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1.
Hypertens Res ; 46(11): 2535-2542, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37673958

RESUMEN

Adrenal vein sampling (AVS) is the standard procedure for distinguishing unilateral primary aldosteronism (PA) from bilateral PA. In cases where only one adrenal vein is successfully cannulated, it has been suggested that subtype classification can be determined based on the ratio of the concentration of aldosterone between the adrenal vein and the inferior vena cava (AV/IVC index). However, diagnostic performance of the ipsilateral versus contralateral AV/IVC index in predicting lateralization has not been directly compared. In a retrospective cohort of 133 patients with confirmed PA who underwent successful AVS, the performance of the AV/IVC index to predict laterality was evaluated and the area under the receiver operating characteristic (AUROC) curves was calculated. In detecting left unilateral PA (n = 47), the AUROC of the right AV/IVC index (RAV/IVC) was significantly higher than the AUROC of the left AV/IVC (LAV/IVC) index (0.967 vs. 0.871, p = 0.008). In detecting right unilateral PA (n = 30), the AUROC of the LAV/IVC index tended to be higher than that of the RAV/IVC index, but the difference did not reach statistical significance (0.966 vs. 0.906, p = 0.08). In detecting left unilateral PA, the sensitivities of the RAV/IVC and LAV/IVC indices were 83% and 46%, respectively, while the specificities of both were above 90%. In detecting right unilateral PA, the sensitivities of the LAV/IVC and RAV/IVC indices were 80% and 43%, respectively, while the specificities of both were above 90%. The AV/IVC index has superior diagnostic performance in detecting contralateral unilateral PA compared to ipsilateral unilateral PA.


Asunto(s)
Aldosterona , Hiperaldosteronismo , Humanos , Vena Cava Inferior/diagnóstico por imagen , Hiperaldosteronismo/diagnóstico , Estudios Retrospectivos , Glándulas Suprarrenales/irrigación sanguínea
2.
Expert Rev Hematol ; 14(7): 593-605, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34139952

RESUMEN

Introduction: Inferior vena cava (IVC) filters are mechanical filtration devices designed as an alternative to surgical ligation/plication of the IVC. Their use has been controversial, especially with the introduction of retrievable filters and expanded/prophylactic indications.Areas covered: Authors discuss the types of available IVC filters, indications for placement, evidence on their effectiveness in general and specific patient populations, procedural considerations, off-label use, complications, and filter retrieval. This review is based on manuscripts/abstracts published from 1960 to 2021 on venous thromboembolism and IVC filters.Expert opinion: Despite the limited data on their effectiveness and survival benefit, IVC filters continue to play an important role in the treatment of patients with venous thromboembolism (VTE) who cannot receive standard anticoagulation. There is no role of IVC filters in patients without VTE. While retrievable filters are desirable for short-term use, a dedicated team-based approach, and advanced training are required for their successful removal. Newer devices are promising in improving patient safety . The device manufacturers and regulatory agencies should consider specific approaches to track device-related adverse events. Population-based studies are required to establish optimal patient population who would benefit from these devices. .


Asunto(s)
Embolia Pulmonar , Filtros de Vena Cava , Tromboembolia Venosa , Coagulación Sanguínea , Remoción de Dispositivos/efectos adversos , Humanos , Embolia Pulmonar/etiología , Estudios Retrospectivos , Filtros de Vena Cava/efectos adversos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control
3.
Radiol Case Rep ; 15(9): 1423-1427, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32642010

RESUMEN

Abdominal surgery in patients with cirrhosis and portal hypertension remains a challenge due to higher risk of morbidity and mortality. Preoperative elective transjugular intrahepatic portosystemic shunt (TIPS) is increasingly being used in these patient population. Herein, we report a case of 65-year-old male with biopsy-proven ascending colon cancer and cirrhosis. As a sequalae of portal hypertension, patient also had large caput medusae which posed significant challenge to the surgical approach for resection of the colon cancer. The patient was managed initially with placement of TIPS to decompress the portal pressures and caput medusae and allow safe surgical field for curative resection of the colon cancer. Following this, the patient underwent uneventful laparoscopic right hemicolectomy.

