Rapamycin and Starvation Mitigate Indomethacin-Induced Intestinal Damage through Preservation of Lysosomal Vacuolar ATPase Integrity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, antipyretic, and analgesic properties and are among the most commonly used drugs. Although the cause of NSAID-induced gastric ulcers is well understood, the mechanism behind small intestinal ulcers remains elusive. In this study, we examined the mechanism through which indomethacin (IM), a prominent NSAID, induces small intestinal ulcers, both in vitro and in vivo. In IEC6 cells, a small intestinal epithelial cell line, IM treatment elevated levels of LC3-II and p62. These expression levels remained unaltered after treatment with chloroquine or bafilomycin, which are vacuolar ATPase (V-ATPase) inhibitors. IM treatment reduced the activity of cathepsin B, a lysosomal protein hydrolytic enzyme, and increased the lysosomal pH. There was a notable increase in subcellular colocalization of LC3 with Lamp2, a lysosome marker, post IM treatment. The increased lysosomal pH and decreased cathepsin B activity were reversed by pretreatment with rapamycin (Rapa) or glucose starvation, both of which stabilize V-ATPase assembly. To validate the in vitro findings in vivo, we established an IM-induced small intestine ulcer mouse model. In this model, we observed multiple ulcerations and heightened inflammation following IM administration. However, pretreatment with Rapa or fasting, which stabilize V-ATPase assembly, mitigated the IM-induced small intestinal ulcers in mice. Coimmunoprecipitation studies demonstrated that IM binds to V-ATPase in vitro and in vivo. These findings suggest that IM induces small intestinal injury through lysosomal dysfunction, likely due to the disassembly of lysosomal V-ATPase caused by direct binding. Moreover, Rapa or starvation can prevent this injury by stabilizing the assembly. SIGNIFICANCE STATEMENT: This study elucidates the largely unknown mechanisms behind small intestinal ulceration induced by indomethacin and reveals the involvement of lysosomal dysfunction via vacuolar ATPase disassembly. The significance lies in identifying potential preventative interventions, such as rapamycin treatment or glucose starvation, offering pivotal insights that extend beyond nonsteroidal anti-inflammatory drugs-induced ulcers to broader gastrointestinal pathologies and treatments, thereby providing a foundation for novel therapeutic strategies aimed at a wide array of gastrointestinal disorders.

Molecular docking, characterization, ADME/toxicity prediction, and anti-ulcer activity of new quercetin derivatives on indomethacin-induced gastric ulcer in mice.

Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs.

Topical rhubarb charcoal-crosslinked chitosan/silk fibroin sponge scaffold for the repair of diabetic ulcers improves hepatic lipid deposition in db/db mice via the AMPK signalling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is closely linked to metabolic syndrome, characterised by insulin resistance, hyperglycaemia, abnormal lipid metabolism, and chronic inflammation. Diabetic ulcers (DUs) comprise consequential complications that arise as a result of T2DM. To investigate, db/db mice were used for the disease model. The findings demonstrated that a scaffold made from a combination of rhubarb charcoal-crosslinked chitosan and silk fibroin, designated as RCS/SF, was able to improve the healing process of diabetic wounds in db/db mice. However, previous studies have primarily concentrated on investigating the impacts of the RSC/SF scaffold on wound healing only, while its influence on the entire body has not been fully elucidated. MATERIAL AND METHODS: The silk fibroin/chitosan sponge scaffold containing rhubarb charcoal was fabricated in the present study using a freeze-drying approach. Subsequently, an incision with a diameter of 8 mm was made on the dorsal skin of the mice, and the RCS/SF scaffold was applied directly to the wound for 14 days. Subsequently, the impact of RCS/SF scaffold therapy on hepatic lipid metabolism was assessed through analysis of serum and liver biochemistry, histopathology, quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blotting. RESULTS: The use of the RCS/SF scaffold led to an enhancement in the conditions associated with serum glucolipid metabolism in db/db mice. An assessment of hepatic histopathology further confirmed this enhancement. Additionally, the qRT-PCR analysis revealed that treatment with RCS/SF scaffold resulted in the downregulation of genes associated with fatty acid synthesis, fatty acid uptake, triglyceride (TG) synthesis, gluconeogenesis, and inflammatory factors. Moreover, the beneficial effect of the RCS/SF scaffold on oxidative stress was shown by assessing antioxidant enzymes and lipid peroxidation. Additionally, the network pharmacology analysis verified that the adenosine monophosphate-activated protein kinase (AMPK) signalling pathway had a vital function in mitigating non-alcoholic fatty liver disease (NAFLD) by utilizing R. officinale. The measurement of AMPK, sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FASN), and acetyl CoA carboxylase (ACC) gene and protein expression provided support for this discovery. Furthermore, the molecular docking investigations revealed a robust affinity between the active components of rhubarb and the downstream targets of AMPK (SREBP1 and FASN). CONCLUSION: By regulating the AMPK signalling pathway, the RCS/SF scaffold applied topically effectively mitigated hepatic lipid accumulation, decreased inflammation, and attenuated oxidative stress. The present study, therefore, emphasises the crucial role of the topical RCS/SF scaffold in regulating hepatic lipid metabolism, thereby confirming the concept of "external and internal reshaping".

