Effects of sunitinib on immunoreactivity of vimentin, E-cadherin and S100 in kidneys of streptozotocin induced diabetic mice.

Diabetes mellitus (DM) affects many organs including kidney. Tyrosine kinase can cause hypoglycemia and sunitinib is an inhibitor of tyrosine kinase. We investigated the possible effects of sunitinib on the kidney of streptozotocin (STZ) induced type 1 diabetic mice. We used 28 CD 1 type male mice divided into four groups of seven. Type 1 diabetes was induced by injection of STZ. Group 1 was the untreated control. Group 2 comprised non-diabetic mice + sunitinib. Both groups 1 and 2 exhibited normal blood glucose levels. Group 3 comprised STZ treated diabetic mice + saline. Group 4 were diabetic mice + sunitinib treatment. Kidneys were removed after 8 weeks. The immunoreactivities of vimentin, E-cadherin and S100 were assessed. Immunostaining of vimentin, E-cadherin and S100 was located in both the glomeruli and tubules of the kidney. We found that the number of vimentin and E-cadherin positive glomeruli and tubules were increased after sunitinib treatment compared to saline treated diabetic mice. The number of vimentin labeled tubules was decreased in the sunitinib treated group compared to diabetic + saline groups. Differences in the number of S100 positive tubules and glomeruli between groups 3 and 4 were not statistically significant. The effect of sunitinib on experimental diabetic mice appears to be related to levels of vimentin, E-cadherin and S100 in the glomeruli and tubules of the kidney, and sunitinib may protect against renal damage from DM.

Effect of testosterone supplementation on nitroso-redox imbalance, cardiac metabolism markers, and S100 proteins expression in the heart of castrated male rats.

The aim of this study was to investigate the effects of castration and testosterone supplementation on nitroso-redox status, cardiac metabolism markers, and S100 proteins expression in the heart of male rats. 50 male Wistar rats were randomized into five groups with ten animals each: group 1: control intact (CON); group 2: sham operated (Sh-O); group 3: sesame oil-treated rats (S-oil); group 4: gonadoectomized (GDX); and group 5: gonadoectomized rats treated with testosterone (GDX-T) for 8 weeks. Our results showed myofibrillar weaving, apoptosis, inflammation, and fibrosis (as reflected by increased activity of MMP 9 and MMP 2) in the heart of gonadoectomized rats. Testosterone supplementation restored the normal structure of the heart. In addition, a state of nitroso-redox imbalance was observed in the heart of castrated rats with increased NO (425.1 ± 322.8 vs. 208 ± 67.06, p Ë‚ 0.05) and MDA (33.18 ± 9.45 vs. 22.04 ± 7.13, p Ë‚ 0.05) and decreased GSH levels (0.71 ± 0.13 vs. 1.09 ± 0.19, p = 0.001). Testosterone treatment leads to a re-establish of only NO levels (425.1 ± 322.8 vs. 210.4 ± 114.3, p > 0.05). Markers of cardiac metabolism showed an enhancement of LDH activity (12725 ± 4604 vs. 5381 ± 3122, p Ë‚ 0.05) in the heart of castrated rats. This was inversed by testosterone replacement (12725 ± 4604 vs. 5781 ± 5187, p Ë‚ 0.05). Furthermore, castration induced heart's accumulation of triglycerides (37.24 ± 6.17 vs. 27.88 ± 6.47, p Ë‚ 0.05) and total cholesterol (61.44 ± 3.59 vs. 54.11 ± 7.55, p Ë‚ 0.05), which were significantly reduced by testosterone supplementation (29.03 ± 2.47 vs. 37.24 ± 6.17, p Ë‚ 0.05) and (47.9 ± 4.15 vs. 61.44 ± 3.59, p Ë‚ 0.001). Cardiomyocytes of castrated rats showed a decreased immunoexpression of S100 proteins compared to control animals. A restoration of S100 proteins immunostaining in cardiomyocyte cytoplasm was observed after testosterone supplementation. These findings confirm the deleterious effects of testosterone deficiency on cardiac function and highlight the involvement of nitric oxide, metalloproteinases 2 and 9, and S100 proteins.