4.
World J Urol ; 37(10): 2175-2182, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30560299

RESUMEN

PURPOSE: To evaluate the efficacy and outcome of superselective vesical arterial embolization in the management of severe intractable hematuria secondary to hemorrhagic cystitis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of nine patients with severe intractable hematuria treated with superselective vesical artery embolization at our institution between March 2003 and February 2015. There were six males and three females with a mean age of 56.1 years. Seven patients had transitional cell carcinoma (TCC) of urinary bladder and had undergone transurethral resection of bladder tumor and pelvic radiotherapy. One patient had synchronous renal pelvis and bladder TCC. One patient had aortoarteritis and was receiving cyclophosphamide therapy and another patient had carcinoma cervix post-pelvic radiotherapy. Following the failure of conservative management, superselective vesical artery catheterization and embolization was performed with 300-500-µ PVA particles in all patients. Coil embolization of inferior gluteal artery followed by particle embolization of vesical arteries was done in one patient in whom superior, inferior vesical and inferior gluteal arteries were arising as a trifurcation. RESULTS: The technical success rate was 100% with complete cessation of hematuria within 48 h in all patients. No significant complications were noted, except for post-embolization syndrome in one patient, which improved on symptomatic treatment. During a mean follow-up period of 14.45 months (ranging from 3-28 months), one patient had mild recurrent hematuria (at 2 months) which resolved spontaneously. CONCLUSIONS: Superselective vesical artery embolization is a safe and effective procedure in controlling intractable life-threatening hematuria in a select group of patients who have failed conventional treatment protocols. This procedure may be considered as the treatment of choice since it usually obviates the need for emergency surgery in these severely ill patients.


Asunto(s)
Cistitis/complicaciones , Embolización Terapéutica/métodos , Hematuria/etiología , Hematuria/terapia , Hemorragia/complicaciones , Arterias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Vejiga Urinaria/irrigación sanguínea
5.
Bioconjug Chem ; 29(11): 3606-3613, 2018 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30247899

RESUMEN

The diagnosis and prognosis of the disease associated with lipid irregularity are areas of extreme significance. In this direction, fluoranthene based yellow fluorescent probes (FLUN-550, FLUN-552, FLUN-547) were designed and synthesized by conjugating the ethanolamine headgroup of the phospholipid phosphatidyl-ethanolamine present in biological membranes. Owing to unique photophysical properties and aqueous compatibility, these probes were successfully employed for staining lipid droplets (LDs) in preadipocytes and Leishmania donovani promastigotes. Furthermore, using the fluorescent probes FLUN-550 and FLUN-552 we successfully imaged and quantitatively detected the excess accumulation of lipids in a liver section of Plasmodium yoelii MDR infected mice (3- to 4-fold) and the tissue sections of third stage human cervical cancer patients (1.5- to 2-fold) compared to normal tissues. To the best of our knowledge, this is the first report of yellow fluorescent probes for imaging and quantitative detection of LDs in human cervical cancer tissues. These new yellow fluorescent lipid probes (FLUN-550 and FLUN-552) showed great potential for diagnosis of cervical cancer patients.


Asunto(s)
Colorantes Fluorescentes/metabolismo , Gotas Lipídicas/metabolismo , Hígado/metabolismo , Hígado/parasitología , Plasmodium yoelii/patogenicidad , Neoplasias del Cuello Uterino/metabolismo , Células 3T3-L1 , Animales , Teoría Funcional de la Densidad , Femenino , Humanos , Leishmania donovani/metabolismo , Ratones , Coloración y Etiquetado
6.
Sci Rep ; 8(1): 2303, 2018 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-29396506

