The Relationship between Annual Airborne Pollen Levels and Occurrence of All Cancers, and Lung, Stomach, Colorectal, Pancreatic and Breast Cancers: A Retrospective Study from the National Registry Database of Cancer Incidence in Japan, 1975-2015.

Suppression of risk factors including smoking, overdrinking and infections by human papilloma and hepatitis B and C viruses has been recommended for cancer prevention; however, identification of other environmental risk factors has not been enough. Besides the 2003 report that Kawasaki disease may be triggered by pollen exposure, 40 Japanese specific intractable diseases have recently been reported as "pollen diseases," also potentially triggered by pollen exposure．Various human organs are affected by pollen exposure, leading to systemic vasculitis; autoimmune connective tissue diseases, inflammatory bowel diseases and intractable neuromuscular and bone diseases, suggesting the common effects of pollen exposure on fundamental functions of vital metabolism. In this context, cancer and malignant tumors may be another group of intractable diseases triggered by epigenetic pollen exposure. Thus, this study compared the number of newly registered patients with 24 types of cancer and airborne pollen levels measured from 1975 to 2015. We searched for statistical correlations with Bonferroni correction between the annual number of newly registered patients for all cancers or for each of lung, stomach, colorectal, pancreatic and breast cancers in the patient-registry year "x", and annual airborne pollen levels measured in the same year as "x", or 1-7 years prior to the year "x". The number of newly registered patients for lung, and pancreatic cancers in the patient-registry year "x" was highly correlated with airborne pollen levels measured 2 years prior to "x". That for breast cancer was correlated with pollen levels measured 2 and 5 years prior to "x". To our knowledge, this is the first rapid communication of the association between pollen levels and cancer incidence.

Suppressive influence of seasonal influenza epidemic on Kawasaki disease onset.

  Kawasaki disease (KD) is an acute systemic vasculitis presenting as an infantile febrile disease. In Japan, the widespread cedar plantation commenced in 1945 has been correlated with the increased incidences of both KD and allergic rhinitis (pollinosis) since the early 1960s. We previously showed that KD was a pollen-induced, delayed-type hypersensitivity that displays biphasic peaks in both summer and winter. KD incidences decrease suddenly around February, particularly after influenza epidemics. Here we investigated the reason for a drastic decrease in KD onsets directly before spring pollen release following rapid increase after autumn pollen release leading to the biphasic pattern. We separately analyzed weekly incidences of KD and influenza in Tokyo (1987-2010) and Kanagawa (1991-2002). Repeated measures for the analysis of variance followed by Bonferroni's multiple comparison tests were performed to compare KD incidence over 3 consecutive weeks, including the weeks when the mean KD prevalence showed the steepest decrease. Next, the week with peak influenza incidence was reset for each year. KD incidence over 3 consecutive weeks, including the new origin week (adjusted week 0), was similarly analyzed. In Tokyo and Kanagawa, KD incidence significantly decreased only after resetting the influenza peak time. These findings suggested that influenza epidemics suppressed KD onset.

A combination of cross correlation and trend analyses reveals that Kawasaki disease is a pollen-induced delayed-type hyper-sensitivity disease.

Based on ecological analyses we proposed in 2003 the relation of Kawasaki Disease (KD) onset causing acute febrile systemic vasculitis, and pollen exposure. This study was aimed at investigating the correlation between pollen release and the change in the numbers of KD patients from 1991 to 2002 in Kanagawa, Japan. Short-term changes in the number of KD patients and medium- to long-term trends were analyzed separately. Short-term changes in the number of KD patients showed a significant positive cross correlation (CC) with 9- to 10-month delay following pollen releases, and a smaller but significant CC with 3- to 4-month delay. Further, a temporal relationship revealed by positive CC distribution showed that pollen release preceded KD development, suggesting that pollen release leads to KD development. A trend in patient numbers was fitted by an exponential curve with the time constant of 0.005494. We hypothesized that the trend was caused by the cumulative effects of pollen exposure for elapsed months on patients who may develop KD. By comparing the time constants of fitted exponential curve for each pollen accumulation period with 0.005494, the exposure period was estimated to be 21.4 months, which explains why approximately 50% of patients developed KD within 24 months from birth.

