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1.
Int J Pharm ; 631: 122539, 2023 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-36572266

RESUMEN

Increasing interest in developing antifibrotic therapies became a paramount priority due to the globally raised incidence of deaths secondary to hepatic cirrhosis. This work deals with the development of innovative antifibrotic pirfenidone -loaded lecithin core nanocapsules. This with the intention to target the liver and to increase the drug bioavailability, reducing drug liver toxicity, and studying the associated hepatic microenvironment changes. PFD-loaded lecithin nanocapsules (PFD-LENCs) were prepared using the natural lipoid S45 for its dual benefits of being both a lipid and an amphiphilic surfactant. The selected formulation exhibited in vitro sustained drug release up to 24 h compared to free PFD, which is consistent with the studied pharmacokinetic profile. The studied cytotoxicity of PFD as well as PFD-LENCs exhibited negligible cytotoxicity in normal oral epithelial cells. For exploring the capability of the PFD-LENCs in reaching the liver; in vivo tracing using CLSM, in vivo biodistribution to the vital organs were conducted and electron microscopic examination for depicting nanoparticles in liver tissue was performed. Results revealed the capability of the prepared fluorescent LENC2 in reaching the liver, PFD-LENCs detection in the Disse space of the liver and the significant accumulation of PFD-LENCs in liver tissue compared to the other tested organs. The assessment of the necro-inflammatory, antioxidant and the anti-fibrotic effect of PFD-LENCs (50 & 100 mg/kg) exhibited a significant decrease of liver enzymes, TNF-α, TGF-ß, Col-1, α-SMA, and TIMP-1, and a significant increase of catalase enzyme and MMP2 compared to free PFD. EM studies, revealed often detection of dendritic cells in PFD-LENCs (100 mg/kg) treated mice and abnormal collagen structure which can represent an adjunct contribution to the antifibrotic mechanism of PFD-LENCs. In conclusion, the development of this innovative PFD loaded lecithin nanocapsules achieved a targeting ability to the liver, controlled drug release, thereby increase the PFD therapeutic value in downregulating hepatic fibrosis in adjunct with the reduction of liver toxicity.


Asunto(s)
Lecitinas , Nanocápsulas , Ratones , Animales , Distribución Tisular , Cirrosis Hepática/tratamiento farmacológico , Piridonas/farmacocinética
2.
Adv Pharm Bull ; 12(4): 641-644, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36415639

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative organism of COVID-19. Since this disease is considered new and does not have an approved curative protocol, many researchers have tackled the possible options for COVID-19 prevention and therapeutic approaches. We address herein the phenomena of cytokine storm (the main cause of death) associating with the late stage of COVID19. Cytokine storm is undertaken in an attempt to provide information about its possible underlying causes, and to clarify some points that can be of value in guiding treatment practices for a clinical trial.

3.
Ultrastruct Pathol ; 46(1): 1-17, 2022 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-35139747

RESUMEN

Research centers around the world are competing to develop therapeutic and prophylactic agents to provide new intervention strategies that could halt or even help slow the progression of the COVID19 pandemic. This requires a deep understanding of the biology and cytopathology of the interaction of SARS-CoV-2 with the cell. This review highlights the importance of electron microscopy (EM) in better understanding the morphology, the subcellular morphogenesis, and pathogenesis of SARS-CoV-2, given its nanometric dimensions. The study also underscores the value of cryo-electron microscopy for analyzing the structure of viral protein complex at atomic resolution in its native state and the development of novel antibodies, vaccines, and therapies targeting the trimeric S spike proteins and the viral replication organelles. This review highlighted the emergence in a short period of time of several viral variants of concern with enhanced transmissibility and increased infectivity. This is due to the elevated affinity of the host receptor with acquired adaptive mutations in the spike protein gene of the virus.Subsequently, to the technical improvement of EM resolutions and the recent promising results with SARS-CoV2 variant structure determination, antibodies production, and vaccine development, it is necessary to maximize our investigations regarding the potential occurrence of immune pressure and viral adaptation secondary to repeated infection and vaccination.