RESUMEN

Autophagy, a regulated nutrient recycling program can affect both cell survival and cell death. Here, we show that Ormeloxifene (ORM), a selective estrogen receptor modulator approved for oral contraceptive use induces autophagic flux in ovarian cancer cells, which is activated by an ER stress response upstream of autophagy. The ER stress response is characterized by activation of IRE1α, PERK and ATF6 and is under regulation of JNK. Pharmacological inhibition of either autophagy or ER stress increased cell survival, as did silencing of autophagy proteins LC3 and Beclin 1, implying that ORM-induced autophagy is pro-death in nature. Ultrastructural observations of treated cells confirmed stages of autophagic maturation. Caspase-dependent apoptosis succeeded these events and was characterized by generation of reactive oxygen species and disruption of mitochondrial membrane potential. A concomitant inhibition of the Akt/mTOR axis was also observed with possible regulation of Akt by ORM. ORM inhibited tumor growth in ovarian xenograft model and displayed autophagic activity. In summary, in vitro and in vivo results reveal that ORM induces autophagy-associated cell death to attenuate proliferation of ovarian cancer cells. Our results demonstrate that using ORM in combination with ER stress and autophagy modulators could offer better therapeutic outcome in ovarian cancer.


Asunto(s)
Antineoplásicos/metabolismo , Apoptosis , Autofagia , Benzopiranos/metabolismo , Transducción de Señal , Respuesta de Proteína Desplegada , Animales , Antineoplásicos/administración & dosificación , Benzopiranos/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Xenoinjertos , Humanos , Ratones , Trasplante de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Resultado del Tratamiento
7.
Cureus ; 10(11): e3576, 2018 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-30656080

RESUMEN

Behcet's disease is inflammatory vasculitis that has a high incidence of mortality in patients with pulmonary artery aneurysm (PAA) formation. Traditionally, patients with Behcet's disease and PAA rupture undergo invasive surgical management. Surgical intervention; however, has been shown to have high complication, failure, and mortality rates. It has become a more contemporary practice to utilize the interventional embolization of pulmonary artery aneurysms (PAAs) in patients with Behcet's disease and other various etiologies because of its inherent minimally invasive nature and decreased risk for complications. The management paradigm for treating PAAs has shifted toward endovascular embolization even in severe or emergent cases where surgical management was once thought to be the standard. The following case is a testimony to the practicality of interventional embolization in the setting of a symptomatic patient presenting with PAAs.

8.
Cell Mol Life Sci ; 75(3): 563-588, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28900667

RESUMEN

In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4ß7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101's affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis.


Asunto(s)
Etilenos/uso terapéutico , Integrinas/antagonistas & inhibidores , Leishmania donovani/enzimología , Leishmaniasis Visceral/tratamiento farmacológico , NADH NADPH Oxidorreductasas/efectos de los fármacos , Animales , Células Cultivadas , Cricetinae , Modelos Animales de Enfermedad , Etilenos/farmacología , Femenino , Interacciones Huésped-Parásitos/efectos de los fármacos , Integrinas/efectos de los fármacos , Leishmania donovani/efectos de los fármacos , Leishmania donovani/metabolismo , Leishmaniasis Visceral/metabolismo , Leishmaniasis Visceral/patología , Masculino , Ratones , Ratones Endogámicos BALB C , NADH NADPH Oxidorreductasas/metabolismo , Oxidación-Reducción/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
9.
Sci Rep ; 7(1): 3384, 2017 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-28611397