Mechanism of pigmentation by minocycline in murine B16 melanoma cells.

Long-term treatment with minocycline is known to induce pigmentation or discoloration in tissues but how remains unclear. We investigated the mechanism of pigmentation using B16 melanoma cells. First, we confirmed that intracellular melanin levels increased on minocycline treatment. Then, using the reverse transcriptase-polymerase chain reaction (RT-PCR), we found the expression of mRNA of tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2, to also be significantly increased by treatment with minocycline at 5 µg/ml for 72 h. These results suggest that the minocycline-induced stimulation of melanogenesis occurs at the transcriptional level. Western-blotting revealed slight phosphorylation of extracellular signal-regulated kinase (ERK) 30-60 min after the minocycline treatment. The mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 and the p38 inhibitor SB203580 were used to examine the signaling pathway associated with the mRNA expression of tyrosinase, TRP-1, or TRP-2 when B16 melanoma cells were treated with minocycline. The SB203580 inhibited the mRNA expression of tyrosinase and TRP-1, suggesting the minocycline-induced melanogensis occurred via a p38 signaling pathway.

Effect of heterocyclic pyrimidine compounds on UVB-induced cell damage in human keratinocytes and on melanogenesis in mouse B16 cells.

We investigated the protective effect of several heterocyclic pyrimidine compounds against ultraviolet B (UVB)-induced damage in human keratinocyte HaCaT cells, as well as the inhibitory effect on melanogenesis in B16 melanoma cells. One of the compounds examined, 2-piperadino-6-methyl-5-oxo-5,6-dihydro(7H)pyrrolo[3,4d]pyrimidine maleate (MS-818), showed low cytotoxicity even at 500 microM. At 50-500 microM, MS-818 dose-dependently suppressed the UVB (100 mJ/cm(2))-induced elevation of tumor necrosis factor alpha (TNF-alpha), one of the trigger cytokines for cell death, in HaCaT cells. In addition, MS-818 (100 microM) markedly inhibited melanogenesis in B16 melanoma cells via downregulation of tyrosinase expression mediated by microphthalmia-associated transcription factor (MITF) and extracellular signal-regulated kinase (ERK). In conclusion, MS-818 protected epidermal cells from UVB-induced damage and also suppressed melanogenesis in melanoma cells. It appears to be a good candidate for a new UVB-protective and whitening agent for application in cosmetics.

In vivo treatment with a nonapeptide thymic hormone, facteur thymique serique (FTS), ameliorates chronic colitis induced by dextran sulphate sodium in mice.

Facteur thymique serique (FTS), a thymic hormone with nonapeptide is involved in T cell differentiation in intestine. Here we investigated the effect of FTS on dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were subcutaneously treated with 1 mug/mouse/day of FTS daily. FTS did not affect the course of acute colitis induced by DSS as assessed by survival rate, clinical activity of diseases, extent of tissue damage of colons. On the other hand, FTS significantly ameliorated chronic colitis induced by multiple cycles of DSS as reflected by lower lethality, weight loss, clinical scores and histological scores. The levels of interferon (IFN)-gamma, interleukin 1(IL-1)-beta, and IL-12p40 in the culture supernatants of lamina propria (LP) cells of colon without any stimulation and IFN-gamma by T cells in the LP T cells under T cell receptor (TCR) triggering were reduced in FTS-treated mice, whereas the levels of IL-10 by LP cells and LPT cells were higher in FTS-treated mice. Thus, FTS may serve to suppress inflammation in DSS-induced chronic colitis accompanied by increased IL-10 production.

Protective effect of serum thymic factor, FTS, on cephaloridine-induced nephrotoxicity in rats.

