Boosting oxygen evolution reaction rates with mesoporous Fe-doped MoCo-phosphide nanosheets.

Transition metal-based catalysts are commonly used for water electrolysis and cost-effective hydrogen fuel production due to their exceptional electrochemical performance, particularly in enhancing the efficiency of the oxygen evolution reaction (OER) at the anode. In this study, a novel approach was developed for the preparation of catalysts with abundant active sites and defects. The MoCoFe-phosphide catalyst nanosheets were synthesized using a simple one-step hydrothermal reaction and chemical vapor deposition-based phosphorization. The resulting MoCoFe-phosphide catalyst nanosheets displayed excellent electrical conductivity and a high number of electrochemically active sites, leading to high electrocatalytic activities and efficient kinetics for the OER. The MoCoFe-phosphide catalyst nanosheets demonstrated remarkable catalytic activity, achieving a low overpotential of only 250 mV to achieve the OER at a current density of 10 mA cm-2. The catalyst also exhibited a low Tafel slope of 43.38 mV dec-1 and maintained high stability for OER in alkaline media, surpassing the performance of most other transition metal-based electrocatalysts. The outstanding OER performance can be attributed to the effects of Mo and Fe, which modulate the electronic properties and structures of CoP. The results showed a surface with abundant defects and active sites with a higher proportion of Co2+ active sites, a larger specific surface area, and improved interfacial charge transfer. X-ray photoelectron spectroscopy (XPS) analysis revealed that the catalyst's high activity originates from the presence of Mo6+/Mo4+ and Co2+/Co3+ redox couples, as well as the formation of active metal (oxy)hydroxide species on its surface.

Unveiling the regulatory role of miRNAs in stroke pathophysiology and diagnosis.

Stroke, a major global cause of mortality, leads to a range of problems for those who survive. Besides its brutal events, stroke also tends to have a characteristic of recurrence, making it a complex disease involving intricate regulatory networks. One of the major cellular regulators is the non-coding RNAs (ncRNA), specifically microRNAs (miRNAs), thus the possible functions of miRNAs in the pathogenesis of stroke are discussed as well as the possibility of using miRNA-based therapeutic approaches. Firstly, the molecular mechanisms by which miRNAs regulate vital physiological processes, including synaptic plasticity, oxidative stress, apoptosis, and the integrity of the blood-brain barrier (BBB) are reviewed. The miRNA indirectly impacts stroke outcomes by regulating BBB function and angiogenesis through the targeting of transcription factors and angiogenic factors. In addition, the tendency for some miRNAs to be upregulated in response to hypoxia, which is a prevalent phenomenon in stroke and various neurological disorders, highlights the possibility that it controls hypoxia-inducible factor (HIF) signaling and angiogenesis, thereby influencing the integrity of the BBB as examples of the discussed mechanisms. Furthermore, this review explores the potential therapeutic targets that miRNAs may offer for stroke recovery and highlights their promising capacity to alleviate post-stroke complications. This review provides researchers and clinicians with valuable resources since it attempts to decipher the complex network of miRNA-mediated mechanisms in stroke. Additionally, the review addresses the interplay between miRNAs and stroke risk factors as well as clinical applications of miRNAs as diagnostic and prognostic markers.

Melodic maestros: Unraveling the role of miRNAs in the diagnosis, progression, and drug resistance of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly lethal form of pleural cancer characterized by a scarcity of effective therapeutic interventions, resulting in unfavorable prognoses for afflicted individuals. Besides, many patients experience substantial consequences from being diagnosed in advanced stages. The available diagnostic, prognostic, and therapeutic options for MPM are restricted in scope. MicroRNAs (miRNAs) are a subset of small, noncoding RNA molecules that exert significant regulatory influence over several cellular processes within cell biology. A wide range of miRNAs have atypical expression patterns in cancer, serving specific functions as either tumor suppressors or oncomiRs. This review aims to collate, epitomize, and analyze the latest scholarly investigations on miRNAs that are believed to be implicated in the dysregulation leading to MPM. miRNAs are also discussed concerning their potential clinical usefulness as diagnostic and prognostic biomarkers for MPM. The future holds promising prospects for enhancing diagnostic, prognostic, and therapeutic modalities for MPM, with miRNAs emerging as a potential trigger for such advancements.