RESUMEN

Marine fish antimicrobial peptide, chrysophsin-1 possesses versatile biological activities but its non-selective nature restricts its therapeutic possibilities. Often small alterations in structural motifs result in significant changes in the properties of concerned proteins/peptides. We have identified GXXXXG motif in chrysophsin-1. Glycine residue(s) of this motif in Chrysophsin-1 was/were replaced with alanine, valine and proline residue(s). Of these, proline-substituted Chrysophsin-1 analogs exhibited significantly reduced cytotoxicity towards mammalian cells. Further, these analogs showed broad-spectrum activity against Gram-positive, Gram-negative bacteria, Methicillin-resistant Staphylococcus aureus strains and fungi and also retained antibacterial activity in presence of physiological salts, serum and at elevated temperatures indicative of their therapeutic potential. These Chrysophsin-1 analogs also inhibited lipopolysaccharide (LPS) induced pro-inflammatory responses in THP-1 cells and in murine primary macrophages. One of these single proline-substituted Chrysophsin-1 analogs inhibited LPS-stimulated pro-inflammatory cytokine production in BALB/c mice and elicited appreciable survival of mice administered with a lethal dose of LPS in a model of severe sepsis. The data for the first time showed the implication of GXXXXG motifs in functional and biological properties of an antimicrobial peptide and could be useful to design novel anti-microbial and anti-endotoxin peptides by employing this motif.


Asunto(s)
Secuencias de Aminoácidos , Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Bacterias/crecimiento & desarrollo , Diseño de Fármacos , Hongos/crecimiento & desarrollo , Lipopolisacáridos/antagonistas & inhibidores , Animales , Antiinfecciosos/química , Péptidos Catiónicos Antimicrobianos/química , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana
10.
Acta Biomater ; 57: 170-186, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28483698

RESUMEN

Introducing cell-selectivity in antimicrobial peptides (AMPs) without compromising the antimicrobial and anti-endotoxin properties is a crucial step towards the development of new antimicrobial agents. A peptide designed on phenylalanine heptad repeat possesses significant cytotoxicity along with desired antimicrobial and anti-endotoxin properties. Amino acid substitutions at 'a' and/or 'd' positions of heptad repeats of AMPs could alter their helical structure in mammalian membrane-mimetic environments and cytotoxicity towards mammalian cells. Since proline is a helix breaker, effects of selective proline substitution(s) at 'a' and/or 'd' positions of a 15-residue peptide designed on phenylalanine heptad repeat (FR-15) were investigated. Proline-substituted FR-15 variants were highly selective toward bacteria and fungi over hRBCs and murine 3T3 cells and also retained their antibacterial activities at high salt, serum and elevated temperatures. These non-cytotoxic variants also inhibited LPS-induced production of pro-inflammatory cytokines/chemokines in human monocytes, THP-1, RAW 264.7 and in BALB/c mice. The two non-cytotoxic variants (FR8P and FR11P) showed potent anti-cancer activity against highly metastatic human breast cancer cell line MDA-MB-231 with IC50 values less than 10µM. At sub-IC50 concentrations, FR8P and FR11P also showed anti-migratory and anti-invasive effects against MDA-MB-231 cells. FR8P and FR11P induced cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. Overall the results demonstrated the utilization of selective phenylalanine to proline substitution in a heptad repeat of phenylalanine residues for the design of cell-selective, broad-spectrum AMPs with significant anti-cancer properties. STATEMENT OF SIGNIFICANCE: We have demonstrated a methodology to design cell-selective potent antimicrobial and anti-endotoxin peptides by utilizing phenylalanine zipper as a template and replacement of phenylalanine residue(s) from "a" and/or "d" position(s) with proline residue(s) produced non-cytotoxic AMPs with improved antibacterial properties against the drug-resistant strains of bacteria. The work showed that the 'a' and 'd' positions of the phenylalanine heptad repeat could be replaced by an appropriate amino acid to control cytotoxicity of the peptide without compromising its potency in antimicrobial and anti-endotoxin properties. The direct bacterial membrane targeting mechanism of proline substituted analogs of parent peptide makes difficult for bacteria to grow resistance against them. The peptides designed could be lead molecules in the area of sepsis as they possess significant anti-LPS activities for in vitro and in vivo. Interestingly since cancer cells and bacterial cell membranes possess the structural resemblances, the cancer cells are also targets for these peptides making them lead molecules in this field. However, unlike in bacteria where the peptides showed membrane permeabilization property to lyse them, the peptides induced apoptosis in MDA-MB-231 breast cancer cells to inhibit their proliferation and growth. The results are significant because it reveals that "a" and "d" positions of a phenylalanine zipper can be utilized as switches to design cell-selective, antimicrobial, anti-endotoxin and anticancer peptides.