Correction of anxiety disorders: focus on a comorbid patient.

The exact cause of the development of anxiety disorders (AD) in present time has not been fully established and is a subject of debate in many countries. Interest in studying the mechanisms of action of proteins of S100 group, in particular, neurospecific protein S100b, is caused by its participation in processes of integrative activity of brain/neuron and development of diseases of nervous system. The functions of S100 proteins determine their influence on synaptic plasticity and participation in the regulation of stress-realizing and stress-limiting systems, the imbalance of which (primarily, the insufficiency of the GABA-ergic system) is the neurobiological basis of the majority of anxiety-depressive pathologies. Preparations regulating the activity of S100 protein have a distinct clinical anti-anxiety effect and additionally contribute to the restoration of neuronal plasticity processes.

TSLP Down-Regulates S100A7 and ß-Defensin 2 Via the JAK2/STAT3-Dependent Mechanism.

Elevated T-helper type 2 cytokines in atopic skin, such as IL-4 and IL-13, were thought to be responsible for an impaired expression of antimicrobial proteins, which may contribute to the increased susceptibility to skin infections in patients with atopic dermatitis. In this study, the relationship between thymic stromal lymphopoietin and antimicrobial proteins and the involved molecular pathway was defined in normal human epidermal keratinocytes and human skin equivalent model. Stimulation of normal human epidermal keratinocytes with thymic stromal lymphopoietin decreased both mRNA and levels of S100A7 and human ß-defensin 2 in a dose-dependent manner, and the regulation was JAK2/STAT3-dependent. Thymic stromal lymphopoietin decreased the antimicrobial protein expression, even in the presence of IL-17, which is their strong inducer. STAT3 directly regulated the S100A7 and human ß-defensin 2 promoters in normal human epidermal keratinocytes. Immunohistochemically, lesional atopic skin stained more intensely with phospho-STAT3 compared with healthy control. Our results show that up-regulated thymic stromal lymphopoietin may contribute to the deficiency of antimicrobial proteins in atopic dermatitis, including S100A7 and human ß-defensin 2, by a JAK2/STAT3-dependent mechanism and that STAT3/Sin3a might directly control the transcriptional activity of the antimicrobial protein promoters in normal human epidermal keratinocytes. Taken together, a key role of the JAK2/STAT3/Sin3a signaling pathway in thymic stromal lymphopoietin-mediated immune response in normal human epidermal keratinocytes might give us clues to understanding the pathological signal transductions in atopic dermatitis.

Critical role of serum response factor in podocyte epithelial-mesenchymal transition of diabetic nephropathy.

PURPOSE: To investigate the expression and function of serum response factor in podocyte epithelial-mesenchymal transition of diabetic nephropathy. METHODS: The expression of serum response factor, epithelial markers and mesenchymal markers was examined in podocytes or renal cortex tissues following high glucose. Serum response factor was upregulated by its plasmids and downregulated by CCG-1423 to investigate how it influenced podocyte epithelial-mesenchymal transition in diabetic nephropathy. Streptozotocin was used to generate diabetes mellitus in rats. RESULTS: In podocytes after high glucose treatment, serum response factor and mesenchymal markers increased, while epithelial markers declined. Similar changes were observed in vivo. Serum response factor overexpression in podocytes induced expression of Snail, an important transcription factor mediating epithelial-mesenchymal transition. Blockade of serum response factor reduced Snail induction, protected podocytes from epithelial-mesenchymal transition and ameliorated proteinuria. CONCLUSION: Together, increased serum response factor activity provokes podocytes' epithelial-mesenchymal transition and dysfunction in diabetic nephropathy. Targeting serum response factor by small-molecule inhibitor may be an attractive therapeutic strategy for diabetic nephropathy.

Knockdown of S100A4 impairs arecoline-induced invasiveness of oral squamous cell carcinomas.

