SUMMARY Metallothionein is a low molecular weight, cysteine‐rich, stress response protein that can act as an antioxidant and as an immunosuppressive agent in instances of antigen‐dependent adaptive immunity. In this context, we assessed the therapeutic potential and mechanisms of action of metallothionein in a collagen‐induced arthritis model. Repeated administration of metallothionein‐I + II during the course of disease dramatically reduced the incidence and severity of the disease. Joint tissues isolated from boostered paws of metallothionein‐I + II‐treated mice expressed significantly reduced levels of proinflammatory mediators, such as tumour necrosis factor (TNF)‐α and cyclooxygenase‐2, when compared with those of control‐treated mice. Lymph node cells obtained from metallothionein‐I + II ‐injected mice exhibited a significant decrease in the proliferative response and a remarkable increase in tumour growth factor (TGF)‐β production in response to type II collagen. Taken together, these results suggest that metallothionein‐I + II promote the development of type II collagen‐specific, TGF‐β‐producing cells to antagonize the expansion of arthritogenic cells. This could lead to local suppression of inflammatory responses by inhibiting the expression of proinflammatory molecules. Thus, this study demonstrates the suppressive effects of metallothionein on collagen‐induced arthritis, and indicates that there may be a potential therapeutic application for manipulation of metallothionein during the treatment of autoimmune disorders.
Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy.
Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically reduces methionine-R-sulfoxide to methionine. A recent genetic study showed that the MSRB3 gene is associated with autosomal recessive hearing loss in human deafness DFNB74. However, the precise role of MSRB3 in the auditory system and the pathogenesis of hearing loss have not yet been determined. This work is the first to generate MsrB3 knockout mice to elucidate the possible pathological mechanisms of hearing loss observed in DFNB74 patients. We found that homozygous MsrB3(-/-) mice were profoundly deaf and had largely unaffected vestibular function, whereas heterozygous MsrB3(+/-) mice exhibited normal hearing similar to that of wild-type mice. The MsrB3 protein is expressed in the sensory epithelia of the cochlear and vestibular tissues, beginning at E15.5 and E13.5, respectively. Interestingly, MsrB3 is densely localized at the base of stereocilia on the apical surface of auditory hair cells. MsrB3 deficiency led to progressive degeneration of stereociliary bundles starting at P8, followed by a loss of hair cells, resulting in profound deafness in MsrB3(-/-) mice. The hair cell loss appeared to be mediated by apoptotic cell death, which was measured using TUNEL and caspase 3 immunocytochemistry. Taken together, our data suggest that MsrB3 plays an essential role in maintaining the integrity of hair cells, possibly explaining the pathogenesis of DFNB74 deafness in humans caused by MSRB3 deficiency.
The vertebrate skeletal system has various functions, including support, movement, protection, and the production of blood cells. The development of cartilage and bones, the core components of the skeletal system, is mediated by systematic inter- and intracellular communication among multiple signaling pathways in differentiating progenitors and the surrounding tissues. Recently, Pannexin (Panx) 3 has been shown to play important roles in bone development in vitro by mediating multiple signaling pathways, although its roles in vivo have not been explored. In this study, we generated and analyzed Panx3 knockout mice and examined the skeletal phenotypes of panx3 morphant zebrafish. Panx3(-/-) embryos exhibited delays in hypertrophic chondrocyte differentiation and osteoblast differentiation as well as the initiation of mineralization, resulting in shortened long bones in adulthood. The abnormal progression of hypertrophic chondrogenesis appeared to be associated with the sustained proliferation of chondrocytes, which resulted from increased intracellular cAMP levels. Similarly, osteoblast differentiation and mineralization were delayed in panx3 morphant zebrafish. Taken together, our results provide evidence of the crucial roles of Panx3 in vertebrate skeletal development in vivo.
Transgenic mice containing novel oncogene HCCR-2 were generated to analyse the phenotype and to characterize the role of HCCR-2 in cellular events. Mice transgenic for HCCR-2 developed breast cancers and metastasis. The level of p53 in HCCR-2 transgenic mice was elevated in most tissues including breast, brain, heart, lung, liver, stomach, kidney, spleen, and lymph node. We examined whether stabilized p53 is functional in HCCR-2 transgenic mice. Defective induction of p53 responsive genes including p21 WAF1 , MDM2, and bax indicates that stabilized p53 in HCCR-2 transgenic mice exists in an inactive form. These results suggest that HCCR-2 represents an oncoprotein that is related to breast cancer development and regulation of the p53 tumor suppressor.