Asunto(s)
COVID-19 , SARS-CoV-2 , Microscopía por Crioelectrón , Humanos , Microscopía Electrónica , ARN Viral
4.
Biotechnol Bioeng ; 118(1): 17-29, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32856740

RESUMEN

Liver tissue engineering aims to create transplantable liver grafts that can serve as substitutes for donor's livers. One major challenge in creating a fully functional liver tissue has been to recreate the biliary drainage in an engineered liver construct through integration of bile canaliculi (BC) with the biliary ductular network that would enable the clearance of bile from the hepatocytes to the host duodenum. In this study, we show the formation of such a hepatic microtissue by coculturing rat primary hepatocytes with cholangiocytes and stromal cells. Our results indicate that within the spheroids, hepatocytes maintained viability and function for up to 7 days. Viable hepatocytes became polarized by forming BC with the presence of tight junctions. Morphologically, hepatocytes formed the core of the spheroids, while cholangiocytes resided at the periphery forming a monolayer microcysts and tubular structures extending outward. The spheroids were subsequently cultured in clusters to create a higher order ductular network resembling hepatic lobule. The cholangiocytes formed functional biliary ductular channels in between hepatic spheroids that were able to collect, transport, and secrete bile. Our results constitute the first step to recreate hepatic building blocks with biliary drainage for repopulating the whole liver scaffolds to be used as transplantable liver grafts.


Asunto(s)
Conductos Biliares/metabolismo , Hepatocitos/metabolismo , Esferoides Celulares/metabolismo , Ingeniería de Tejidos , Animales , Conductos Biliares/citología , Células Cultivadas , Hepatocitos/citología , Hígado , Ratas , Esferoides Celulares/citología
5.
Drug Deliv Transl Res ; 11(5): 1943-1957, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33006742

RESUMEN

Our work tackles the combined advantages of both nanotechnology and the bioadhesive gel properties which were utilized to design an ocular drug delivery system that is capable to treat ocular inflammation. Nanoparticles encapsulating an antibiotic drug, ofloxacin, were fabricated using emulsion solvent evaporation technique adopting 23 full factorial design to evaluate the effect of formulation parameters: that is to say, the molecular weight of the polymer (polycaprolactone), amount of Kolliphor P188, and presence of the charge inducer (chitosan hydrochloride) on the measured responses: drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The results show that the optimized LPCL-NP2 formulation (composed of low molecular weight polycaprolactone, 500 mg of Kolliphor P188, 0.25% chitosan hydrochloride, and 50 mg ofloxacin)  displayed a sphere shape with EE%, PS, PDI, and ZP values of 89.73 ± 0.04%, 195.4 ± 13.17 nm, 0.323 ± 0.01, and 55.4 ± 0.66 mV, respectively. DSC study confirmed the amorphous nature of the drug. The optimized nanoparticle formulation was then further incorporated into the following two ocular formulations: gel (LPCL-NP2-G4) and in situ forming gel (LPCL-NP2-ISG4). The penetration of optimized ocular formulations was assessed by confocal laser scanning microscopy. The antimicrobial study was conducted  for the following three ocular formulations: LPCL-NP2 presented as eye drops, LPCL-NP2-G4, and LPCL-NP2-ISG4 as well as the market product using rabbits which were infected in their eyes with Escherichia coli. Results revealed that rabbits treated with LPCL-NP2-ISG4 demonstrated a remarkable antibacterial efficacy and evident low bacterial growth which was additionally assured by the histopathological examination of eye biopsies compared with the other investigated groups. Thus, a novel ofloxacin-loaded nanoparticle formulation based on polycaprolactone is presented in the form of mucoadhesive non-irritating in situ forming ocular gel possessing a superior antibacterial activity. Graphical abstract.


