380 research outputs found
Correlation between mean and minimum joint space measurements in a long-term trial with glucosamine sulfate, an osteoarthritis modifying agent
peer reviewe
Culture Medium Factorial Design Optimization for Fibrinolytic Enzymes Production by Bionectria sp.
Thrombotic diseases can be clinically treated with fibrinolytic enzymes and many attempts have been made at laboratory level to increase fibrinolytic enzymes production from microbial sources and to reduce the process cost, including culture medium design, optimization of environmental conditions, and over expression with genetically modified strains. In this contribution we present the optimization of culture medium composition and incubation temperature for fibrinolytic enzyme production by Bionectria sp., a selected fungal strain from Las Yungas (Tucumán). Optimization was carried out at Erlenmeyer scale (100-mL working volume) via factorial design methodology. All trials included a common mineral base (%, w/v: NaCl 0.2, KH2PO4 0.05, MgSO4·7H2O 0.05). According to four factorial designs it could be demonstrated the convenience of using soy peptone as N-source, glucose as C-source, and the possibility to eliminate starch, meat peptone and meat extract from original medium composition, whilst 25°C was selected as the optimal incubation temperature. Results showed that culture medium could be successfully optimized by factorial design, achieving a reduction in the production process costs by means of a decrease in culture medium components, the improvement in culture broth rheology, mycelial morphology and mass/energy transfer, and the subsequent two-fold enhancement in productivity.Fil: Arnau, Victor Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Rovati, Jose Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Figueroa, L. I. C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Fariña, Julia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaXLVI Reunión Anual Sociedad Argentina de Investigaciones Bioquímicas y MolecularesPuerto Madryn, Chubut, ArgentinaArgentinaSociedad Argentina de Investigaciones Bioquímicas y Moleculare
Experimental Pharmacology of Glucosamine Sulfate
Several clinical studies demonstrated that glucosamine sulfate (GS) is effective in controlling osteoarthritis (OA), showing a structure-modifying action. However, little is known about the molecular mechanism(s) by which GS exerts such action and about the effects of GS at a tissue level on osteoarthritic cartilage and other joint structures. Here we provide mechanistic evidence suggesting that in vitro GS attenuates NF-κB activation at concentrations in the range of those observed after GS administration to volunteers and patients, thus strengthening previous findings. Furthermore, we describe the effects of GS at a tissue level on the progression of the disease in a relevant model of spontaneous OA, the STR/ort mouse. In this model, the administration of GS at human corresponding doses was associated with a significant decrease of OA scores. Histomorphometry showed that the lesion surface was also significantly decreased, while the number of viable chondrocytes within the matrix was significantly increased. GS improved the course of OA in the STR/Ort mouse, by delaying cartilage breakdown as assessed histologically and histomorphometrically
095 PHARMACOLOGY OF THE STR/ORT MOUSE AS A MODEL FOR OSTEOARTHRITIS: RESPONSIVENESS TO EP4 ANTAGONISTS AND AGGRECANASE INHIBITORS
Reciprocal interference between the NRF2 and LPS signaling pathways on the immune-metabolic phenotype of peritoneal macrophages
The metabolic and immune adaptation to extracellular signals allows macrophages to carry out specialized functions involved in immune protection and tissue homeostasis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that coordinates cell redox and metabolic responses to stressors. However, the individual and concomitant activation of NRF2 and inflammatory pathways have been poorly investigated in isolated macrophages. We here took advantage of reporter mice for the transcriptional activities of NRF2 and nuclear factor-kB (NF\u3baB), a key transcription factor in inflammation, and observe a persisting reciprocal interference in the response of peritoneal macrophages to the respective activators, tert-Butylhydroquinone (tBHQ) and lipopolysaccharide (LPS). When analyzed separately by gene expression studies, these pathways trigger macrophage-specific metabolic and proliferative target genes that are associated with tBHQ-induced pentose phosphate pathway (PPP) with no proliferative response, and with opposite effects observed with LPS. Importantly, the simultaneous administration of tBHQ + LPS alters the effects of each individual pathway in a target gene-specific manner. In fact, this co-treatment potentiates the effects of tBHQ on the antioxidant enzyme, HMOX1, and the antibacterial enzyme, IRG1, respectively; moreover, the combined treatment reduces tBHQ activity on the glycolytic enzymes, TALDO1 and TKT, and decreases LPS effects on the metabolic enzyme IDH1, the proliferation-related proteins KI67 and PPAT, and the inflammatory cytokines IL-1\u3b2, IL-6, and TNF\u3b1. Altogether, our results show that the activation of NRF2 redirects the metabolic, immune, and proliferative response of peritoneal macrophages to inflammatory signals, with relevant consequences for the pharmacological treatment of diseases that are associated with unopposed inflammatory responses
Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency.
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25 mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while beta-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment. The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and beta-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain. In conclusion, the present study demonstrates that 25 mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results
Crystalline Glucosamine Sulfate in the Treatment of Osteoarthritis: Evidence of Long-Term Cardiovascular Safety from Clinical Trials
Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats.
The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin
ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen
Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells,
including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen
receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed
at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of
female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed
that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other
immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that
involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell
phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β,
with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion
through caspase-1 activation
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