OBJECTIVES: Metastasis is the most common cause of oral squamous cell carcinoma (OSCC)-related death. The physiological function of S100A4 in the pathogenesis of areca quid chewing-associated OSCC has not been uncovered. METHOD: OSCC tissues from areca quid chewers were analyzed by immunohistochemistry for S100A4 expression. The functions of S100A4 in invasiveness of arecoline-treated oral epithelial (OE) cells were determined by loss function approaches. RESULTS: Expression of S100A4 was positively correlated with clinical grading and lymph node metastasis of OSCC. Upregulated S100A4 is correlated with poor survival outcome of OSCC patients. Arecoline led to dose-dependent elevation of S100A4 expression in oral epithelial (OE) cells. Down-regulation of S100A4 significantly reversed arecoline-induced oncogenecity in OE cells. The additions of pharmacological agents LY294002, SP600125, and CAY10585 were found to inhibit arecoline-induced S100A4 expression in OE cells. CONCLUSION: Arecoline-induced S100A4 expression was down-regulated by LY294002, SP600125, or CAY10585 treatment. Targeting S100A4 might offer a new strategy for the treatment of OSCC patients with metastasis.

Influence of Tacrolimus (FK506) on Nerve Regeneration Using Allografts: A Rat Sciatic Nerve Model.

PURPOSE: FK506 is an immunosuppressant agent used to prevent rejection after organ transplantation. The aim of the present study was to assess effects of tacrolimus (FK506) on peripheral nerve regeneration using allografts in a rat sciatic nerve model. MATERIALS AND METHODS: Thirty male white Wistar rats were divided randomly into a normal control (NC) group (n = 10), an allograft (ALLO) group (n = 10), and an FK506-treated (ALLO/FK506) group (n = 10). In the NC group, the left sciatic nerve was exposed through a gluteal muscle incision and, after homeostasis, the muscle was sutured. In the ALLO group, the left sciatic nerve was exposed through a gluteal muscle incision and transected proximal to the tibioperoneal bifurcation, where a 10-mm segment was excised. The same procedure was performed in the ALLO/FK506 group. The harvested nerves of the ALLO group served as allografts for the ALLO/FK506 group and vice versa. The NC and ALLO groups received sterile olive oil 300 µL intraperitoneally once a day for 1 week and the ALLO/FK506 group received FK506 300 µL (1 mg/kg) intraperitoneally once a day for 1 week. RESULTS: Behavioral, functional, and biomechanical recovery and gastrocnemius muscle mass showed earlier regeneration of axons in the ALLO/FK506 than in the ALLO group (P < .05). Histomorphometric and immunohistochemical studies also showed earlier regeneration of axons in the ALLO/FK506 than in the ALLO group (P < .05). CONCLUSIONS: Administration of FK506 could accelerate functional recovery of the sciatic nerve after nerve allografting. It could have clinical implications for the surgical management of patients after facial nerve transection.

Ketoprofen combined with artery graft entubulization improves functional recovery of transected peripheral nerves.

The objective was to assess the local effect of ketoprofen on sciatic nerve regeneration and functional recovery. Eighty healthy male white Wistar rats were randomized into four experimental groups of 20 animals each: In the transected group (TC), the left sciatic nerve was transected and nerve cut ends were fixed in the adjacent muscle. In the treatment group the defect was bridged using an artery graft (AG/Keto) filled with 10 microliter ketoprofen (0.1 mg/kg). In the artery graft group (AG), the graft was filled with phosphated-buffer saline alone. In the sham-operated group (SHAM), the sciatic nerve was exposed and manipulated. Each group was subdivided into four subgroups of five animals each and regenerated nerve fibres were studied at 4, 8, 12 and 16 weeks post operation. Behavioural testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices showed earlier regeneration of axons in AG/Keto than in AG group (p < 0.05). Immunohistochemical study clearly showed more positive location of reactions to S-100 in AG/Keto than in AG group. When loaded in an artery graft, ketoprofen improved functional recovery and morphometric indices of the sciatic nerve. Local usage of this easily accessible therapeutic medicine is cost saving and avoids the problems associated with systemic administration.

Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 "alarmins" psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis.

The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as "alarmins" to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.

Decoy-DNA against special AT-rich sequence binding protein 1 inhibits the growth and invasive ability of human breast cancer.