The objectives of this research were to determine the effects of beta-mercaptoethanol (beta-ME) and fetal bovine serum (FBS) on in vitro development of bovine embryos derived from oocytes matured and fertilized in vitro and to examine the mechanism through which beta-ME may influence embryo development. A 2 x 2 factorial treatment arrangement was used to evaluate the effect of 0 or 100 microM beta-ME and 0% or 10% FBS on embryos cultured in Medium 199 (M199) in the absence of somatic cells. Embryos were randomly allocated within stage of development (< 8 cells or 8-16 cells) to one of four treatment combinations and were cultured for 6 days. Both beta-ME and FBS promoted increased (p < 0.01) development of embryos to the blastocyst stage, and their effects were greater (p < 0.01) in 8- to 16-cell embryos than in embryos having fewer than 8 cells at the initiation of treatment. The cysteine and cystine content of M199, with and without beta-ME, were determined by HPLC. Medium supplemented with beta-ME contained neither cysteine nor cystine, and it is suggested that these compounds were converted into a mixed disulfide between cysteine and beta-ME. These results indicate that beta-ME is capable of enhancing bovine embryo development in a cell-free, serum-free culture system.
The aim of this research was to determine the effects of L-cysteine and beta-mercaptoethanol on the in vitro development of bovine embryos that had been produced in vitro. A 2 x 3 factorial arrangement of treatments was used to evaluate the effect of 0.63 or 6.9 microM L-cysteine and 0, 10, or 100 microM beta-mercaptoethanol on the development of bovine embryos in a chemically defined medium. Embryos containing 6 to 8 cells were randomly allocated to one of the six treatment combinations and were cultured for 7 d. Both beta-mercaptoethanol and L-cysteine increased the number of embryos that reached the blastocyst stage of development, although no interaction was observed between the compounds. Embryos that were cultured in the presence of beta-mercaptoethanol had more cells at the blastocyst stage than did embryos cultured in medium without beta-mercaptoethanol. These findings provide evidence that beta-mercaptoethanol and L-cysteine promote increased embryonic development and that beta-mercaptoethanol increases the number of cells in bovine embryos produced in vitro and cultured in a cell-free, protein-free culture system.
BackgroundDiabetes is characterized by hyperglycemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The aim of the present study was to investigate the effects of ginger on various tissues (i.e., pancreas, kidney, and liver) and insulin resistance in streptozotocin-induced diabetic mice. The pleasant aroma of ginger comes from the constituents present in its volatile oil, while its non-volatile pungent phytochemicals consist of gingerols, shogaols, and paradols.MethodsThis research was conducted to determine the effects of 6-shogaol administration on blood glucose and insulin production in type 1 diabetic mice. Mice were intraperitoneally injected with shogaol at 5 or 10 mg/kg body weight. Untreated mice were injected with an equivalent volume of buffer, three times a week for 2 weeks. The animals were randomly divided into four experimental groups: control group mice (n = 3) were given an intraperitoneal (IP) injection of streptozotocin (STZ) vehicle (1 mL citrate buffer/100 g body weight) at day 1 and received an IP injection of 6-shogaol vehicle [1 mL buffer (0.5% DMSO, 10% Tween 20, and 89.5% PBS)/100 g body weight] every other day for 4 consecutive days.Results6-Shogaol exhibited an antidiabetic effect by significantly decreased the level of blood glucose, body weight and attenuated the above pathological changes to the normal levels in the diabetic mice, and has effect against pancreas, kidney, liver damage in the diabetic mice. Since, 6-shogaol prevented the damage for STZ induced stress.Conclusion6-Shogaol can be used as a therapeutic agent for preventing complications in diabetic patients. Diabetic treatment consider the 6-shogaol as a pharmatheuticals or combination drug with herbal plant or others 6-shogaol may be a good therapeutic drug because it covers not only pancreatic β-cell but also liver and kidney. Ginger may be ideal because they contain a variety of pharmacological compounds with different known pharmacological actions.
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