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to increase superoxide disumutase (SOD) levels in senescence-accelerated mice. In the present study, we examined the effect of FTS on cephaloridine (CER)-induced nephrotoxicity in vivo and in vitro. We previously reported that CER led to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney. So, we also investigated whether FTS has an effect on ERK activation induced by CER. Treatment of male Sprague-Dawley rats with intravenous CER (1.2 g/kg) for 24 h markedly increased BUN and plasma creatinine levels and urinary excretion of glucose and protein, decreased creatinine clearance and also led to marked pathological changes in the proximal tubules, as revealed by electron micrographs. An increase in phosphorylated ERK (pERK) was detected in the nuclear fraction prepared from the rat kidney cortex 24 h after CER injection. Pretreatment of rats with FTS (50 microg/kg, i.v.) attenuated the CER-induced renal dysfunction and pathological damage. FTS also suppressed CER-induced ERK activation in the kidney. In vitro treatment of the established cell line, LLC-PK1 cells, with FTS significantly ameliorated CER-induced cell injury, as measured by lactate dehydrogenase (LDH) leakage. Our results, taken together with our previous report that MEK inhibitors ameliorated CER-induced renal cell injury and ERK activation induced by CER, suggest that FTS participates in protection from CER-induced nephrotoxicity by suppressing ERK activation induced by CER.

Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models.

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.

Serum thymic factor prevents LPS-induced pancreatic cell damage in mice via up-regulation of Bcl-2 expression in pancreas.

The protective effect of synthetic serum thymic factor (FTS) nonapeptide on lipopolysaccharide (LPS)-induced pancreatic cell damage in 10-week-old BALB/c male mice was investigated. Mice were divided into three groups. Group I was treated with LPS (10 micro g/head; i.p.) (LPS-treated mice). Group II was administered with FTS (50 micro g/head; i.p.) 24 hr before treatment with LPS and complemented immediately before LPS injection with FTS (50 micro g/head; i.p.) (FTS-administered mice). Group III was only treated with the same volume of saline (control mice). Treatment of LPS in vivo resulted in the destruction of pancreatic acinar cells. In those cells, many apoptotic cells were detected by immunohistochemistry using an anti-single stranded DNA antibody. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) revealed that LPS treatment also caused low or a lack of insulin expression in pancreatic islets. In contrast, morphological change was not seen and apoptotic cell death was suppressed in pancreatic cells of FTS-administered mice. Moreover, insulin expression was normal in those mice. FTS administration enhanced expression of Bcl-2 mRNA levels in pancreatic tissues and IL-6 mRNA levels in splenocytes significantly compared with those of LPS treatment at 3 hr after LPS injection. These findings suggest that FTS prevents LPS-induced cell damage via enhancing Bcl-2 expression in the pancreas and systemic IL-6 production.

MS-818 accelerates mobilization of endothelial progenitor cells and differentiation to endothelial cells.

MS-818 that is a synthetic pyrimidine compound and shown to have neurotrophic actions, enhanced basic fibroblast growth factor (bFGF)-induced angiogenesis in vivo. However, the mechanism and whether MS-818 affects endothelial cells (ECs) directly is not known. Here, the authors investigated whether MS-818 alone could induce angiogenesis and tried to clarify the mechanism of neovascularization by MS-818 in terms of angiogenesis and vasculogenesis. The authors show that MS-818 affects ECs directly and induces migration of and tube formation by ECs in vitro (angiogenesis). Furthermore, the authors demonstrate that MS-818 mobilizes endothelial progenitor cells (EPCs) from the bone marrow and potentiates their differentiation to ECs (vasculogenesis). The effect of MS-818 on the endothelial differentiation was further confirmed with an in vitro differentiation system using mouse embryonic stem cells. MS-818 activates the mitogen-activated protein kinase (MAPK) pathway but not the phosphoinositol 3-kinase (PI3K)-Akt pathway in ECs. These results indicate that MS-818, a synthetic compound, promotes both angiogenesis and vasculogenesis.

Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models.

Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H2O2), and H2O2 is then converted into harmless water (H2O) and oxygen (O2) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.