The emerging role of miRNAs in Merkel cell carcinoma pathogenesis: Signaling pathway crosstalk.

Merkel cell carcinoma (MCC) is an uncommon invasive form of skin cancer that typically manifests as a nodule on the face, head, or neck that is flesh-colored or bluish-red in appearance. Rapid growth and metastasis are hallmarks of MCC. MCC has the second-greatest mortality rate among skin cancers after melanoma. Despite the recent cascade of molecular investigations, no universal molecular signature has been identified as responsible for MCC's pathogenesis. The microRNAs (miRNAs) play a critical role in the post-transcriptional regulation of gene expression. Variations in the expression of these short, non-coding RNAs have been associated with various malignancies, including MCC. Although the incidence of MCC is very low, a significant amount of study has focused on the interaction of miRNAs in MCC. As such, the current survey is a speedy intensive route revealing the potential involvement of miRNAs in the pathogenesis of MCC beyond their association with survival in MCC.

miRNAs driving diagnosis, prognosis and progression in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive form of skin malignancy with a high recurrence commonly within two to three years of initial diagnosis. The incidence of MCC has nearly doubled in the past few decades. Options for diagnosing, assessing, and treating MCC are limited. MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that play an important role in controlling many different aspects of cell biology. Many miRNAs are aberrantly expressed in distinct types of cancer, with some serving as tumor suppressors and others as oncomiRs. Therefore, the future holds great promise for the utilization of miRNAs in enhancing diagnostic, prognostic, and therapeutic approaches for MCC. Accordingly, the goal of this article is to compile, summarize, and discuss the latest research on miRNAs in MCC, highlighting their potential clinical utility as diagnostic and prognostic biomarkers.

The role of mitochondrial/metabolic axis in development of tamoxifen resistance in breast cancer.

Only a few investigations, to our knowledge, have examined the bioenergetics of Tamoxifen (TMX) resistant individuals and reported altered mitochondrial activity and metabolic profile. The primary cause of TMX resistance is firmly suggested to be metabolic changes. Metabolic variations and hypoxia have also been linked in a bidirectional manner. Increased hypoxic levels correlate with early recurrence and proliferation and have a negative therapeutic impact on breast cancer (BC) patients. Hypoxia, carcinogenesis, and patient death are all correlated, resulting in more aggressive traits, a higher chance of metastasis, and TMX resistance. Consequently, we sought to investigate the possible role of the metabolic/hypoxial axis Long non-coding RNA (LncRNA) Taurine up-regulated 1 (TUG-1), Micro-RNA 186-5p (miR-186), Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-α), and Hypoxia-Inducible Factor-1 (HIF-1) in the development of TMX resistance in BC patients and to correlate this axis with tumor progression. Interestingly, this will be the first time to explore epigenetic regulation of this axis in BC.

The potential role of miRNAs in the pathogenesis of adrenocortical carcinoma - A focus on signaling pathways interplay.

Adrenocortical carcinoma (ACC) is a highly malignant infrequent tumor with a dismal prognosis. microRNAs (miRNAs, miRs) are crucial in post-transcriptional gene expression regulation. Due to their ability to regulate multiple gene networks, miRNAs are central to the hallmarks of cancer, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, induction/access to the vasculature, activation of invasion and metastasis, reprogramming of cellular metabolism, and avoidance of immune destruction. ACC represents a singular form of neoplasia associated with aberrations in the expression of evolutionarily conserved short, non-coding RNAs. Recently, the role of miRNAs in ACC has been examined extensively despite the disease's rarity. Hence, the current review is a fast-intensive track elucidating the potential role of miRNAs in the pathogenesis of ACC besides their association with the survival of ACC.

Metabolic/hypoxial axis predicts tamoxifen resistance in breast cancer.