Asunto(s)
Quitosano , Nanopartículas , Animales , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Inflamación , Ofloxacino , Tamaño de la Partícula , Conejos
6.
AAPS PharmSciTech ; 21(7): 283, 2020 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-33051708

RESUMEN

Ciclopirox olamine (CPO) is a topical wide-spectrum antimycotic agent that possesses antifungal, antibacterial and anti-inflammatory activities. Loading CPO into a hybridized vesicular system is expected to enhance its buccal permeation and hence, therapeutic activity, whereas the frequent administration and side effects are reduced. Vesicular systems with high penetration ability were prepared based on cholesterol, Lipoid S45 or Phospholipon 90H, with span 60 while incorporating a penetration enhancer (Labrafac or labrasol) followed by full assessment of their size, entrapment efficiency, and drug release profiles. The optimum formulation, composed of Lipoid S45 and Labrafac, possessed the smallest vesicle size (346.1 nm), highest entrapment efficiency (94.4%), and sustained CPO release pattern, and was characterized for its morphology and thermal properties. This powerful mixture of the penetration enhancers (Lipoid S45 and Labrafac) in the designed hybridized vesicles was thoroughly investigated for their characteristics after being incorporated in bioadhesive gel. Moreover, enhanced antifungal activity was demonstrated either upon testing the designed formulation on agar plates or in vivo upon treating infected rabbits with the proposed formulation. Results suggest that the presented bioadhesive gel incorporating the CPO-loaded vesicles can be a promising delivery system that can offer a prolonged localized antifungal treatment with enhanced therapeutic effect.


Asunto(s)
Antifúngicos/administración & dosificación , Ciclopirox/administración & dosificación , Adhesivos , Administración Bucal , Agar , Animales , Antifúngicos/uso terapéutico , Candidiasis Bucal/tratamiento farmacológico , Candidiasis Bucal/microbiología , Colesterol/química , Ciclopirox/uso terapéutico , Composición de Medicamentos , Liberación de Fármacos , Excipientes , Nanopartículas , Tamaño de la Partícula , Conejos , Reología
7.
Ultrastruct Pathol ; 44(2): 203-210, 2020 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-32216509

RESUMEN

Background: Recent studies implicate the role of microRNAs in the pathogenesis of hepatocellular carcinoma (HCC). This study was designed to induce HCC, in an experimental model, with the prospect to study the molecular pathophysiologic changes accompanying the development of HCC and the effect of miRNA-195 vector on the process of hepatocarcinogenesis.Methodology: This study incorporated three groups of male albino mice; one control group and two other groups injected intraperitoneal with diethylnitrosamine (DEN) weekly for 12 weeks for the gradual induction of HCC. The third group was injected intra-hepatic with miR-195 vector 1 month after DEN injection. At the 8th and 12th weeks post-DEN treatment, the tumor-associated biomarkers alpha-fetoprotein (AFP), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-α) were assessed in the serum of all mice. Hepatic specimens were subjected to ultra-structural pathological examination as well as to caspase-3 and survivin genes expression analysis.Results: All the assessed serological and molecular parameters of HCC development, in the miRNA-195-treated group of mice, showed a significant increase, versus the DEN-treated group, whereas survivin was significantly down-regulated, in the miR-195-treated group (P < 0.001). Additionally, ultra-structural criteria of HCC were depicted, in the 12th week, in DEN-injected group, versus the 8th week, in the miRNA-195-treated group.Conclusions: Intra-hepatic injection of miRNA-195 vector induced apoptotic gene expression and suppressed anti-apoptotic gene but these favorable anti-cancer effects could not counteract the inflammatory, and subsequently, the oncogenic effect probably caused by vector administration. Therefore, further studies are required to investigate the effect of miRNA in combination with anti-inflammatory medications.


Asunto(s)
Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , MicroARNs/farmacología , Animales , Carcinógenos/toxicidad , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina/toxicidad , Modelos Animales de Enfermedad , Neoplasias Hepáticas/inducido químicamente , Masculino , Ratones
8.
APMIS ; 127(2): 93-105, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30698308