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways.

AIMS: Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model. MAIN METHODS: In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 µg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day. KEY FINDINGS: NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin. SIGNIFICANCE: In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

Resultados de la angioplastia simple en pacientes con isquemia crítica debida a enfermedad exclusiva del sector infrapoplíteo / Percutaneous ballon angioplasty of infrapopliteal lesions for critical limb ischaemia. Experience of one centre

INTRODUCCIÓN: La isquemia crítica se define como dolor de reposo, úlcera o gangrena de la extremidad (estadios IV-VI de Rutherford) en pacientes con enfermedad arterial periférica. El tratamiento endovascular ha demostrado ser una opción válida en el sector infrapoplíteo. MATERIAL Y MÉTODOS: Estudio retrospectivo, descriptivo, registrado en nuestro centro desde 2005 hasta 2015. El diagnóstico se hizo mediante cartografía doppler prequirúrgica y arteriografía intraoperatoria. Describimos como resultado primario el porcentaje de amputación. Como resultados secundarios describimos el éxito clínico a los 6, 12 y 24 meses, el tiempo de hospitalización y la necesidad de amputación menor. El éxito técnico se define como la posibilidad de realizar angioplastia de al menos un vaso y lograr permeabilidad hasta algún arco. Se describe también la mortalidad. RESULTADOS: Incluye 72 extremidades y a 68 pacientes (53 hombres y 15 mujeres) con edad media de 73,4±11,4 años, 75% hipertensos, 80,5% diabéticos, 54% dislipidémicos, 13,8% fumadores activos, 33% con cardiopatía isquémica, 22% con insuficiencia renal, que presentaban isquemia crítica (87,5% en estadio V-VI de Rutherford) debida exclusivamente a enfermedad del sector infrapoplíteo. Realizamos angioplastias simples de un vaso distal (59,8%) o más (40,2%), con éxito técnico del 97%. Las lesiones se definieron como 48,6% de miembros con estenosis y 51,4% miembros con oclusión. El porcentaje de amputación mayor fue del 25%. En el análisis univariante con las variables estudiadas, la amputación mayor tuvo relación estadísticamente significativa (p = 0,014) con el intento fallido de recanalización de alguno de los vasos enfermos. El éxito clínico fue del 72, 47,2 y del 26,4% a los 6, 12 y 24 meses, respectivamente. La mediana de hospitalización fue de 18 días (rango 3-45). La mediana de seguimiento fue de 365 días (rango 6-2.555) y la mortalidad del 25%. CONCLUSIÓN: Nuestros resultados demuestran que la angioplastia simple en el tratamiento de la isquemia crítica debida a enfermedad del sector infrapoplíteo es una técnica válida, ya que permite tratar pacientes con elevada morbilidad con una aceptable tasa de salvamento del miembro

INTRODUCTION: Critical limb ischaemia is defined as rest pain, limb ulcers, or gangrene (IV- VI Rutherford Classification) in patients with peripheral arterial disease. Endovascular treatment has been shown to be a suitable option in below-the-knee lesions. MATERIALS AND METHODS: A retrospective, descriptive study was conducted on patients diagnosed with critical limb ischaemia secondary to isolated infrapopliteal lesions, registered in our centre from 2005 to 2015. Diagnosis was made with Doppler ultrasonound mapping and intraoperative angiography. Technical success was defined as performing one vessel angioplasty. Primary end-point was overall limb salvage. Secondary end-points were described as clinical success, and overall mortality. RESULTS: The study included a total 72 limbs of 68 patients (53 men and 15 women) with a mean age of 73.4±11.4 years. Of these, 75% were hypertensive, 80.5% were diabetics, 22% had renal failure. A Rutherford classification of V-VI was observed in 86% of patients. One-vessel angioplasty was the most frequent treatment in 59.8%, and 2 or more vessels in 40.2%. There was 97% technical success. Overall limb salvage was 75%. Clinical success rates at 6, 12 and 24 months were 72, 47.2, and 26.4%, respectively. The median hospital stay was 18 days (range 12-35), with a median follow-up of 365 days (range 180-730). Overall mortality during follow up was 25%. CONCLUSION: Our results are similar as those described in the literature, and demonstrate that balloon angioplasty is a useful technique in critical limb ischaemia patients with infrapopliteal lesions, and has an adequate limb rate salvage