We sought in our cross-sectional study to investigate the role of metabolic/hypoxial axis in the development of tamoxifen (TMX) resistance in BC patients. Quantification of plasma LncRNA Taurine upregulated-1 (TUG-1), miRNA 186-5p (miR-186), serum Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-1 α) and Hypoxia Inducible Factor-1 (HIF-1α) was done in a cohort of patients divided into TMX-sensitive and TMX-resistant candidates. Multiple logistic regression and Receiver Operating Characteristic curve were developed for significant predictors. Plasma TUG-1 and miR-186 were significantly elevated in TMX resistant patients. Serum proteins SIRT3, PPAR-1 α and HIF-1α were deficient in TMX resistant patients compared to TMX sensitive patients, respectively. miR-186 was associated with respiratory symptoms, while, HIF-1α was associated with metastases in TMX resistant patients. Strong correlations were found between all parameters. A predictive model was constructed with TUG-1 and HIF-1α to estimate TMX resistance in BC patients with 88.3% sensitivity and 91.6% specificity. Hypoxia and metabolic dysregulations play important role in the development of TMX resistance in BC patients. Correlation between hypoxia, carcinogenesis and patient's mortality have led to more aggressive phenotypes, increased risk of metastasis and resistance to TMX.

Loss of RAR-α and RXR-α and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent.

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/ lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in Nacetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase- 3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

Association between interleukin 28B polymorphism and sustained virological response to sofosbuvir plus daclatasvir in chronic hepatitis C genotype 4 Egyptian patients.

WHAT IS KNOWN AND OBJECTIVE: Sofosbuvir has been approved as the first nonstructural protein 5B polymerase inhibitor with pan-genotypic activity against the hepatitis C (HCV) virus. Daclatasvir is a first-in-class hepatitis C virus nonstructural protein 5A replication complex inhibitor. We aimed to evaluate the usefulness of the reference single nucleotide polymorphism (rs12979860) interleukin 28B (CC genotype) for predicting sustained virological response to sofosbuvir plus daclatasvir in Egyptian patients infected with HCV-4. METHODS: Samples were collected at week zero. One hundred and thirty-one patients who reached the end of treatment (at week 12) were divided into three groups, according to their interleukin 28B genotype: Group A included 31 patients (CC genotype), group B included 79 patients (CT genotype) and group C had 21 patients (TT genotype). All patients received treatment for 3 months in the form of sofosbuvir plus daclatasvir with ribavirin (in case of cirrhotic patients) or without ribavirin (in case of non-cirrhotic patients). RESULTS AND DISCUSSION: Sustained virological response rate was significantly higher in patients with IL28B (CC genotype) vs. (non-CC genotype) (100 vs.88%) (p < 0.0001).These patients also showed lower rates of post-treatment relapse and non-response, compared with the CT and TT patients (0% vs. (7.59% and 28.5%, respectively) (p < 0.0001). Also, patients with CC genotype showed higher sustained virological response than non-CC genotypes on both cirrhotic (100% vs. 68.75%) and non-cirrhotic patients (100% vs. 91.66%) (p ≤ 0.0001). WHAT IS NEW AND CONCLUSION: Our results suggest that IL28B genotype contributes to the prediction of response to sofosbuvir plus daclatasvir.

Concomitant inhibition of hedgehog signalling and activation of retinoid receptors abolishes bleomycin-induced lung fibrosis.

Pulmonary fibrosis is a devastating disease with unknown treatment. All-trans retinoic acid (ATRA) attenuates bleomycin-induced lung fibrosis by different mechanistic pathways. However, the role of retinoid receptors in lung fibrosis is still unclear. Forskolin (FSK), a potent inhibitor for the revolutionary hedgehog (Hh) signalling pathway, has a promising antifibrotic effect on other organs such as the liver. This study investigates the interplay between the retinoid receptors modulation and the Hh signalling pathway in bleomycin (BLM)-induced pulmonary fibrosis. Rats were randomised and administrated a single dose of 7.5 mg/kg of BLM alone and with ATRA, FSK and both of them. The effects of FSK and ATRA on lung functions, oxidative stress markers (malondialdehyde [MDA], glutathione [GSH], superoxide dismutase [SOD] and catalase [CAT]), retinoid markers (retinoic acid receptors [RAR] and rexinoid X receptors [RXR]) and Hh signalling markers (patched homolog 1 [Ptch-1], Smoothened [Smo] and glioblastoma-2 [Gli-2]) were assessed. In single therapies, ATRA and FSK ameliorated BLM-induced lung fibrosis. On the contrary, a combination of both drugs synergistically reversed the effect of BLM-induced lung fibrosis, as indicated by the enhancement of lung functions and the decrease of the α-smooth muscle actin (α-SMA) expression and collagen deposition. Additionally, FSK and ATRA ameliorated oxidative stress and inflammation, reduced transforming growth factor ß1 (TGF-ß1) levels and reversed the effect of BLM on the mRNA expression of Ptch-1, Smo and Gli-2. FSK inhibited the Hh pathway and also activated protein kinase A (PKA) that is, in part, involved in phosphorylation of RAR/RXR heterodimer (a key step in retinoid receptor activation). The present results suggest that a combination of FSK and ATRA has a promising therapeutic value for lung fibrosis management.