RESUMEN

This study aims to assess the value of carbamoyl phosphate synthetase 1 (CPS1), as a non-invasive serum marker, for the evolution of chronic HCV infection and hepatic fibrosis. Seventy-two patients with HCV positive serum RNA and 15 health volunteers were enrolled in this study. Out of 72 patients, 10 patients had decompensated liver with ascites. Quantitative analysis of CPS1 was performed in the harvested sera and corresponding liver biopsies using ELISA and immunohistochemistry techniques respectively. Also, mitochondrial count using electron microscopy, urea analysis and conventional liver tests were done. Patients were grouped into (F1 + F2) and (F3 + F4) representing stages of moderate and severe fibrosis respectively. Tissue and serum CPS1 (s.CPS1) correlated significantly in moderate and severe fibrosis. Patients with severe fibrosis showed significantly higher levels of s.CPS1 (p-value ≤ 0.05) and significantly lower mitochondrial counts (p-value = 0.0065) than those with moderate fibrosis. S.urea positively correlated with s.CPS1 only in the decompensated group, at which s.urea reached maximal levels. In conclusion, s.CPS1 is a potential non-invasive marker for the assessment of severity and progression of HCV in relation to mitochondrial dysfunction. Also, increased s.urea with the progression of the disease is mainly due to a concurrent renal malfunction, which needs further investigation.


Asunto(s)
Carbamoil-Fosfato Sintasa (Amoniaco)/sangre , Hepatitis C Crónica/patología , Cirrosis Hepática/patología , Mitocondrias/patología , Adulto , Anciano , Biomarcadores/sangre , Femenino , Hepatitis C Crónica/mortalidad , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Mitocondrias/ultraestructura , Pronóstico , Urea/sangre
9.
J Cell Physiol ; 234(6): 9328-9337, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30334569

RESUMEN

The potential inhibitory effect of the antidiabetic and anti-inflammatory drug, metformin on thioacetamide (TAA)-induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA-induced HIF-1α, mTOR, the profibrogenic biomarker α-smooth muscle actin, tissue inhibitor of metalloproteinases-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF-1α) and the serum levels of TNF-α ( r = 0.797), IL-6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA-induced hepatic injuries in rats, which is associated with the inhibition of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.


Asunto(s)
Biomarcadores/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/patología , Cirrosis Hepática/patología , Hígado/patología , Metformina/farmacología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Enfermedad Crónica , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Hepatocitos/ultraestructura , Hígado/efectos de los fármacos , Hígado/lesiones , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Masculino , Sustancias Protectoras/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Tioacetamida
10.
Int J Pharm ; 544(1): 129-140, 2018 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-29655798

RESUMEN

Wound healing following skin injury is a natural phenomenon that usually lacks quality, rapidity, and aesthetics. Thus, the purpose of this study was to fabricate a new easily applied in situ gel of cefadroxil (CDX) loaded chitosan nanoparticles (CDX-CSNPs) that could promote wound healing, capable of inhibiting the possible accompanying bacterial infection. The nanoparticles were prepared by double emulsion technique and the influence of formulation parameters on drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were investigated using a full factorial design. The results show that the optimized CDX-CSNP1 composed of low molecular weight chitosan (0.2%w/v) was spherical with EE%, PS, PDI and ZP of 84.25 ±â€¯0.02, 408.30 ±â€¯53.17 nm, 0.458 ±â€¯0.048 and 22.80 ±â€¯0.57 mV, respectively. DSC and XRD studies confirmed the amorphous nature of the drug. After ensuring the safety and non toxicity of CDX-CSNP1 in situ gel through cytotoxic study, the antibacterial activity was evaluated using a rat skin infection model against Staphylococcus aureus. Compared to the rats treated with free CDX, the CDX-CSNP1 treated group revealed a remarkable accelerated wound healing process and bacterial clearance which was further confirmed by the histopathological examination of skin biopsies.


Asunto(s)
Antibacterianos/administración & dosificación , Vendajes , Cefadroxilo/administración & dosificación , Quitosano/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Antibacterianos/química , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Infecciones Bacterianas/tratamiento farmacológico , Cefadroxilo/química , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Portadores de Fármacos/química , Liberación de Fármacos , Fibroblastos/efectos de los fármacos , Geles , Humanos , Masculino , Nanopartículas/química , Ratas , Piel/efectos de los fármacos , Piel/lesiones , Piel/microbiología , Piel/patología , Cicatrización de Heridas/efectos de los fármacos
11.
Ultrastruct Pathol ; 42(2): 97-107, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29424576

