Effect of PKM2 on Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Myeloma Bone Disease / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression of pyruvate kinase M2 (PKM2) in bone marrow mesenchymal stem cells (BMSCs) in myeloma bone disease (MBD) and its effect on osteogenic and adipogenic differentiation of BMSCs.@*METHODS@#BMSCs were isolated from bone marrow of five patients with multiple myeloma (MM) (MM group) and five with iron deficiency anemia (control group) for culture and identification. The expression of PKM2 protein were compared between the two groups. The differences between osteogenic and adipogenic differentiation of BMSCs were assessed by using alkaline phosphatase (ALP) and oil red O staining, and detecting marker genes of osteogenesis and adipogenesis. The effect of MM cell line (RPMI-8226) and BMSCs co-culture on the expression of PKM2 was explored. Functional analysis was performed to investigate the correlations of PKM2 expression of MM-derived BMSCs with osteogenic and adipogenic differentiation by employing PKM2 activator and inhibitor. The role of orlistat was explored in regulating PKM2 expression, osteogenic and adipogenic differentiation of MM-derived BMSCs.@*RESULTS@#Compared with control, MM-originated BMSCs possessed the ability of increased adipogenic and decreased osteogenic differentiation, and higher level of PKM2 protein. Co-culture of MM cells with BMSCs markedly up-regulated the expression of PKM2 of BMSCs. Up-regulation of PKM2 expression could promote adipogenic differentiation and inhibit osteogenic differentiation of MM-derived BMSCs, while down-regulation of PKM2 showed opposite effect. Orlistat significantly promoted osteogenic differentiation in MM-derived BMSCs via inhibiting the expression of PKM2.@*CONCLUSION@#The overexpression of PKM2 can induce the inhibition of osteogenic differentiation of BMSCs in MBD. Orlistat can promote the osteogenic differentiation of BMSCs via inhibiting the expression of PKM2, indicating a potential novel agent of anti-MBD therapy.

Orlistat induces ferroptosis-like cell death of lung cancer cells / 医学前沿

Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P < 0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.

Características demográficas, clínicas y reacciones adversas de personas con sobrepeso y obesidad: consumidores de orlistat atendidos por centro de atención telefónica (2009 ­ 2017) / Demographic and clinical characteristics, and adverse reactions of people with overweight and obesity consumers of orlistat, attended by a call center (2009 ­ 2017)

Resumen Introducción Las enfermedades crónicas van en ascenso y están asociadas al incremento ponderal. Se requieren estrategias multidisciplinarias para su control. Métodos El diseño es descriptivo, observacional y retrospectivo. Los objetivos de esta comunicación son describir las características demográficas, clínicas y reacciones adversas de personas con sobrepeso y obesidad consumidores de orlistat, atendidos por un centro de atención telefónica durante el periodo 2009 a 2017; e identificar al profesional de la salud más consultado por ellos. La información se obtuvo desde una base de datos existente de un programa de atención a personas con sobrepeso u obesidad, interesadas en usar orlistat (prospectos) o usuarios (pacientes). El estudio se llevó a cabo en México y duró siete años. Las variables estudiadas fueron demográficas, clínicas y reacciones adversas. Resultados Se reunieron 311 913 solicitudes de 126 607 sujetos (104 711 prospectos interesados en consumir orlistat y 21 896 pacientes que ya lo tomaban). Las principales actividades fueron llamadas al sujeto (35,9%). Hubo 104 711 solicitudes: 82 810 (79,1%) prospectos y 21 896 (20,9%) pacientes. El 79,9% fue de sexo femenino. El intervalo de edad predominante fue de 32 a 45 años. Se detectaron 43 reacciones adversas (0,02%); las más comunes fueron dolor abdominal (0,05%) y cefalea (0,03%). Conclusiones La población más interesada en el control ponderal en este estudio es la femenina (79,9%) y el grupo etario de 32 a 45 años. El profesional más consultado fue el nutriólogo. Solo se obtuvo el índice de masa corporal (29,2 kilogramos por metro cuadrado) de los sujetos que desarrollaron 43 reacciones adversas, las más comunes fueron dolor abdominal y cefalea.