"Triple-negative" (TN) breast cancers, which are characterized by estrogen receptor (-), progesterone receptor (-), and human epidermal growth factor receptor 2 (-), are typically associated with poor prognosis because of their aggressive tumor phenotypes. In recent years, the number of patients with breast cancers has remarkably increased, but there are only few available drugs for treatment of TN breast cancers. The development of novel drugs targeting TN breast cancer is urgently required. In the present study, we focused on the function of special AT-rich sequence binding protein 1 (SATB1) as a target molecule for the treatment of TN breast cancers. By recruiting chromatin remodeling enzymes and transcriptional factors, SATB1 regulates the expression of >1,000 genes related to cell growth and translocation. We synthesized a decoy DNA against SATB1, including the recognition sequence of SATB1. We examined the inhibitory effects of the decoy DNAs on cellular proliferation of a TN metastatic breast cancer cell line (MDA-MB-231). SATB1-decoy DNA inhibited the proliferation of MDA-MB-231 cells. Especially, it was significant that SATB1-decoy DNA drastically reduced the invasive and metastatic capacity of MBA-MB-231 cells. Further, in the case of MCF7 cells (SATB1-negative breast cancer cell line), SATB1-decoy DNA did not exhibit any inhibitory effect. These data suggest that SATB1-decoy DNA may be an effective candidate for use as a molecular-targeting drug for treatment of TN breast cancer.

Effect of recombinant human erythropoietin on serum S100B protein and interleukin-6 levels after traumatic brain injury in the rat.

Erythropoietin (EPO) has a neuroprotective effect in the animal model of ischemia/hypoxia, but the mechanisms underlying the EPO effect in traumatic brain injury (TBI) are not well understood. This study examined the potential neuroprotective mechanisms of recombinant human EPO (rhEPO) in rats after TBI. Sixty healthy adult male Sprague-Dawley rats were randomly divided into 5 groups: 1000 U/kg rhEPO-treated, 3000 U/kg rhEPO-treated, 5000 U/kg rhEPO-treated, citicoline, and normal saline (control) groups. The TBI model was based on the modified Feeney's free falling model. Serum samples were collected at 6 hours, 24 hours, 3 days, 5 days, and 7 days after trauma. The serum S100B protein and interleukin-6 (IL-6) levels were measured after treatment in each group with double antibody sandwich enzyme-linked immunosorbent assay. Both serum S100B protein and IL-6 levels were significantly lower in 3000 U/kg rhEPO-treated and 5000 U/kg rhEPO-treated groups (p < 0.001). The decrease in serum S100B protein level was correlated with the dosage of rhEPO. Medium doses of rhEPO achieved the optimum decreases in the serum IL-6 level. Therefore, inhibition of the composition and secretion of S100B protein and IL-6 levels by EPO might be one of the mechanisms involved in decreasing inflammatory reaction in the brain, and may be responsible for the neuroprotective effect after TBI.

Increased serum S100B levels in chronic schizophrenic patients on long-term clozapine or typical antipsychotics.

S100B is a calcium-binding protein, mainly produced and secreted by astrocytes, and it mediates the interaction among glial cells and between glial cells and neurons. Recently, several studies have shown increased serum 100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. To examine the potentially differential effect of clozapine compared to typical antipsychotics on serum S100B and the relationship between S100B levels and psychopathology in patients with schizophrenia, 63 physically healthy patients with schizophrenia were compared with 50 age-, sex-matched normal controls. The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum S100B levels were measured by sandwich ELISA. The results showed that S100B levels were significantly elevated in chronic patients with schizophrenia than in healthy controls (p<0.0001). As compared with healthy controls, there was a significant increase in S100B levels in patients treated with both clozapine and typical antipsychotics (both p<0.0001). However, no significant difference in S100B was found between patients treated with clozapine and typical antipsychotic subgroups (p>0.05). Furthermore, there was no significant correlation between S100B and standardized drug doses or the duration of taking neuroleptic medications (both p>0.05). In addition, no significant correlation was observed between S100B and PANSS total score and its subscale scores (all >0.05). These findings suggest that serum S100B levels in chronic schizophrenia under antipsychotic medication may be increased, suggesting that a dysfunction of astrocytes and/or oligodendrocytes may play a role in the pathogenesis of schizophrenia. Long term treatment with both typical and atypical antipsychotics may produce similar effects on the S100B serum levels, which however remains to be characterized in a large sample of first-episode, medication-naïve patients with schizophrenia using a longitudinal design.