Suppressor mechanism of serum thymic factor on tumor necrosis factor-alpha-induced apoptosis in the mouse pancreatic beta-cell line.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine considered to play a key role in beta-cell destruction in insulin-dependent diabetes mellitus (IDDM). Serum thymic factor (Facteur thymique serique; FTS) is a nonapeptide thymus hormone known to inhibit IDDM in a mouse model. In this study, the effect of TNF-alpha on the murine pancreatic beta-cell line MIN6 was examined. Cell shrinkage and detachment were seen in cells treated with 0-50 ng/ml TNF-alpha for 12h. Oligonucleosomal DNA fragmentation was determined from non-adherent cells, indicating that the TNF-alpha-induced cell destruction was attributed to apoptosis. Fragmented DNA was quantified by enzyme-linked immunosorbent assay to measure the amount of histone-bound oligonucleosomes. FTS was treated with TNF-alpha and the percentage of fragmented DNA was analyzed. The data indicate a distinct reduction of fragmented DNA at a concentration of 1 ng/ml FTS. Expression of TNF receptor I, inducible form of nitric oxide synthase (iNOS), interleukin-1 beta-converting enzyme (ICE), Bcl-2, and nuclear factor kappa B (NF-kappa B) was analyzed by reverse transcriptase-polymerase chain reaction to investigate the suppressor mechanism of FTS on TNF-alpha-induced apoptosis. FTS treatment suppressed the expression of iNOS and Bcl-2 mRNA in TNF-alpha-treated cells. The expression of NF-kappa B mRNA in TNF-alpha-treated cells was enhanced after FTS treatment, while that of ICE mRNA did not change in TNF-alpha-treated cells with or without FTS treatment. These results suggest that the inhibition of MIN6 cell death by FTS on TNF-alpha-induced apoptosis is caused by a negative feedback mechanism involving the inhibition of iNOS induction.

Individuals exhibiting conspicuous nevi (lentigo simplex) are resistant to allergic rhinitis/conjunctivitis (pollinosis), but those who do not show increased susceptibility to pollinosis.

We investigated 115 individuals in Tokyo from two groups of persons with conspicuous nevi on the head, neck, and arms, etc. (nevus-positive group) and persons who do not exhibit such nevi (nevi-negative group) interviewing them to determine whether they suffered from allergic rhinitis/conjunctivitis (pollinosis) and examining them for the presence and extent of nevi. There was a distinct correlation: only 5 persons among 85 individuals of the nevus-positive group suffered from pollinosis, and all 30 people in the nevus-negative group had pollinosis. Thus, individuals exhibiting conspicuous nevi are resistant to pollinosis, but those who do not show increased susceptibility to pollinosis.

Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors.

We have produced a novel rat IgG(2a) monoclonal antibody against a stage-specific fetal brain glycoprotein of 68 kDa (FGP68), and succeeded in applying it to staining paraffin sections. To gain some insight into the pathobiological significance of this FGP68, this monoclonal antibody was used in immunohistochemical studies to compare the expression of FGP68 and Ki-67 antigen (MIB-1) in 235 primary brain tumors. Approximately half of the glioblastomas multiforme (GBMs) (44/75) and anaplastic astrocytomas (9/17) as well as some astrocytomas (5/30), medulloblastomas (2/14) and primitive neuroectodermal tumors (2/10) had tumor cells that expressed FGP68; however, pilocytic astrocytomas (0/7), oligodendrogliomas (0/15), ependymomas (0/6), schwannomas (0/21), meningiomas (0/22) and pituitary adenomas (0/18) did not express FGP68. The values of the MIB-1 labeling index were statistically higher in GBMs (0.005< P<0.01, Wilcoxon rank-sum test) and anaplastic astrocytomas (0.025< P<0.05) that expressed FGP68 than in those that did not. Normal brain tissue from 20 individuals aged 3-75 years was negative for FGP68 and MIB-1. We conclude that primary brain tumors express FGP68, one of the oncofetal proteins derived from fetal brain, and that FGP68 expression in certain brain tumor cells may depend, in part, on proliferation potential. Based on the possibility that the stage-specific FGP68 plays an important role in brain embryogenesis, some of FGP68-expressing tumor cells might phylogenetically revert to more primitive cells.

Role of a synthetic pyrimidine compound, MS-818, in reduction of infarct size and amelioration of sensorimotor dysfunction following permanent focal cerebral ischemia in rats.