Rápida cicatrización de la úlcera venosa con técnica TAPIRS (ecoesclerosis del eje axial, perforantes y terminal insuficientes) más vendaje multicapa. Ensayo clínico / Rapid healing of venous ulcers with terminal, axial and perforator interruption of the reflux source (TAPIRS) plus multilayer bandage: A clinical trial

INTRODUCCIÓN: Las úlceras venosas (UV) son las úlceras más frecuentes de las extremidades, y generan morbilidad importante y altos costos para los sistemas de salud. Las técnicas quirúrgicas usadas para el control de la hipertensión venosa han venido siendo remplazadas con mayor frecuencia por procedimientos mínimamente invasivos como la escleroespuma. OBJETIVO: Determinar el tiempo de cicatrización de la UV con un protocolo de manejo que incluyó la oclusión venosa endoluminal con escleroespuma ecoguiada del eje axial, perforantes y terminal insuficientes (técnica TAPIRS) más curaciones con vendaje multicapas (VM) hasta la cicatrización de la herida. MATERIAL Y MÉTODOS: Ensayo clínico prospectivo no controlado (cuasiexperimental) en pacientes con UV (CEAP C6) realizado en la consulta externa de cirugía vascular, durante 2013-2014. Se incluye a 17 pacientes mayores de 18 años, portadores de una UV con eje axial insuficiente, e índice tobillo-brazo mayor a 0,8. Se analizaron en total 17 extremidades. Se realizó inyección de escleroespuma (técnica de Tessari) usando polidocanol al 3% en el sistema venoso superficial con oclusión del eje venoso axial, perforantes y terminal asociados al lecho de la úlcera, guiada por ecodoppler junto con aplicación de VM y curación según las condiciones de la herida. Se realizaron controles clínicos y fotográficos en cada curación, aplicación de VM hasta el cierre de la UV y controles ecográficos a la 4 y 12 semanas. RESULTADOS: El promedio de edad fue de 56,4 años, la duración de la úlcera activa previamente al tratamiento fue de 2,96 años, todas las UV cicatrizaron antes de las 7 semanas, con una tasa de cierre de 3,92 cm2/semana y el tiempo de cierre de la úlcera fue de 3,92 semanas (24 días). CONCLUSIÓN: La oclusión endoluminal venosa usando la técnica TAPIRS (cierre de los ejes axiales, perforantes y terminales insuficientes con escleroespuma ecoguiada) junto a la aplicación de VM es una técnica que favorece la rápida cicatrización de las UV

INTRODUCTION: Chronic venous ulcers (CVU) are the most common ulcers occurring in the lower limbs, having a high morbidity and place a high financial strain on the health system. The traditional surgical techniques are being replaced by minimally invasive procedures, such as foam sclerotherapy. OBJECTIVE: The aim of this study was to determine CVU healing times and rates using the terminal, axial and perforator interruption of the reflux source (TAPIRS) protocol, which included an endoluminal venous occlusion with ultrasound-guided foam and a multilayer bandage system until achieving ulcer healing. MATERIAL AND METHODS: A prospective uncontrolled trial was conducted on patients with chronic venous leg ulcers (CEAP [clinical, etiological, anatomical and pathological elements] C6) during 2013 and 2014. A total of 17 patients aged 18 years and over, presenting with venous insufficiency, CVU, and an ankle-brachial index greater than 0.8, were included, and total of 17 limbs were analysed. All of the patients were subjected to endoluminal occlusion with ultrasoundguided foam in the axial superficial venous system and perforator and terminal veins near to the ulcer, using Tessari method with 3% polidocanol. Follow-up was carried out at every week and a doppler test was conducted after 4 and 12 weeks. RESULTS: The mean age of the patients was 56.4 years. The active ulcer duration prior to treatment was 2.96 years. The study showed that all CVU were healing before 7 weeks, the healing rate was 3.92 cm2/week, and the time until the ulcer was healed was 3.53 weeks (24 days). CONCLUSIONS: The minimally invasive ablation of terminal, axial and perforator reflux with compression in patients is a technique that leads to faster healing times of CVU

SEOM guidelines for the management of Malignant Melanoma 2015

All melanoma patients must be confirmed histologically and resected according to Breslow. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon must be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 therapy. Up to 10 years follow up is recommended for melanoma patients with dermatologic examinations and physical exams (AU)

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Crohn’s disease and systemic lupus erythematosus: a rare and challenging association

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Valoración geriátrica / Geriatric assessment

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