Apixaban exhibits anti-arthritic effects by inhibiting activated factor X-mediated JAK2/STAT3 and MAPK phosphorylation pathways.

Activated factor X (FXa) is strongly linked to various inflammatory events. This study aimed to investigate the effect of FXa on janus kinase2/signal transducers and activators of transcription3 (JAK2/STAT3) and mitogen-activated protein kinase (MAPK) phosphorylation in relation to rheumatoid arthritis (RA). It also extends its scope to explore the possible anti-arthritic effects of apixaban, a selective FXa inhibitor. Rats were allocated into normal control; complete Freund's adjuvant (CFA, 0.4 ml/4 days/12 days); FXa (120 µg/kg/day/3 days) and CFA + FXa groups as well as three treated groups including CFA + apixaban; FXa + apixaban and CFA + FXa + apixaban. Apixaban was administered at a dose of 10 mg/kg/12 h for15 days. By the end of the experimental period, tissue samples were collected for the assessment of phosphorylated (p)-JAK2, STAT3, MAPK, matrixmetalloprotein-1 (MMP-1) and protease-activated receptor 2. Furthermore, Serum interleukin-6 (IL-6), platelet-derived growth factor (PDGF), anti-citrullinated protein antibody (ACPA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma level of FXa and prothrombin time were evaluated. In support, histopathological and macroscopical examinations were performed. FXa activated JAK2, STAT3 and MAPK phosphorylation through activation of PAR 2, PDGF and IL-6 and concomitantly led to a significant elevation in ACPA, MMP-1 and 8-OHdG. Apixaban markedly amended FXa-induced changes. Conclusively, the current study revealed that FXa may have a drastic role in RA progression and pathogenesis at least through stimulation of JAK2/STAT3 and MAPK phosphorylation. Furthermore, apixaban exerted robust arthro-protective effects. These beneficial outcomes could be attributed to its ability to impede JAK2/STAT3 and MAPK activation, as well as to its antioxidant property.

Cyclosporin A activates human hepatocellular carcinoma (HepG2 cells) proliferation: implication of EGFR-mediated ERK1/2 signaling pathway.

One of the most common causes of cancer mortality worldwide is hepatocellular carcinoma (HCC). Extracellular signal-regulated kinase (ERK1/2) pathway has been shown to play an important role in the development and progression of HCC. Here, we demonstrate that the immunosuppressive agent cyclosporin A (CsA) has the ability to increase the cellular growth in HCC (HepG2 cells) via activation of ERK1/2 signaling cascade. It was found that ERK1/2 phosphorylation induced by CsA was highly reduced in the presence of the reactive oxygen species (ROS) scavenger polyethylene glycol-superoxide dismutase (PEG-SOD). Furthermore, it was observed that inhibition of metalloproteinase activity using TAPI-2 prevents ERK1/2 activation by CsA. Moreover, a disintegrin and metalloproteinase domain 17 (ADAM-17) activity was found to be critical for ERK phosphorylation by CsA. In addition, CsA-induced ERK phosphorylation was highly reduced in the presence of either neutralizing anti-heparin-binding-epidermal growth factor (HB-EGF) antibody or UO126 (MEK inhibitor). By using the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, it was found that EGFR is critical for ERK phosphorylation induced by CsA. Furthermore, CsA-induced cell proliferation was strongly reduced in the presence of either PEG-SOD or TAPI-2 or neutralizing anti-ADAM17 antibody or neutralizing anti-HB-EGF antibody or AG1478 or UO126. Collectively, these data demonstrate that CsA has the ability to activate ERK1/2 signaling cascade that could be translated into an increase in HepG2 cell proliferation. Furthermore, these data support the role of ROS, ADAM-17, and EGFR in ERK1/2 signaling activation and subsequent cell proliferation induced by CsA in HepG2 cells.