RESUMEN

Early detection of hepatocellular carcinoma (HCC) is crucial for successful therapy. The present work examined the value of ultrastructural morphometric image analysis of hepatocyte nuclei in patients with chronic hepatitis C virus (HCV) versus HCC cases with chronic HCV and the corresponding surgical tumor-free safe margins (TFMs), to highlight any early predictive signs of neoplastic cellular transformation. This work also performed an immunohistochemical assessment of cytokeratin 19 (CK19) and Ki-67-positive cells to visualize any associated proliferative activity in the examined groups. The results showed significant decrease in the hepatocyte nuclear surface areas in the HCC and TFMs versus those in the HCV cases. The hepatocyte nucleolar surface area was significantly increased in the HCC cases versus that in the HCV cases. This increase was associated with a significant increase in Ki-67-positive cells in the HCC cases compared to those in the other groups. Conversely, the mean number of CK 19-positive cells was significantly reduced in the HCC cases compared to the cell numbers in TFMs and HCV cases with severe hepatic fibrosis. Liver progenitor cells (LPCs) were discerned in the reactive ductules and canaliculo-ductular junctions that characterized TFMs. LPCs were sporadically distributed in the liver lobules and reactive bile ductules in the HCC samples. In conclusion, CK 19 represents an important marker for distinguishing between dysplastic and malignant liver nodules. Electron microscopic morphometric image analysis may be considered as adjunct factor for assessing hepatocyte malignant transformation. Wider scale studies are needed to authenticate these results.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/patología , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/ultraestructura , Carcinoma Hepatocelular/virología , Transformación Celular Neoplásica/ultraestructura , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Humanos , Interpretación de Imagen Asistida por Computador , Inmunohistoquímica , Queratina-19/análisis , Queratina-19/biosíntesis , Neoplasias Hepáticas/ultraestructura , Neoplasias Hepáticas/virología , Microscopía Electrónica de Transmisión
12.
Ultrastruct Pathol ; 41(3): 209-226, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28494215

RESUMEN

Hepatitis C virus represents one of the rising causes of hepatocellular carcinoma (HCC). Although the early diagnosis of HCC is vital for successful curative treatment, the majority of lesions are diagnosed in an irredeemable phase. This work deals with a comparative ultrastructural study of experimentally gradually induced HCC, surgically resected HCC, and potential premalignant lesions from HCV-infected patients, with the prospect to detect cellular criteria denoting premalignant transformation. Among the main detected pathological changes which are postulated to precede frank HCC: failure of normal hepatocyte regeneration with star shape clonal fragmentation, frequent elucidation of hepatic progenitor cells and Hering canals, hepatocytes of different electron density loaded with small sized rounded monotonous mitochondria, increase junctional complexes bordering bile canaliculi and in between hepatocyte membranes, abundant cellular proteinaceous material with hypertrophied or vesiculated rough endoplasmic reticulum (RER), sequestrated nucleus with proteinaceous granular material or hypertrophied RER, formation of lipolysosomes, large autophagosomes, and micro-vesicular fat deposition. In conclusion, the present work has visualized new hepatocytic division or regenerative process that mimic splitting or clonal fragmentation that occurs in primitive creature. Also, new observations that may be of value or assist in predicting HCC and identifying the appropriate patient for surveillance have been reported. Moreover, it has pointed to the possible malignant potentiality of liver stem/progenitor cells. For reliability, the results can be subjected to cohort longitudinal study.


Asunto(s)
Carcinoma Hepatocelular/ultraestructura , Hepatitis C/complicaciones , Hepatocitos/ultraestructura , Neoplasias Hepáticas/ultraestructura , Carcinoma Hepatocelular/virología , Diagnóstico Diferencial , Femenino , Hepatocitos/virología , Humanos , Neoplasias Hepáticas/virología , Masculino , Reproducibilidad de los Resultados , Células Madre/ultraestructura
13.
Ultrastruct Pathol ; 40(5): 276-87, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27409252

RESUMEN

The present work deals with the simultaneous ultrastructure and triple immunofluorescence study of the three main hepatic fibrogenic cells, hepatic stellate cell, myofibroblast (MF), and fibroblast, in a group of hepatitis C virus (HCV) RNA positive patients, as their exact interrelation behavior in vivo with the progress of hepatic fibrosis is still inadequate. In this study, for the first time, cells having the morphological characteristic of MF and not bone marrow fibrocytes were revealed in liver portal vessels. This necessitates the reevaluation of the available knowledge concerning bone marrow fibrocyte. Also, the distribution, cellular interrelations, and the fate of MF were highlighted.