Asunto(s)
Sustitución de Aminoácidos , Antibacterianos , Péptidos Catiónicos Antimicrobianos , Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Escherichia coli/crecimiento & desarrollo , Células 3T3 , Animales , Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Ratones , Fenilalanina/química , Fenilalanina/genética , Prolina/química , Prolina/genética , Células RAW 264.7 , Secuencias Repetitivas de Aminoácido , Células THP-1
11.
J Mater Chem B ; 5(14): 2580-2587, 2017 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-32264036

RESUMEN

In order to address the existing limitations of the commercially available fluorescent probe CMAC (7-amino-4-chloromethylcoumarin), a new series of highly fluorescent donor-acceptor 7-hydroxy-coumarin derivatives was prepared and these derivatives were used as vacuole specific fluorescent probes for live cell imaging of unicellular parasitic protozoa L. donovani promastigotes and yeast cells S. pombe and S. cerevisiae. The synthesized 7-hydroxy-coumarins exhibited interesting photophysical properties and have advantages such as excitation in the visible region, good water solubility, photo-stability, good quantum yield and low cytotoxicity.

12.
Apoptosis ; 21(8): 941-53, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27315817

RESUMEN

Naphthoquinones are known to exhibit a broad range of biological activities against microbes, cancer and parasitic diseases and have been widely used in Indian traditional medicine. Plumbagin is a plant-derived naphthoquinone metabolite (5-hydroxy-2-methyl-1,4-naphthoquinone) reported to inhibit trypanothione reductase, the principal enzyme and a validated drug target involved in detoxification of oxidative stress in Leishmania. Here, we report the mechanistic aspects of cell death induced by plumbagin including physiological effects in the promastigote form and ultrastructural alterations in both promastigote and amastigote forms of Leishmania donovani which till now remained largely unknown. Our observations show that oxidative stress induced by plumbagin resulted in depolarization of the mitochondrial membrane, depletion in ATP levels, elevation of cytosolic calcium, increase in caspase 3/7-like protease activity and lipid peroxidation in promastigotes. Apoptosis-like cell death induction post plumbagin treatment was confirmed by biochemical assays like Annexin V/FITC staining, TUNEL as well as morphological and ultrastructural studies. These findings collectively highlight the mode of action and importance of oxidative stress inducing agents in effectively killing both forms of the Leishmania parasite and opens up the possibility of exploring plumbagin and its derivatives as promising candidates in the chemotherapy of Leishmaniasis.


Asunto(s)
Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Leishmania donovani/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Naftoquinonas/farmacología , Adenosina Trifosfato/metabolismo , Anexina A5/metabolismo , Calcio/metabolismo , Caspasas/metabolismo , Células Cultivadas , Citosol/efectos de los fármacos , Citosol/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Etiquetado Corte-Fin in Situ/métodos , Leishmania donovani/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
13.
Antimicrob Agents Chemother ; 60(6): 3687-99, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27067326