Light to moderate alcohol consumption is associated with S100beta and amyloid beta levels in healthy older adults.

Heavy alcohol consumption has been associated with several adverse neurocognitive outcomes in older adults, though little is known about lower consumption levels. No study has investigated the associations between S100beta and amyloid beta (Abeta) serum levels (biomarkers that provide evidence of neurological pathology) and light to moderate alcohol consumption in healthy older adults without neurological conditions. Thirty-five healthy older adults underwent neuropsychological testing and fasting blood draw with subsequent serum S100beta and Abeta 1-40 level quantification. Increased S100beta levels were associated with increased frequency of alcohol consumption and increased total monthly consumption of alcohol. Increased Abeta levels were associated with increased quantity of alcohol consumption. Further work investigating possible mechanisms is needed, particularly longitudinal studies and studies employing neuroimaging.

Nitric oxide test during cardiac catheterization decreases the serum concentrations of S100B protein in adult patients with idiopathic pulmonary hypertension.

OBJECTIVE: Cardiac catheterization (CC) is a life-threatening procedure in adult patients. Complicated by idiopathic arterial pulmonary hypertension (IPAH), there is a potential risk of central nervous system (CNS) damage. We measured serum levels of a well-established brain damage marker, namely S100B, collected before, during and after CC in adult patients in whom the nitric oxide (NO) test had been performed. MATERIAL AND METHODS: In 12 adult patients who had undergone CC for IPAH diagnosis, we recorded clinical and standard monitoring procedures (laboratory variables and echocardiographic patterns) and serum concentrations of S100B before (time 0), during (time 1) and after the NO test (time 2) and at 24 h after (time 3) the procedure in samples obtained from the systemic and pulmonary circulation. Patients were subdivided into NO test responders (n=6) and non-responders (n=6). Neurological evaluation was performed at admission and at discharge from hospital. RESULTS: Adult patients subjected to CC showed no overt neurological injury at discharge from hospital. No significant differences (p > 0.05 for all) in S100B serum levels between groups at times 0, 1 and 3 have been shown independently from the sampling site. It was noteworthy that the concentration of protein in the responders group at time 2 was significantly decreased (p < 0.05, for all) compared to the responder group and to baseline values. A significant correlation was found between arterial oxygen partial pressure and individual S100B concentration in the pulmonary and systemic bloodstream in the entire study group (R = -0.66 and R = 0.71, respectively; p < 0.05, for both). CONCLUSIONS: The data suggest that S100B protein assessment, as well as the NO test, may be useful when monitoring possible CNS damage during CC in patients with IPAH, and may also be valuable in relation to brain functions, especially when performed as an emergency procedure in severely hypoxic patients.

Theoretical study on binding of S100B protein.

S100B protein is one of the factors involved in the down-regulation of tumor suppressor protein p53, a transcription activator that signals for cycle arrest and apoptosis. As the inactivation of normal p53 functions is found in over half of human cancers, restoration of normal p53 functions through the destruction or prevention of S100B--p53 complexes represents a possible approach for the development of anti-cancer drugs. The aim of this work was to propose the S100B binding interface through an examination of the literature and use of molecular modeling (MM) techniques with AutoDock program and the AMBER force field. We propose two residues in the S100B binding pocket (Val56, Phe76) and two residues on the protein surface (Val52, Ala83) are essential for ligand binding. The data presented here indicate that interactions with these four residues are necessary for a reduction in the incidence of the S100B--p53 complex. Additionally, we have tried to explain a mechanism for the action of pentamidine, the best-known S100B ligand, and have proposed two S100B--pentamidine structures. The results presented here may be useful for the efficient design of new S100B ligands.

Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator.