Introduction Chronic diseases are on the rise and are associated with weight gain. Multidisciplinary strategies are required for its control. Methods The design was descriptive, observational and retrospective. The objectives of this communication were to describe the demographic and clinical characteristics and adverse reactions of overweight and obese people who were consumers of orlistat, attended by a call center during the period 2009 to 2017; and to identify the healthcare professional most consulted by them. The information was obtained from an existing database of a program of attention to people with overweight or obesity, interested in using orlistat (prospects) or users (patients). The study was carried out in Mexico and lasted seven years. The variables studied were demographic, clinical and adverse reactions. Results A total of 311,913 requests were collected from 126 607 subjects (104 711 prospects interested in consuming orlistat and 21 896 patients who already took it). The main activities were phone calls to the subject (35.9%). There were 104 711 requests: 82 810 (79.1%) prospects and 21 896 (20.9%) patients. 79.9% of all were female. The predominant age interval was 32 to 45 years. 43 adverse reactions (0.02%) were detected; the most common were abdominal pain (0.05%) and headache (0.03%). Conclusions The population most interested in weight control in this study was the female population (79.9%) and the age group from 32 to 45 years. The most consulted healthcare professional was the nutritionist. Only the body mass index (29.2 kilograms per square meter) of the subjects who developed 43 adverse reactions was obtained. There were 43 adverse reactions, the most common being abdominal pain and headache.

Perfil de resistencia antimicrobiana en bacilos Gram negativos no fermentadores aislados en fuentes hídricas / Antimicrobial resistance profile in non-fermenting gram negative bacilli isolated in water resources

La amplia distribución de los bacilos gram negativos no fermentadores en medios ambientales como el agua y especies vegetales cobra importancia al ser reconocidos como agentes causales de enfermedades en pacientes inmunocomprometidos, de allí la relevancia del porque debemos conocer la prevalencia y perfil de susceptibilidad de estos microorganismos en ambientes no hospitalarios. Materiales y Métodos: Estudio transversal, realizado en muestras hídricas de fuentes naturales y artificiales de almacenamiento para el consumo humano en la ciudad de Bogotá y municipios aledaños. La identificación se realizó a través de pruebas IMVIC y el perfil de resistencia a través del método de kirby bauer o E-TEST®. Resultados: Se obtuvieron 42 muestras, 7 (16,6%) con aislamientos de interés: 3 (60%) Pseudomonas spp, 2 (20%) Acinetobacter spp, 1 (10%) Sphingomonas paucimobilis y 1 (10%) Pantoea spp. El 70% presento resistencia a la ceftriaxona, el 30% a cefoxitina, 20% a gentamicina, 10% a ciprofloxacina y 10% a piperacilina-tazobactam. No se presentó resistencia a imipenem. Conclusión: 5 de 7 aislamientos revelaron un BGNNF de importancia en infección en humanos, siendo importante la resistencia encontrada a la ceftriaxona.

The wide distribution of non-fermenting gram negative bacilli in environmental media such as water and plants becomes important as they are recognized a cause of diseases in immunocompromised patients, that’s the reason why we should to know the prevalence and the susceptibility profile of these microorganisms in non-hospital environments. Materials and Methods: Cross-sectional study done with samples of natural and artificial water storage for human consumption in the city of Bogotá and surrounding municipalities. The identification was made through IMVIC tests and the resistance profile through the kirby bauer or E-TEST® method. Results: 42 samples were obtained, 7 (16.6%) with isolates of interest: 3 (60%) Pseudomonas spp, 2 (20%) Acinetobacter spp, 1 (10%) Sphingomonas paucimobilis and 1 (10%) Pantoea spp. The 70% had resistance to ceftriaxone, 30% to cefoxitin, 20% to gentamicin, 10% to ciprofloxacin and 10% to piperacillin-tazobactam. No resistance to imipenem was shown. Conclusion: 5 of 7 isolates revealed a BGNNF of importance in infection in humans, with an important resistance to ceftriaxone.

Metformin versus orlistat in the treatment of overweight and obese women with polycystic ovary syndrome (PCOS): A systematic review and meta-analysis