OBJECT: A synthetic heterocyclic pyrimidine compound, MS-818 (2-piperadino-6-methyl-5-oxo-5,6-dihydro-(7H) pyrrolo-[3,4-d] pyrimidine maleate) is reported to have a variety of biological activities including neurite outgrowth, astrocyte differentiation, suppression of neuronal apoptosis, regeneration of injured peripheral nerves, fracture repairs, angiogenesis, and superovulation. To be able to explicate the neurotrophic effects of MS-818, the authors evaluated its effect on the reduction of infarct volume and amelioration of sensorimotor dysfunction in a rat model of focal ischemia. METHODS: Forty male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and assigned to one of four treatment groups (10 animals in each group). The MS-818 (1, 5, or 10 mg/kg) or phosphate-buffered saline (control group) was administered intraperitoneally at onset of ischemia and again 24 hours later. The rats were killed 48 hours after they underwent surgery to induce stroke, and infarct volume was determined using an image-analysis computer software program following staining with 2,3,5-triphenyltetrazolium chloride. Postischemic neurological deficit and body weight were also assessed. CONCLUSIONS: Significant reductions in infarct volume (total and cortical infarction) were found in all the MS-818-treated groups compared with the control group. Furthermore, MS-818 induced significant amelioration of sensorimotor dysfunction, as indicated by the results of forelimb and hindlimb placing tests. The present findings suggest that MS-818, which has a much smaller molecular weight than neurotrophic peptides. represents a new approach to the treatment of focal cerebral ischemia.

Acceleration by MS-818 of early muscle regeneration and enhanced muscle recovery after surgical transection.

The synthesized pyrimidine compound MS-818 has neurotrophic effects in several kinds of neuronal cells, but its effect with respect to muscle cells remains unknown. We therefore examined the effects of MS-818 on regeneration for 12 weeks in a wounded area (damaged and gap areas) of cut muscle in adult rats. The right semitendinosus muscles of treated and control groups were severed and sutured at the belly and the left semitendinosus muscles were left intact. MS-818 was administered intraperitoneally to the treated group at a dose of 5 mg/kg once daily. Control rats received an equal volume of physiological saline. A reference group underwent no surgical procedure. MS-818 significantly increased the maximal isometric twitch tension (Tmax) compared to control and reference rats after week 4 (approximately 1.4-fold control value; 0.6-fold reference value). Northern blotting showed that MS-818 enhanced myogenin mRNA expression to about 1.5-fold above the control level at 2, 4, and 7 days after surgery. Immunohistochemical and histochemical studies showed significant enhancement in the treated group since myogenic cells expressed desmin and were positive for neonatal myosin, and the fiber diameters and numbers of premature myofibers and end plates were increased when compared with those in the control group. These results show that MS-818 accelerated the proliferation and differentiation of activated satellite cells and the fusion of myotubes to form immature myofibers. At week 12, Tmax, fiber diameter, and number of end plates in the treatment group recovered 60, 85, and more than 100%, respectively, compared to the reference group. The mechanism of MS-818 effects on the accelerated regeneration of cut muscle is discussed.

Effects of thymic hormone on reactive oxygen species-scavengers and renal function in tacrolimus-induced nephrotoxicity.

The effects of a thymic hormone (Facteur thymique serique; FTS) on renal reactive oxygen species-scavenging enzymes or substances in heminephrectomized rats with and without tacrolimus-induced nephrotoxicity were studied. Rats received both oral dose of tacrolimus (5 mg/kg/day) and subcutaneous administration of three dosages of FTS (5, 50, and 250 microg/kg/day) over 28 days (Group A). In Group B, they received three dosages of FTS alone (0.5, 5, and 50 microg/kg/day) or FTS 50 microg/kg/day with tacrolimus over 28 days. Each dose of FTS (Group A) partially elevated renal creatinine clearances. Tacrolimus enhanced renal glutathione reductase (GSH-R) activities and glutathione (GSH) and depressed catalase (CAT) activities. FTS increased GSH levels and GSH-R activities. Although FTS alone did not change CAT activities, CAT activities recovered as a result of concomitant use of FTS (Groups A and B). A significant positive correlation was found between CAT activity and creatinine clearance. These findings suggest that FTS is useful for the prevention of tacrolimus-induced nephrotoxicity, and that the increase of renal CAT activity in the defense mechanism of FTS might be important for cell protection against active oxygen species.