Functional characterization of α7 nicotinic acetylcholine and NMDA receptor signaling in SH-SY5Y neuroblastoma cells in an ERK phosphorylation assay.

In the present study, the functional properties of α7 nicotinic acetylcholine receptors (α7 nAChRs) and N-methyl-D-aspartate receptors (NMDARs) endogenously expressed in SH-SY5Y human neuroblastoma cells were characterized in an extracellular-signal regulated kinase (ERK) phosphorylation assay. Both choline and N-methyl-D-aspartate (NMDA) mediated robust concentration-dependent increases in ERK phosphorylation in the SH-SY5Y cells, exhibiting EC50 values in good agreement with those reported for the agonists at recombinant α7 nAChRs and NMDARs, respectively. Importantly, the responses evoked by choline (10 mM) and by NMDA (50 µM) were significantly inhibited by the α7-selective antagonist α-bungarotoxin (100 nM) and by the NMDAR-selective antagonist MK-801 (50 µM), respectively. The increased ERK phosphorylation levels observed upon co-application of choline (1, 3, 10 mM) and NMDA (50 µM) compared to those produced by the two agonists on their own were fully reconcilable with additive effects and did not reveal substantial synergy between α7 nAChR and NMDAR signaling. Interestingly, however, the responses evoked by the "choline (10 mM) - NMDA (50 µM)" combination were almost completely inhibited by α-bungarotoxin (100 nM) as well as by MK-801 (50 µM), suggesting some sort of a link between α7 nAChR- and NMDAR-mediated ERK phosphorylation. Finally, oligomeric amyloid-ß1-42 peptide (1000 nM) mediated robust inhibition of the ERK phosphorylation induced by choline (10 mM), NMDA (50 µM) and the "choline (10 mM) - NMDA (50 µM)" combination. In conclusion, ERK phosphorylation measurements in SH-SY5Y cells provides a robust assay for studies of α7 nAChR- and NMDAR-mediating signaling and putative functional interactions between the receptors.

Probing the putative α7 nAChR/NMDAR complex in human and murine cortex and hippocampus: Different degrees of complex formation in healthy and Alzheimer brain tissue.

α7 nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartate receptors (NMDARs) are key mediators of central cholinergic and glutamatergic neurotransmission, respectively. In addition to numerous well-established functional interactions between α7 nAChRs and NMDARs, the two receptors have been proposed to form a multimeric complex, and in the present study we have investigated this putative α7 nAChR/NMDAR assembly in human and murine brain tissues. By α-bungarotoxin (BGT) affinity purification, α7 and NMDAR subunits were co-purified from human and murine cortical and hippocampal homogenates, substantiating the notion that the receptors are parts of a multimeric complex in the human and rodent brain. Interestingly, the ratios between GluN1 and α7 levels in BGT pull-downs from cortical homogenates from Alzheimer's disease (AD) brains were significantly lower than those in pull-downs from non-AD controls, indicating a reduced degree of α7 nAChR/NMDAR complex formation in the diseased tissue. A similar difference in GluN1/α7 ratios was observed between pull-downs from cortical homogenates from adult 3xTg-AD and age-matched wild type (WT) mice, whereas the GluN1/α7 ratios determined in pull-downs from young 3xTg-AD and age-matched WT mice did not differ significantly. The observation that pretreatment with oligomeric amyloid-ß1-42 reduced GluN1/α7 ratios in BGT pull-downs from human cortical homogenate in a concentration-dependent manner provided a plausible molecular mechanism for this observed reduction. In conclusion, while it will be important to further challenge the existence of the putative α7 nAChR/NMDAR complex in future studies applying other methodologies than biochemical assays and to investigate the functional implications of this complex for cholinergic and glutamatergic neurotransmission, this work supports the formation of the complex and presents new insights into its regulation in healthy and diseased brain tissue.

Exosomal miR-940 maintains SRC-mediated oncogenic activity in cancer cells: a possible role for exosomal disposal of tumor suppressor miRNAs.