Asunto(s)
Fibroblastos/ultraestructura , Células Estrelladas Hepáticas/ultraestructura , Hepatitis C/patología , Cirrosis Hepática/patología , Miofibroblastos/ultraestructura , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Hepatitis C/complicaciones , Humanos , Ácido Hialurónico , Cirrosis Hepática/virología , Microscopía Confocal , Microscopía Electrónica de Transmisión
14.
J Egypt Soc Parasitol ; 46(1): 57-66, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27363041

RESUMEN

The prevalence of methicillin-resistant Staphyloccoccus aureus (MRSA) strains has presented a new challenge in antimicrobial medication. Linezolid is a new drug with potent activity on Gram-positive pathogens such as MRSA. The aim of the study was to investigate the in vitro activity of linezolid alone and in combination with imipenem, vancomycin or rifampicin to determine the most active therapy against MRSA strains. Twenty clinical MRSA strains were isolated from patients admitted to inpatient departments and outpatient clinics of Theodor Bilharz Research Institute. Standard strain MRSA ATCC 43300 was included as a control. The MICs of MRSA strains to linezolid, vancomycin, imipenem and rifampicin were evaluated using E test. Time-kill curve were used to assess the in vitro activity of linezolid (at 8x MIC) alone and in combination with imipenem (at 32x MIC), vancomycin or rifampicin (at 8x MIC). Scanning and transmission electron microscopy were performed to compare bacterial morphological alterations owing to the different combi- nations. Time-kill studies showed synergistic effect when linezolid combined with imipenem was tested against all the MRSA strains. Linezolid plus vancomycin or rifampicin combinations did not display any synergism or antagonism. Scanning and transmission electron microscopy observations confirmed the interactions observed in time kill experiments. Linezolid in combination with subinhibitory concentrations of imipenem can be bactericidal against MRSA strains and appears to be a promising combination for the treatment of MRSA infections. No synergistic activity was seen when the linezolid and vancomycin or rifampicin were combined. Linezolid could prevent the emergence of mutants resistant to rifampicin


Asunto(s)
Antibacterianos/farmacología , Linezolid/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/administración & dosificación , Quimioterapia Combinada , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana
15.
Clin Chem Lab Med ; 52(9): 1319-28, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24803609

RESUMEN

BACKGROUND: Development of non-invasive markers that can predict the stages of hepatic fibrosis without resorting to repeated liver biopsies is still an important goal to evaluate the effectiveness of antifibrotic treatment. The present work investigates the value of the assessment of peripheral circulating reelin, in which the liver represents its prime source, as a marker for monitoring hepatic fibrogenesis. METHODS: Seventy-four cases with chronic hepatitis positive for serum HCV RNA and 15 healthy volunteers were enrolled in this study. Assessment of reelin in the harvested serum and in 64 corresponding liver biopsies using immunofluorescence technique was done. The results were evaluated in relation to the stages and quantitative morphometric analysis of hepatic fibrosis as well as the serum levels of the validated biomarker hyaluronic acid. RESULTS: Significant correlation was detected between the levels of serum reelin and the semiquantitative assessment of reelin immunoreactivity in liver tissue, the stages of hepatic fibrosis, the morphometrically determined collagen and serum hyaluronic acid with a correlation coefficient of 0.675, 0.623, 0.479, 0.772, respectively with p<0.001. The sensitivity and the specificity of reelin for the determination of advanced (F2+F3) and significant fibrosis (F2-F4) were nearly comparable to the result of hyaluronic acid. In addition the area under curve (AUC) were 0.859, 0.871 for the reelin versus 0.878, and 0.891 for the hyaluronic acid. CONCLUSIONS: In conclusion serum reelin may be considered an additional useful parameter for monitoring the progression of hepatic fibrosis in HCV-infected patients specially in those with active rheumatological conditions which result in an increase in serum hyaluronic acid.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/sangre , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/sangre , Proteínas de la Matriz Extracelular/metabolismo , Hepatitis C Crónica/sangre , Hepatitis C Crónica/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/metabolismo , Proteínas del Tejido Nervioso/sangre , Proteínas del Tejido Nervioso/metabolismo , Serina Endopeptidasas/sangre , Serina Endopeptidasas/metabolismo , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Análisis Químico de la Sangre , Colágeno/metabolismo , Progresión de la Enfermedad , Egipto , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Hepatitis C Crónica/patología , Humanos , Ácido Hialurónico/sangre , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteína Reelina
16.
APMIS ; 119(1): 66-75, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21143528

