Interestingly, HS increased CIS-induced apoptosis and oxidative stress more clearly in A549 cells indicating that HS extract in combination with CIS could increase the efficacy of CIS in the treatment of cancer.

Vincamine Ameliorates Epithelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis in Rats; Targeting TGF-ß/MAPK/Snai1 Pathway.

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease that leads to respiratory failure and death. Vincamine is an indole alkaloid obtained from the leaves of Vinca minor and acts as a vasodilator. The present study aims to investigate the protective activity of vincamine against EMT in bleomycin (BLM)-induced pulmonary fibrosis via assessing the apoptotic and TGF-ß1/p38 MAPK/ERK1/2 signaling pathways. In bronchoalveolar lavage fluid, protein content, total cell count, and LDH activity were evaluated. N-cadherin, fibronectin, collagen, SOD, GPX, and MDA levels were determined in lung tissue using ELISA. Bax, p53, bcl2, TWIST, Snai1, and Slug mRNA levels were examined using qRT-PCR. Western blotting was used to assess the expression of TGF-ß1, p38 MAPK, ERK1/2, and cleaved caspase 3 proteins. H & E and Masson's trichrome staining were used to analyze histopathology. In BLM-induced pulmonary fibrosis, vincamine reduced LDH activity, total protein content, and total and differential cell count. SOD and GPX were also increased following vincamine treatment, while MDA levels were decreased. Additionally, vincamine suppressed the expression of p53, Bax, TWIST, Snail, and Slug genes as well as the expression of factors such as TGF-ß1, p/t p38 MAPK, p/t ERK1/2, and cleaved caspase 3 proteins, and, at the same time, vincamine increased bcl2 gene expression. Moreover, vincamine restored fibronectin, N-Catherine, and collagen protein elevation due to BLM-induced lung fibrosis. In addition, the histopathological examination of lung tissues revealed that vincamine attenuated the fibrotic and inflammatory conditions. In conclusion, vincamine suppressed bleomycin-induced EMT by attenuating TGF-ß1/p38 MAPK/ERK1/2/TWIST/Snai1/Slug/fibronectin/N-cadherin pathway. Moreover, it exerted anti-apoptotic activity in bleomycin-induced pulmonary fibrosis.

Nephroprotective effect of AT-MSCs against cisplatin-induced EMT is improved by azilsartan via attenuating oxidative stress and TGF-ß/Smad signaling.

The nephrotoxicity of cisplatin (CIS) is a significant complication that challenges its clinical applicability. The epithelial to mesenchymal transition (EMT) may be included in the pathogenesis of CIS-evoked nephrotoxicity. Therefore, the current study aimed to evaluate, for the first time, the possible protective effect of AZL and/or AT-MSCs against CIS-induced EMT in rats on molecular bases. Fifty-four healthy Wistar male albino rats were used in this study. Different biochemical markers of kidney function as well as oxidative stress parameters were investigated. Additionally, renal histopathological study was performed. The expression of EMT-related proteins and genes was evaluated by western blotting and qRT-PCR. CIS markedly increased SCr, BUN, uric acid and renal MDA levels, with concomitant decrease in serum total protein, renal GSH level and SOD activity. Furthermore, it suppressed the expression of Cdh1 gene, increased the α-SMA, Acta2, Cdh2 and Vim genes expression, down regulated the expression of E-cad protein and up-regulated the α-SMA, TGF-ß1, p-Smad2/3 and Snail proteins expression. Kidney tissues showed severe histopathological alterations and extensive collagen accumulation. Conversely, the treatment with either AZL or AT-MSCs significantly attenuated these alterations caused by CIS. Interestingly, the combined therapy of AZL and AT-MSCs has a superior ameliorative effect than AT-MSCs alone. In conclusion, this study, for the first time, revealed that AZL and/ or AT-MSCs successfully ameliorated the CIS-induced EMT via the inhibition of oxidative stress and TGF-ß/Smad signaling pathway. Intriguingly, AZL enhanced the effect of AT-MSCs making them promising agents for kidney protection against CIS-induced EMT.

Inhibition of NF-kB/IL-6/JAK2/STAT3 Pathway and Epithelial-Mesenchymal Transition in Breast Cancer Cells by Azilsartan.

Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2, and increased the mRNA level of bax. Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways.

Dual Topoisomerase I/II Inhibition-Induced Apoptosis and Necro-Apoptosis in Cancer Cells by a Novel Ciprofloxacin Derivative via RIPK1/RIPK3/MLKL Activation.

Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine its anticancer activity against HepG2 and A549 cancer cells, and investigate the possible molecular mechanism underlying this activity by examining its ability to inhibit the topo I/II activity and to induce the apoptotic and necro-apoptotic pathways. Molecular docking, cell viability, cell migration, colony formation, cell cycle, Annexin V, lactate dehydrogenase (LDH) release, ELISA, and western blotting assays were utilized. Molecular docking results showed that this novel ciprofloxacin derivative exerted dual topo I and topo II binding and inhibition. It significantly inhibited the proliferation of A549 and HepG2 cancer cells and decreased their cell migration and colony formation abilities. In addition, it significantly increased the % of apoptotic cells, caused cell cycle arrest at G2/M phase, and elevated the LDH release levels in both cancer cells. Furthermore, it increased the expression of cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins. This novel ciprofloxacin derivative exerted substantial dual inhibition of topo I/II enzyme activities, showed antiproliferative activity, suppressed the cell migration and colony formation abilities for A549 and HepG2 cancer cells and activated the apoptotic pathway. In addition, it initiated another backup deadly pathway, necro-apoptosis, through the activation of the RIPK1/RIPK3/MLKL pathway.

Behavioral, Biochemical and Histopathological effects of Standardised Pomegranate extract with Vinpocetine, Propolis or Cocoa in a rat model of Parkinson's disease.

INTRODUCTION: Parkinsonism is a neurodegenerative disorder. Pomegranate (POM) has been previously shown to have a dopaminergic neuroprotective effect against parkinsonism. OBJECTIVE: The aim of the current study is to investigate the possible effect of POM in combination with each of vinpocetine, propolis, or cocoa in the treatment of parkinsonism disease even without being given as adjuvant to L-dopa . METHODS: Rats were divided into seven groups, one normal and six RT model groups. One of the RT groups (2.5 mg/kg/48 h/10 doses sc), for 20 days served as non-treated parkinsonism model, whereas the others were treated with either L-dopa (10 mg/kg, p.o./day) or with POM (150 mg/kg, p.o./day) together with each of the following; vinpocetine (VIN) (20 mg/kg, p.o./day), propolis (300 mg/kg, p.o./day), cocoa (24 mg/kg, p.o./day). Motor and cognitive performances were examined using four tests (catalepsy, swimming, Y-maze, open field). Striatal dopamine, norepinephrine, serotonin, GABA, glutamate, acetylcholinesterase, GSK-3ß, BDNF levels were assessed as well as MDA, SOD, TAC, IL-1ß, TNF-α, iNOs, and caspase-3. Also, histopathological examinations of different brain regions were determined. RESULTS: Treatment with L-dopa alone or with all POM combination groups alleviated the deficits in locomotor activities, cognition, neurotransmitter levels, acetylcholinesterase activity, oxidative stress, and inflammatory markers as well as caspase-3 expression induced by RT. CONCLUSION: Combinations of POM with each of VIN, propolis, or cocoa have a promising disease-modifying antiparkinsonian therapy even without being given as an adjuvant to L-dopa.

Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines.

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.

Morin alleviates fructose-induced metabolic syndrome in rats via ameliorating oxidative stress, inflammatory and fibrotic markers.

Metabolic syndrome (MBS) is a widespread disease that has strongly related to unhealthy diet and low physical activity, which initiate more serious conditions such as obesity, cardiovascular diseases and type 2 diabetes mellitus. This study aimed to examine the therapeutic effects of morin, as one of the flavonoids constituents, which widely exists in many herbs and fruits, against some metabolic and hepatic manifestations observed in MBS rats and the feasible related mechanisms. MBS was induced in rats by high fructose diet feeding for 12 weeks. Morin (30 mg/ kg) was administered orally to both normal and MBS rats for 4 weeks. Liver tissues were used for determination of liver index, hepatic expression of glucose transporter 2 (GLUT2) as well as both inflammatory and fibrotic markers. The fat/muscle ratio, metabolic parameters, systolic blood pressure, and oxidative stress markers were also determined. Our data confirmed that the administration of morin in fructose diet rats significantly reduced the elevated systolic blood pressure. The altered levels of metabolic parameters such as blood glucose, serum insulin, serum lipid profile, and oxidative stress markers were also reversed approximately to the normal values. In addition, morin treatment decreased liver index, serum liver enzyme activities, and fat/muscle ratio. Furthermore, morin relatively up-regulated GLUT2 expression, however, down-regulated NF-κB, TNF-α, and TGF-ß expressions in the hepatic tissues. Here, we revealed that morin has an exquisite effect against metabolic disorders in the experimental model through, at least in part, antioxidant, anti-inflammatory, and anti-fibrotic mechanisms.