OBJECTIVES: To compare the effects of metformin and orlistat in terms of reduction in weight or BMI, and improvement of ovulation rates, endocrinologic and lipid profiles, and occurrence of adverse events among overweight or obese women diagnosed with PCOS. SEARCH METHODS: We searched Medline, OVID, HERDIN, EMBASE, Cochrane Library and ClinicalTrials.gov for head to head clinical trials of metformin versus orlistat for the treatment of overweight and obese women with PCOS. We also contacted the pharmaceutical companies and did hand-searching to look for related studies. SELECTION CRITERIA: Only randomized controlled trials comparing metformin and orlistat as treatment for overweight and obese PCOS women were included. Other inclusion criteria included: trial period of at least 3 months duration, participants, of any ethnicity, 18-40 years old, who are overweight or obese, and studies with or without non-pharmacologic interventions as part of the treatment regimen. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified through the search strategies were screened by two reviewers. Two authors extracted data on publication characteristics, inclusion and exclusion criteria, intervention and co-intervention, primary and secondary outcomes, and details of study design. Two authors assessed the quality and risk bias of each RCT based on random sequence generation, allocation concealment, blinding of participants, caregivers, and assessors, attrition bias, incomplete outcome data, selective reporting, and publication bias. MAIN RESULTS: We included 5 RCTs (n=221). Overall, treatment effects of orlistat and metformin showed no significant difference in the following outcomes: ovulation rates (RR 0.78; 95% CI 0.41, 1.49), reduction of BMI (MD -0.47; 95%CI:-1.53,0.59), serum testosterone levels (MD -2.15;95% CI -9.64, 5.33), free androgen index MD 3.26; 95% CI -7.91, 14.43), homeostatic model assessment-insulin resistance (3.70; 95% CI -6.74, 14.15), fasting insulin (MD 7.86; 95% CI -3.09, 18.81), HDL-C (MD -1.19 ; 95% CI -4.78, 7.16) and triglycerides (MD -1.95; 95% CI -8.81, 4.90). Orlistat was significantly better than metformin in reducing total cholesterol (MD -6.60; 95% CI -10.79, -2.41), and LDL (MD -5.04; 95% CI -9.64, 5.33), free androgen index (MD 3.26; 95% CI -7.91, 14.43), homeostaic model assessment-insulin resistance (3.70; 95% CI -6.74, 14.15), fasting insulin (MD 7.86; 95% CI -3.09, 18.81), HDL-C (MD -1.19 ; 95% CI -4.78, 7.16) and triglycerides (MD -1.95; 95% CI -8.81, 4.90). Orlistat was significantly better than metformin in reducing total cholesterol (MD -6.60; 95% CI -10.79, -2.41), and LDL (MD -5.04); 95% CI  -9.99, -0.09), and had less adverse events (RR 0.37, 95% CI 0.14, 0.96). AUTHORS' CONCLUSIONS: Metformin and Orlistat have similar effects on weight loss, ovulation rates, and endocrinologic profiles of obese women with PCOS. Orlistat is more effective than metformin in decreasing total cholesterol and LDL -C levels, and has less adverse events than metformin. Therefore, we may recommend orlistat to overweight or obese women with PCOS who also have dyslipidemia. However, caution is given to our interpretations since small sample size, low quality of RCTs, and wide confidence intervals of pooled estimates significantly influence interpretation and recommendations. RCTs with adequately powered study populations are recommended to confirm findings of this review.

Preguntas y respuestas sobre aspectos generales del tratamiento farmacológico en el paciente obeso / Questions and answers about general aspects of the pharmacotherapy for the obese patients

Introducción: a través del uso de la farmacoterapia en el paciente obeso se ha intentado obtener pérdidas de peso, mayores y más rápidas que las reportadas con los métodos convencionales de tratamiento, lo que sin dudas facilita una disminución objetiva de la morbilidad y mortalidad observada en los pacientes con este problema de salud. Objetivos: describir los aspectos generales del tratamiento farmacológico en el paciente obeso y mencionar algunos de los medicamentos usados con este fin. Desarrollo: resulta importante conocer los aspectos generales del tratamiento farmacológico de la obesidad. Consideraciones sobre cómo hacer la selección del fármaco ideal, los principios generales para su uso, cuáles son los criterios de elección de los pacientes y qué fármacos deben ser evitados en el paciente con obesidad, son elementos útiles a conocer para garantizar una asistencia médica de calidad a las personas con obesidad. Productos conocidos e indicados como tratamiento farmacológico de la obesidad pasaron al desuso, por su pobre efectividad o por presentar toda una serie de efectos secundarios. El uso de orlistat o xenical debe de ser la alternativa más común en el tratamiento actual con fármacos para la obesidad. La reciente aprobación de nuevos medicamentos como la lorcaserina (belviq) y qnexa (o qsymia), debe representar una opción de utilidad. Conclusiones: el conocimiento de los aspectos generales del tratamiento farmacológico de la obesidad es indispensable para su uso adecuado. La posibilidad de usar nuevos productos resulta una alternativa esperanzadora(AU)

Introduction: through the use of pharnacotherapy in the obese patients, it has been intended to reach bigger and faster weight loses than those reported by the conventional therapeutic methods, all of which undoubtedly facilitates the objective reduction of morbidity and mortality observed in patients suffering this health problem. Objectives: to describe the general aspects of the drug therapy in the obese patient and to mention some of the drugs used. Development: it is important to know the general aspects of the pharmacotherapy for obesity. Considerations on how to select the optimal drug, the general principles of using it, the criteria for the selection of patients and the types of drugs to be avoided in the obese people are key elements to assure a quality medical care. Some well-known products that were prescribed as pharmaco treatment for obesity are not longer in use because of their ineffectiveness or adverse effects. The use of orlistat or xenical should be the most common alternative to treat this disease at present. The recent approval or new drugs such as Lorcaserina (belviq) and qnexa (qsymia) may represent useful options. Conclusions: the knowledge about the general aspects of the pharmacotherapy aimed at obesity is indispensable. The possibility of using new drugs turns out to be a hopeful alternative(AU)