We have previously shown that interferon-gamma (IFN-gamma) inhibits expression of the metastasis-promoting protein S100A4. In the present study, we further explore the mechanism behind the IFN-gamma-mediated effects on the human S100A4 promoter and demonstrate that IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA). The acidic domain in the N-terminal part of CIITA was crucial for the observed IFN-gamma-induced inhibition of S100A4 promoter activity, probably by binding the histone acetyltransferase CBP/p300. Importantly, overexpression of CIITA significantly reduced the expression of endogenous S100A4. Our data suggest a model where CIITA represses S100A4 transcription through sequestering of CBP/p300, thereby reducing the level of CBP/p300 at the S100A4 promoter, which in turn leads to inhibition of S100A4 transcription.

Effect of cromolyn on S100P interactions with RAGE and pancreatic cancer growth and invasion in mouse models.

BACKGROUND: We previously found that S100P, a member of the S100 protein family, is expressed in more than 90% of pancreatic tumors and is associated with tumor growth and invasion. In the current study, we investigated the ability of the antiallergy drug, cromolyn, to block S100P function. METHODS: Interactions between cromolyn and S100P were investigated using a drug affinity column and by examining cromolyn's effects on coimmunoprecipitation of S100P and receptor for advanced glycation end-products (RAGE). The effects of cromolyn on cell growth, invasion, and nuclear factor-kappaB (NFkappaB) activity of pancreatic cancer cells with (BxPC-3 and MPanc-96) and without (Panc-1) endogenous S100P were investigated by cell proliferation assay, by cell invasion assay, and by luciferase reporter gene assay, respectively. The effects of cromolyn on tumor growth in vivo were investigated in three orthotopic models (n = 20 mice per model) by administration of cromolyn (5 mg/kg body weight, daily) with and without gemcitabine (125 mg/kg body weight, biweekly), the drug currently used to treat pancreatic cancer. Tumor growth was assayed by reporter gene expression. All statistical tests were two-sided. RESULTS: S100P was retained on a cromolyn affinity column. Cromolyn blocked the coimmunoprecipitation of S100P and RAGE. In vitro, cromolyn (100 microM) inhibited S100P-stimulated Panc-1 cell proliferation (S100P, mean = 0.93 U, versus S100P + cromolyn, mean = 0.56 U, difference = 0.37 U; 95% confidence interval [CI] = 0.24 to 0.49 U; P = .001, n = 3), invasion (S100P, mean = 58.0%, versus S100P + cromolyn, mean = 9.4%, difference = 48.6%; 95% CI = 38.8% to 58.8%; P<.001, n = 3), and NFkappaB activity (S100P, mean = 14,460, versus S100P + cromolyn, mean = 7360 photons/s, difference = 7100 photons/s; 95% CI = 3689 to 10 510 photons/s; P = .005, n = 3). In vivo, cromolyn inhibited tumor growth in mice bearing tumor with endogenous S100P (BxPC-3: control, mean = 1.6 x 10(9) photons/s, versus cromolyn, mean = 4.4 x 10(8) photons/s, difference = 1.2 x 10(9) photons/s; 95% CI = 6.2 x 10(8) to 1.6 x 10(9) photons/s; P<.001, n = 5; MPanc-96: control, mean = 1.1 x 10(10) photons/s, versus cromolyn, mean = 4.8 x 10(9) photons/s, difference = 6.2 x 10(9) photons/s; 95% CI = 1.9 x 10(9) to 1.0 x 10(10) photons/s; P = .009, n = 5) and increased the effectiveness of gemcitabine (BxPC-3: gemcitabine, mean = 9.2 x 10(8) photons/s, versus combination, mean = 1.8 x 10(8) photons/s, difference = 7.4 x 10(8) photons/s; 95% CI = 4.5 x 10(8) to 1.0 x 10(9) photons/s; P<.001; MPanc-96: gemcitabine, mean = 4.1 x 10(9) photons/s, versus combination, mean = 2.0 x 10(9) photons/s, difference = 2.1 x 10(9) photons/s; 95% CI = 4.4 x 10(8) to 3.8 x 10(9) photons/s; P<.001). However, cromolyn had no effect on growth of tumors lacking S100P (Panc-1). CONCLUSION: Cromolyn binds S100P, prevents activation of RAGE, inhibits tumor growth, and increases the effectiveness of gemcitabine in experimental models.