Modulatory and Toxicological Perspectives on the Effects of the Small Molecule Kinetin.

Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.

RNA protein kinase SNP at -226 C

BACKGROUND: RNA-dependant protein kinase R (PKR) is a primary mediator in the defence mechanism of interferon against viral replication and pathogenesis during Hepatitis C virus (HCV) infection. In the present study, we have examined the role of Single Nucleotide Polymorphisms (SNPs) in the promoter region of PKR and the serum level of the same protein on the outcome of HCV-infected Egyptian patients. PATIENTS AND METHODS: Genomic DNA was extracted from a total of 135 subjects, including 15 healthy controls, 40 HCV spontaneous resolvers (SRs), and 80 patients with chronic HCV infection. PKR genotyping was assessed using DNA sequencing. Finally, serum levels of PKR, TNF-α, INF-γ, and IL-10 were measured using ELISA technique. RESULTS: Serum levels of PKR, TNF-α, and INF-γ showed a significant increase in SRs as compared to chronic HCV patients. On the other hand, serum levels of IL-10 were significantly higher in chronic HCV patients compared to SRs. The present study demonstrated two novel SNPs in the PKR promoter region: at -226 C/T and -141 C/G. The PKR SNP at -226 C < T correlated with HCV-infected patients (genotype 4a) outcome among Egyptians. Our data showed the unique presence of the TT genotype in SRs group (three patients: 7.5%) in PKR -226 C/T. Interestingly, subjects with the TT genotype were more likely to clear their HCV infection than those with the CC genotype. CONCLUSION: Our work provides more detail about PKR gene polymorphism in HCV genotype 4a as a new clinical tool for anticipating HCV-4a infection outcome.

The global establishment of a highly-fluoroquinolone resistant Salmonella enterica serotype Kentucky ST198 strain.

While the spread of Salmonella enterica serotype Kentucky resistant to ciprofloxacin across Africa and the Middle-East has been described recently, the presence of this strain in humans, food, various animal species (livestock, pets, and wildlife) and in environment is suspected in other countries of different continents. Here, we report results of an in-depth molecular epidemiological study on a global human and non-human collection of S. Kentucky (n = 70). We performed XbaI-pulsed field gel electrophoresis and multilocus sequence typing, assessed mutations in the quinolone resistance-determining regions, detected ß-lactam resistance mechanisms, and screened the presence of the Salmonella genomic island 1 (SGI1). In this study, we highlight the rapid and extensive worldwide dissemination of the ciprofloxacin-resistant S. Kentucky ST198-X1-SGI1 strain since the mid-2000s in an increasingly large number of contaminated sources, including the environment. This strain has accumulated an increasing number of chromosomal and plasmid resistance determinants and has been identified in the Indian subcontinent, Southeast Asia and Europe since 2010. The second substitution at position 87 in GyrA (replacing the amino acid Asp) appeared helpful for epidemiological studies to track the origin of contamination. This global study provides evidence leading to the conclusion that high-level resistance to ciprofloxacin in S. Kentucky is a simple microbiological trait that facilitates the identification of the epidemic clone of interest, ST198-X1-SGI1. Taking this into account is essential in order to detect and monitor it easily and to take rapid measures in livestock to ensure control of this infection.

The role of OmpC and OmpF in acidic resistance in Escherichia coli.

The roles of OmpC and OmpF in acidic resistance (AR) were examined. When ompC and ompF were deleted, AR was decreased. The decreased level of AR seen in the mutant that was deficient in ompC and ompF was elevated by the addition of glutamate, but not by the addition of arginine or lysine. The expression levels of adiA and cadB were diminished by the deletion of ompC and ompF, and the conversion of arginine to agmatine and lysine to cadaverine by intact cells were reduced in the mutant. The expression of gadA/gadB was not affected by the deletion of ompC and ompF. These results suggest that the transport of arginine, lysine, and their decarboxylated products through OmpC and/or OmpF is essential for the survival of Escherichia coli cells under extremely acidic conditions.