Exosomes have emerged as important mediators of diverse biological functions including tumor suppression, tumor progression, invasion, immune escape and cell-to-cell communication, through the release of molecules such as mRNAs, miRNAs, and proteins. Here, we identified differentially expressed exosomal miRNAs between normal epithelial ovarian cell line and both resistant and sensitive ovarian cancer (OC) cell lines. We found miR-940 as abundant in exosomes from SKOV3-IP1, HeyA8, and HeyA8-MDR cells. The high expression of miR-940 is associated with better survival in patients with ovarian serous cystadenocarcinoma. Ectopic expression of miR-940 inhibited proliferation, colony formation, invasion, and migration and triggered G0/G1 cell cycle arrest and apoptosis in OC cells. Overexpression of miR-940 also inhibited tumor cell growth in vivo. We showed that proto-oncogene tyrosine-protein kinase (SRC) is directly targeted by miR-940 and that miR-940 inhibited SRC expression at mRNA and protein levels. Following this inhibition, the expression of proteins downstream of SRC, such as FAK, paxillin and Akt was also reduced. Collectively, our results suggest that OC cells secrete the tumor-suppressive miR-940 into the extracellular environment via exosomes, to maintain their invasiveness and tumorigenic phenotype.

Exosomes: From Garbage Bins to Promising Therapeutic Targets.

Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents.

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients.

The therapeutic effect of pegylated interferon (peg-IFN) alfa-2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa-2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa-2a (160 µg) subcutaneous once weekly and oral weight-based ribavirin (1000-1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170-2178, 2016. © 2016 Wiley Periodicals, Inc.

Coadministration of ezetimibe with pegylated interferon plus ribavirin could improve early virological response in chronic hepatitis C obese Egyptian patients.

BACKGROUND: Ezetimibe has been reported to inhibit viral entry and to reduce BMI and has been proposed as a novel therapeutic agent for chronic hepatitis C (CHC), potentiating the effects of pegylated interferon and ribavirin (peg-IFN/RBV). OBJECTIVE: The aim of the study was to assess the effects of ezetimibe coadministration with peg-IFN/RBV combination on the early virological response (EVR) rates in nonobese and obese patients with CHC genotype 4 (CHC-4). PATIENTS AND METHODS: A total of 144 CHC-4 patients were divided into two groups; group 1 included nonobese patients (n=76) and group 2 included obese patients (n=68). Each group was further subclassified into equal control and treated groups. The control groups received peg-IFN/RBV combination for 24 weeks, and the treated groups received peg-IFN/RBV plus ezetimibe for 12 weeks and then only peg-IFN/RBV for the remaining 12 weeks. RESULTS: The study revealed that EVR significantly improved in the obese patients (85.3 vs. 64.7% in the treated and control groups, respectively, at P<0.05) without any significant improvement in the nonobese patients. Biochemical responses (defined as normalization of alanine aminotransferase at week 12) were markedly improved in the treated groups in both the nonobese and obese groups compared with their respective controls. CONCLUSION: The addition of ezetimibe to peg-IFN/RBV combination significantly improves EVR rates in obese patients compared with nonobese patients, and remarkably improves the biochemical responses in both obese and nonobese patients with CHC-4. This may shed light on a new strategy for the treatment of CHC, particularly in obese Egyptian patients.

Thymoquinone supplementation ameliorates acute endotoxemia-induced liver dysfunction in rats.

Endotoxemia caused by lipopolysaccharide (LPS) produced an inflammatory condition contributing to multiple organ failure. This study was carried out to investigate the effects of thymoquinone (TQ), the main constituent of Nigella sativa seeds, against LPS-induced hepatotoxicity. The obtained data revealed that LPS markedly depleted liver reduced glutathione (GSH) and significantly increased the level of malondialdehyde (MDA) and the activity of caspase-3 enzyme in the liver. Serum tumour necrosis factor-alpha (TNF-alpha) and bilirubin levels and the activities of alkaline phosphatase (ALP) and gamma-glutamyl transferase (gamma-GT) enzymes were markedly increased in LPS-treated rats. TQ supplementation resulted in normalization of liver GSH and decreases in the levels of MDA and caspase-3 activity in the liver with reduction of serum TNF-alpha, serum total bilirubin and the activities of ALP and gamma-GTenzymes. Histopathological examination revealed that TQ administration improved LPS-induced pathological abnormalities in liver tissues. The present study conclude that TQ reduced acute endoxemia-induced liver dysfunction at least in part by its anti-inflammatory, antiapoptotic and antioxidant activities.