S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation.

The p53 paralogues p73, p63 and their respective truncated isoforms have been shown to be critical regulators of developmental and differentiation processes. Indeed, both p73- and p63-deficient mice exhibit severe developmental defects. Here, we show that S100A2 gene, whose transcript and protein are induced during keratinocyte differentiation of HaCaT cells, is a direct transcriptional target of p73beta and DeltaNp63alpha and is required for proper keratinocyte differentiation. Transactivation assays reveal that p73beta and DeltaNp63alpha exert opposite transcriptional effects on S100A2 gene. While DeltaNp63alpha is found in vivo onto S100A2 regulatory regions predominantly in proliferating cells, p73beta is recruited in differentiating cells. Silencing of p73 impairs the induction of S100A2 during the differentiation of HaCaT cells. Moreover, silencing of p73 or S100A2 impairs the proper expression of keratinocyte differentiation markers. Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin.

A single course of antenatal betamethasone reduces neurotrophic factor S100B concentration in the hippocampus and serum in the neonatal rat.

The effects of a single course of antenatal betamethasone on S100B protein concentration were investigated in Fisher 344 rats. On day 20 of gestation, pregnant rats were injected twice 8 h apart with either (1) 170 microg kg(-1) body weight betamethasone ("clinically-equivalent dose", equivalent to 12 mg twice, 24 h apart in humans), (2) half of this dose (equivalent to 6 mg) or (3) vehicle. We report reference values for S100B protein in the serum and different brain regions in both genders at 1, 2, and 21 days after birth. Interestingly, S100B concentration showed a time-dependent and brain region-specific pattern of expression. At P1, S100B was higher in the serum of males compared to females. In addition, we show that both doses of betamethasone decreased S100B concentration in the serum of males at P1, whereas in the hippocampus, it was reduced by the clinically-equivalent dose only. This suggests that lowering the dose of antenatal betamethasone may be less detrimental for brain maturation and therefore we reiterate the need for clinical trials with a low dose regimen.

Effects of chronic administration with nilvadipine against immunohistochemical changes related to aging in the mouse hippocampus.

We investigated the effect of Ca2+ antagonist nilvadipine on age-related immunohistochemical alterations in ubiquitin and S100beta protein of the hippocampal CA1 sector in mice using 8-, 18-, 40-, and 59-week-old mice. No significant changes in the number of neuronal cells were observed in the hippocampal CA1 sector up to 59 weeks after birth. The administration of nilvadipine did not affect the number of the hippocampal CA1 cells of 40-week-old mice. Age-dependent increases in ubiquitin immunoreactivity were observed in the hippocampal CA1 neurons up to 59 weeks after birth. The administration of nilvadipine prevented dose-dependently the increases in the number of ubiquitin-immunoreactive neurons in the hippocampal CA1 sector of 40-week-old mice. S100,beta immunoreactivity was unchanged in the hippocampal CA1 sector up to 40 weeks after birth. In 59-week-old mice, the level of staining of S100beta-immunoreactive cells increased significantly in the hippocampal CA1 sector. The administration of nilvadipine decreased dose-dependently the number of S 100beta-immunoreactive cells in the hippocampal CA1 sector of 40-week-old mice. The present study demonstrates that age-related increases in ubiquitin system may play a pivotal role in protecting neuronal cell damage during aging. In contrast, our results suggest that expression of S 100beta protein in the hippocampal CA1 sector may play an exacerbating factor in some neuronal cells damaged by aging. Our results also demonstrate that nilvadipine, a dihydropyridine-type calcium channel blocker, can prevent dose-dependently the increases in the ubiquitin immunoreactive neurons and decrease the number of S100beta immunoreactive cells in the hippocampal CA1 neurons of aged mice. These results suggest that nilvadipine may offer a new approach for the treatment of neuronal dysfunction in aged humans.