RESUMEN

Piscidin-1 possesses significant antimicrobial and cytotoxic activities. To recognize the primary amino acid sequence(s) in piscidin-1 that could be important for its biological activity, a long heptad repeat sequence located in the region from amino acids 2 to 19 was identified. To comprehend the possible role of this motif, six analogs of piscidin-1 were designed by selectively replacing a single isoleucine residue at a d (5th) position or at an a (9th or 16th) position with either an alanine or a valine residue. Two more analogs, namely, I5F,F6A-piscidin-1 and V12I-piscidin-1, were designed for investigating the effect of interchanging an alanine residue at a d position with an adjacent phenylalanine residue and replacing a valine residue with an isoleucine residue at another d position of the heptad repeat of piscidin-1, respectively. Single alanine-substituted analogs exhibited significantly reduced cytotoxicity against mammalian cells compared with that of piscidin-1 but appreciably retained the antibacterial and antiendotoxin activities of piscidin-1. All the single valine-substituted piscidin-1 analogs and I5F,F6A-piscidin-1 showed cytotoxicity greater than that of the corresponding alanine-substituted analogs, antibacterial activity marginally greater than or similar to that of the corresponding alanine-substituted analogs, and also antiendotoxin activity superior to that of the corresponding alanine-substituted analogs. Interestingly, among these peptides, V12I-piscidin-1 showed the highest cytotoxicity and antibacterial and antiendotoxin activities. Lipopolysaccharide (12 mg/kg of body weight)-treated mice, further treated with I16A-piscidin-1, the piscidin-1 analog with the highest therapeutic index, at a single dose of 1 or 2 mg/kg of body weight, showed 80 and 100% survival, respectively. Structural and functional characterization of these peptides revealed the basis of their biological activity and demonstrated that nontoxic piscidin-1 analogs with significant antimicrobial and antiendotoxin activities can be designed by incorporating single alanine substitutions in the piscidin-1 heptad repeat.


Asunto(s)
Antiinfecciosos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Proteínas de Peces/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Peritonitis/prevención & control , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Línea Celular , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Diseño de Fármacos , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Femenino , Proteínas de Peces/síntesis química , Proteínas de Peces/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/crecimiento & desarrollo , Hemólisis/efectos de los fármacos , Humanos , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Peritonitis/inducido químicamente , Peritonitis/mortalidad , Peritonitis/patología , Ingeniería de Proteínas , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Análisis de Supervivencia
14.
Sci Rep ; 5: 9127, 2015 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-25773522

RESUMEN

IsCT, a 13-residue, non-cell-selective antimicrobial peptide is comprised of mostly hydrophobic residues and lesser cationic residues. Assuming that placement of an additional positive charge in the non-polar face of IsCT could reduce its hydrophobic interaction, resulting in its reduction of cytotoxicity, an analog, I9K-IsCT was designed. Two more analogs, namely, E7K-IsCT and E7K,I9K-IsCT, were designed to investigate the impact of positive charges in the polar face as well as polar and non-polar faces at a time. These amino acid substitutions resulted in a significant enhancement of therapeutic potential of IsCT. IsCT and E7K-IsCT seem to target bacterial membrane for their anti-bacterial activity. However, I9K-IsCT and E7K,I9K-IsCT inhibited nucleic acid and protein syntheses in tested E. coli without perturbing its membrane. This was further supported by the observation that NBD-IsCT localized onto bacterial membrane while NBD-labeled I9K-IsCT and E7K,I9K-IsCT translocated into bacterial cytoplasm. Interestingly, IsCT and E7K-IsCT were significantly helical while I9K-IsCT and E7K,I9K-IsCT were mostly unstructured with no helix content in presence of mammalian and bacterial membrane-mimetic lipid vesicles. Altogether, the results identify two novel cell-selective analogs of IsCT with new prototype amino acid sequences that can translocate into bacterial cytoplasm without any helical structure and inhibit macromolecular syntheses.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/farmacología , Bacterias/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Bacterias/efectos de los fármacos , Bacterias/ultraestructura , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citoplasma/metabolismo , Eritrocitos/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Hemólisis/efectos de los fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Permeabilidad , Transporte de Proteínas
15.
Antimicrob Agents Chemother ; 58(10): 5916-28, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25070112