RESUMEN

The in vivo angiogenic potential of transplanted human umbilical cord blood (UCB) CD133(+) stem cells in experimental chronic hepatic fibrosis induced by murine schistosomiasis was studied. Enriched cord blood-derived CD133(+) cells were cultured in primary medium for 3 weeks. Twenty-two weeks post-Schistosomiasis infection in mice, after reaching the chronic hepatic fibrotic stage, transplantation of stem cells was performed and mice were sacrificed 3 weeks later. Histopathology and electron microscopy showed an increase in newly formed blood vessels and a decrease in the fibrosis known for this stage of the disease. By immunohistochemical analysis the newly formed blood vessels showed positive expression of the human-specific angiogenic markers CD31, CD34 and von Willebrand factor. Few hepatocyte-like polygonal cells showed positive expression of human vascular endothelial growth factor and inducible nitric oxide synthase. The transplanted CD133(+) human stem cells primarily enhanced hepatic angiogenesis and neovascularization and contributed to repair in a paracrine manner by creating a permissive environment that enabled proliferation and survival of damaged cells rather than by direct differentiation to hepatocytes. A dual advantage of CD133(+) cell therapy in hepatic disease is suggested based on its capability of hematopoietic and endothelial differentiation.


Asunto(s)
Antígenos CD/sangre , Sangre Fetal/fisiología , Glicoproteínas/sangre , Cirrosis Hepática/inmunología , Neovascularización Fisiológica/fisiología , Péptidos/sangre , Células Madre/fisiología , Antígeno AC133 , Adulto , Animales , Antígenos CD/inmunología , Femenino , Sangre Fetal/citología , Sangre Fetal/inmunología , Glicoproteínas/inmunología , Humanos , Inmunohistoquímica , Recién Nacido , Cirrosis Hepática/sangre , Ratones , Microscopía Electrónica , Neovascularización Fisiológica/inmunología , Péptidos/inmunología , Trasplante de Células Madre , Células Madre/citología , Células Madre/inmunología , Adulto Joven
17.
APMIS ; 118(4): 277-87, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20402673

RESUMEN

The efficiency of differentiation of bone marrow cells (BMCs) into hepatocytes in vivo and its importance in physiopathological processes is still debated. Murine schistosomiasis was used as a liver injury model and unfractionated male mice BMCs were transplanted through intrahepatic injection into non-irradiated Schistosoma mansoni-infected female mice on their 16th week post-infection. Two weeks after bone marrow transplantation, mice were sacrificed on a weekly basis until 10 weeks. Tracing of male donor-derived cells in female recipient mice livers was carried out by the detection of Y chromosome expression by fluorescent in situ hybridization (FISH) and also of chromodomain Y-linked (CDYL) protein by indirect immunofluorescence (IF). Their transformation into hepatocytes was studied by double labelling indirect IF using antibodies directed against CDYL and mouse albumin. Histopathological and electron microscopic examinations revealed the presence of small hepatocyte-like cells in the periportal tracts and in between the hepatocytes facing the sinusoids. Donor-derived cells showing Y chromosome by FISH and expressing CDYL protein by IF were recovered in the infected transplanted livers. The initial number of these cells increased with increased post-transplantation time. Cells were mainly localized in the periphery of schistosoma granuloma. Few donor-derived cells appeared within the hepatic parenchymal tissue and showed positivity for albumin secretion by double labelling with IF. We suggest that transplanted bone marrow stem cells can repopulate the Schistosoma-infected liver of immunocompetent mice. Their differentiation is a complex event controlled by many factors and needs to be further characterized extensively. The extent and type of liver injury and the number of transplanted cells are important variables in the process of stem cell engraftment and differentiation into functioning hepatic cells that still need to be defined.


