Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C

Objective: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells.Methods and Results: In the presence of 25 μM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 ± 7.3% of control. Similarily, the activation-induced secretion of TNF-α and IL-8 by HMC-1 cells were decreased in the presence of 25 μM CMT-3 to 13.5 ± 4.1% and 9.7 ± 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-α but instead it reduced the expression of TNF-α mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC₅₀ value of 31 μM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.Conclusions: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.Received 18 February 2005; returned for revision 7 March 2005; accepted by A. Falus 21 April 2005     

Changes in older people’s quality of life in the COVID-19 era: a population-based study in Finland

Quality of Life Research - We investigated how quality of life (QoL) changed between 2018 and 2020, and how its related factors, i.e., communication with friends and family, loneliness, and...     

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring’s risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997–2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.     

The effects of d-cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with d-cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. d-Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, d-cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg d-cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Genetic imbalances detected by multiplex ligation-dependent probe amplification in a cohort of patients with oral squamous cell carcinoma—the first step towards clinical personalized medicine

Oral tumors are a growing health problem worldwide; thus, it is mandatory to establish genetic markers in order to improve diagnosis and early detection of tumors, control relapses and, ultimately, delineate individualized therapies. This study was the first to evaluate and discuss the clinical applicability of a multiplex ligation-dependent probe amplification (MLPA) probe panel directed to head and neck cancer. Thirty primary oral squamous cell tumors were analyzed using the P428 MLPA probe panel. We detected genetic imbalances in 26 patients and observed a consistent pattern of distribution of genetic alterations in terms of losses and gains for some chromosomes, particularly for chromosomes 3, 8, and 11. Regarding the latter, some specific genes were highlighted due to frequent losses of genetic material—RARB, FHIT, CSMD1, GATA4, and MTUS1—and others due to gains—MCCC1, MYC, WISP1, PTK2, CCND1, FGF4, FADD, and CTTN. We also verified that the gains of MYC and WISP1 genes seem to suggest higher propensity of tumors localized in the floor of the mouth. This study proved the value of this MLPA probe panel for a first-tier analysis of oral tumors. The probemix was developed to include target regions that have been already shown to be of diagnostic/prognostic relevance for oral tumors. Furthermore, this study emphasized several of those specific genetic targets, suggesting its importance to oral tumor development, to predict patients’ outcomes, and also to guide the development of novel molecular therapies.     

Methylprednisolone acetate induced release of cartilage proteoglycans: determination by high performance liquid chromatography.

A high performance liquid chromatography (HPLC) procedure suitable for the simultaneous determination of the molecular size and concentration of macromolecular hyaluronate and proteoglycans in synovial fluid has been developed. Irrigation of the equine tarsocrural joint with 20 ml physiological saline (PSS) caused a mild inflammation with an increase of proteoglycans in the synovial fluid over the baseline arthrocentesis control sample. Proteoglycan and hyaluronate in the synovial fluid did not interact to form hyaluronate-proteoglycan aggregates, but separated as distinct chromatographic peaks. This suggests that the cartilage derived proteoglycans in synovial fluid in the inflamed joint have been proteolytically cleaved from the non-covalent aggregates containing link protein and hyaluronate. Hyaluronidase digestion completely abolished the hyaluronate peak without affecting the proteoglycans. This seems to indicate that proteoglycan in synovial fluid is unable to interact with hyaluronate in synovial fluid to form cartilage type aggregates. Proteolytic degradation and the time dependent release into the synovial fluid of such digested proteoglycan also resulted from the intra-articular injection of methylprednisolone acetate into normal tarsocrural joints and joints irrigated with PSS. These proteoglycans were insensitive to hyaluronidase but may consist of a protein moiety with attached glycosaminoglycans, as suggested by their sensitivity to proteinase and keratanase/chondroitinase digestion. These observations with cartilage treated with methylprednisolone acetate and mildly stimulated articular cartilage are inconsistent with earlier work on osteoarthritic and rheumatoid articular cartilage and have interesting implications for the pathogenesis and for the therapeutic action of intraarticular corticosteroids. A rapid HPLC procedure applicable to unprocessed small volume samples of synovial fluid gives information simultaneously on hyaluronate and proteoglycan in synovial fluid which is not attainable with immunoradiometric or isotope tracer techniques. It therefore appears to be useful for the analysis of cartilage turnover and destruction in health and disease.