RESUMEN

This study was performed to investigate the mechanistic aspects of cell death induced by a clerodane diterpene (K-09) in Leishmania donovani promastigotes that was previously demonstrated to be safe and orally active against visceral leishmaniasis (VL). K-09 caused depolarization of the mitochondrion and the generation of reactive oxygen species, triggering an apoptotic response in L. donovani promastigotes. Mitochondrial dysfunction subsequently resulted in the release of cytochrome c into the cytosol, impairing ATP production. Oxidative stress caused the depletion of reduced glutathione, while pretreatment with antioxidant N-acetyl cysteine (NAC) was able to abrogate oxidative stress. However, NAC failed to restore the mitochondrial membrane potential or intracellular calcium homeostasis after K-09 treatment, suggesting that the generation of oxidative stress is a downstream event relative to the other events. Caspase-3/-7-like protease activity and genomic DNA fragmentation were observed. Electron microscopy studies revealed gross morphological alterations typical of apoptosis, including severe mitochondrial damage, pyknosis of the nucleus, structural disruption of the mitochondrion-kinetoplast complex, flagellar pocket alterations, and the displacement of organelles. Moreover, an increased number of lipid droplets was detected after K-09 treatment, which is suggestive of altered lipid metabolism. Our results indicate that K-09 induces mitochondrial dysfunction and oxidative stress-mediated apoptotic cell death in L. donovani promastigotes, sharing many features with metazoan apoptosis. These mechanistic insights provide a basis for further investigation toward the development of K-09 as a potential drug candidate for VL.


Asunto(s)
Diterpenos de Tipo Clerodano/farmacología , Leishmania donovani/efectos de los fármacos , Leishmania donovani/metabolismo , Adenosina Trifosfato/metabolismo , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Citocromos c/metabolismo , Glutatión/metabolismo , Leishmania donovani/ultraestructura , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Confocal , Microscopía Electrónica de Transmisión , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Estrés Oxidativo/efectos de los fármacos
16.
Org Lett ; 16(3): 756-9, 2014 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-24410145

RESUMEN

A new class of live cell permeant, nontoxic fluoranthene-based fluorescent probe (FLUN-550) having a high Stokes shift in aqueous medium has been discovered. It showed selective staining of lipid droplets (LDs, dynamic cytoplasmic organelles) at a low concentration without background noise in in vitro live cell imaging of 3T3-L1 preadipocytes, J774 macrophages, MCF7 breast cancer cells, and single-celled, parasitic protozoa Leishmania donovani promastigotes and in vivo nonparasitic soil nematode C. elegans.


Asunto(s)
Antiprotozoarios/química , Caenorhabditis elegans/química , Fluorenos/química , Colorantes Fluorescentes/química , Lípidos/química , Macrófagos/química , Compuestos Policíclicos/química , Animales , Antiprotozoarios/farmacología , Caenorhabditis elegans/metabolismo , Línea Celular Tumoral , Humanos , Lípidos/análisis , Macrófagos/metabolismo , Macrófagos/parasitología , Estructura Molecular , Coloración y Etiquetado
17.
Trop Gastroenterol ; 32(3): 189-95, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22332334

RESUMEN

AIM: To present our experience with management of complex hepatic hydatid cysts (Gharbi type III), using percutaneous large bore catheter drainage followed by active mechanical suction of cyst contents. METHODS: Eleven patients (6 males and 5 females with a mean age of 43.2 years), with 13 complex Gharbi type III hepatic hydatid cysts were included in the study. Under sonography guidance the complex heterogeneous hepatic hydatid cysts were treated percutaneously using large bore drainage catheter and active mechanical suction. RESULTS: Successful drainage of all 13 complex Gharbi type III hepatic hydatid cysts was achieved in all patients (n = 11). The mean duration of catheter placement was 11.3 days (range 7 to 40 days). The most common problem encountered was biliary fistula (n = 3), which was effectively managed with prolonged catheter drainage and/or endoscopic intervention. No serious complications or deaths were encountered. Minor complications were seen in 7 patients including, urticaria in 3, fever in 2 and reactive pleural effusion in 3. All patients responded to symptomatic treatment. Follow up serial ultrasound was performed on all patients, that showed near complete healing in 9 and formation ofpseudotumour in 4 patients. There was no recurrence with a mean follow up of 15.23 months (6 months - 2 years). CONCLUSION: Percutaneous suction and large bore catheter drainage of Gharbi type III hepatic hydatid cysts is a safe and effective alternative therapy.