Asunto(s)
Trasplante de Médula Ósea , Movimiento Celular/fisiología , Células Madre Hematopoyéticas/citología , Hígado/citología , Esquistosomiasis mansoni/cirugía , Animales , Femenino , Técnica del Anticuerpo Fluorescente , Hibridación Fluorescente in Situ , Masculino , Ratones
18.
Ultrastruct Pathol ; 34(2): 62-7, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20192701

RESUMEN

An ultrastructural quantitative assessment of hepatic stellate cells (HSCs) was made in relation to hepatic fibrosis, apoptotic cellular changes, intracellular fat deposition, circulating inflammatory cells in the sinusoids, and the necroinflammatory activity in liver specimens of 33 patients proven to be positive for hepatitis C virus (HCV)-RNA by polymerase chain reaction with the intention that electron microscopy may throw more light on the role of HSCs in the complicated process of fibrogenesis. A detailed review concerning these parameters and observed evidence suggesting the potential properties of HSCs to recycle cellular debris into collagen fibers are reported.


Asunto(s)
Células Estrelladas Hepáticas/ultraestructura , Hepatitis C Crónica/patología , Cirrosis Hepática/patología , Microscopía Electrónica de Transmisión/métodos , Apoptosis/fisiología , Hepacivirus/genética , Hepacivirus/inmunología , Hepacivirus/aislamiento & purificación , Células Estrelladas Hepáticas/química , Hepatitis C Crónica/metabolismo , Humanos , Lípidos/análisis , Cirrosis Hepática/metabolismo , ARN Viral/análisis
19.
Ultrastruct Pathol ; 33(1): 21-7, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19191198

RESUMEN

The present work highlights intracellular viral morphogenesis and virus-host cell interactions in patients proved to be infected with HCV. The material of this study consisted of 28 liver biopsies taken from patients positive for serum HCV-RNA by polymerase chain reaction. Liver biopsies were processed for light and electron microscopic examination. Ultrastructural findings of this work supported a new hypothesis for the turnover of HCV to retrovirus and described the presumed involved mechanism. This novel perception offers important insights that can explain the vague mechanisms of HCV behavior in the infected hepatocytes.


Asunto(s)
Transformación Celular Viral/fisiología , Hepacivirus/fisiología , Hepatitis C Crónica/virología , Interacciones Huésped-Parásitos/fisiología , Retroviridae/fisiología , Hepacivirus/ultraestructura , Hepatocitos/ultraestructura , Hepatocitos/virología , Humanos , Microscopía Electrónica de Transmisión , Retroviridae/ultraestructura
20.
Ultrastruct Pathol ; 30(5): 379-85, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17090517

RESUMEN

Proper handling and processing of urine sample can greatly improve diagnostic sensitivity. This work investigates the value of agarose cell block technique in processing urine samples simultaneously for light and electron microscopic examination, with the prospect to enhance the quality of diagnosis. The material of this study consisted of 45 voided urine samples, processed for the performance of Papanicolaou-stained urine smears, agarose cell blocks paraffin sections stained with hematoxylin & eosin, and electron microscopy-contrasted ultrathin sections. The studied technique increases the sensitivity of urine cytology and opens a new prospect for cytomorphological study.


Asunto(s)
Adenocarcinoma/diagnóstico , Microscopía Electrónica/métodos , Sefarosa , Adhesión del Tejido/métodos , Neoplasias de la Vejiga Urinaria/diagnóstico , Orina/citología , Adenocarcinoma/orina , Citodiagnóstico/métodos , Humanos , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Neoplasias de la Vejiga Urinaria/orina
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