Asunto(s)
Drenaje/instrumentación , Equinococosis Hepática/terapia , Adulto , Anciano , Drenaje/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Succión/efectos adversos , Succión/instrumentación , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía Intervencional
18.
Acta Cytol ; 54(1): 60-2, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20306990

RESUMEN

BACKGROUND: Eosinophilic hepatic pseudotumors (EHP) are known complications of visceral larva migrans (VLM). By radiologic studies, EHP can be suspicious for primary or metastatic hepatic neoplasia. Diagnosis of an EHP by fine needle aspiration (FNA) led to the diagnosis of Toxocara VLM in a patient with suspected hepatic neoplasia. CASE REPORT: A 38-year-old Cambodian man had hepatitis B and chronic hepatitis with grade III portal fibrosis diagnosed in 2003. He had had negative routine alpha-fetoprotein and radiologic screening for hepatic neoplasia until 2006 when abdominal computed tomography revealed a 1.6 x 1.2-cm, ill-defined hypodense lesion in segment VII. Biopsy was recommended in order to exclude hepatocellular carcinoma. FNA of the lesion contained abundant Charcot-Leyden crystals, degenerating eosinophils and necrotic debris. Work-up for nematode larva migrans was recommended. Toxocara antigen IgG titer was significantly elevated leading to a presumptive diagnosis of VLM, and therapy for Toxocara-induced VLM was given. CONCLUSION: Identification of abundant Charcot-Leyden crystals and necrotic eosinophils in an FNA of the liver led to appropriate ancillary diagnostic tests and therapy for visceral larva migrans.


Asunto(s)
Biopsia con Aguja Fina , Eosinofilia/diagnóstico , Absceso Hepático/diagnóstico , Toxocariasis/diagnóstico , Diagnóstico Diferencial , Eosinofilia/parasitología , Humanos , Absceso Hepático/parasitología , Neoplasias Hepáticas/diagnóstico , Masculino , Adulto Joven
19.
Indian J Radiol Imaging ; 20(1): 6-10, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20351984

RESUMEN

Tuberculosis of the orbit is rare, even in places where tuberculosis is endemic. The disease may involve soft tissue, the lacrimal gland, or the periosteum or bones of the orbital wall. Intracranial extension, in the form of extradural abscess, and infratemporal fossa extension has been described. This pictorial essay illustrates the imaging findings of nine histopathologically confirmed cases of orbital tuberculosis. All these patients responded to antituberculous treatment.

20.
World J Gastroenterol ; 15(29): 3681-3, 2009 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-19653349

RESUMEN

Bilhemia or bile mixing with blood is a rare clinical problem. The clinical presentation is usually transient self-resolving hyperbilirubinemia, progressive and rapidly rising conjugated hyperbilirubinemia, or recurrent cholangitis. Endoscopic retrograde cholangiopancreatography (ERCP) plays an important role in diagnosis and management. Biliary decompression with endoscopic sphincterotomy is useful in treating these patients. If not recognized and treated in time, the condition can be fatal in a significant proportion of patients. This usually occurs after blunt or penetrating hepatic trauma due to a fistulous connection between the biliary radicle and portal or hepatic venous radical. Cases have been described due to iatrogenic trauma such as liver biopsy and percutaneous biliary drainage. However, the occurrence after trans-jugular intra-hepatic porto-systemic shunt (TIPS) is very rare. We report a case of bilhemia presenting as rapidly rising bilirubin after TIPS. The patient was managed successfully with ERCP and removal of a blood clot from the common bile duct.


Asunto(s)
Bilirrubina/sangre , Colangiopancreatografia Retrógrada Endoscópica , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Anciano , Bilis , Femenino , Humanos , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/cirugía
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