Decrease In Proliferative Activity Research Articles

CYTOME ANALYSIS OF EFFECTS OF GENOMIC INSTABILITY INDUCED BY DIFFERENTLY SIZED SILVER NANOPARTICLES IN HUMAN WHOLE BLOOD CULTURE

A high bactericidal activity of silver nanoparticles (NHS) suggests the possibility of their use in the preparation of drinking water. On the example of human peripheral blood lymphocytes cultured in micronucleus test with cytochalasin B, effects of genome instability were investigated in a concentration range of 0.005-5.0 mg / l of silver nanoparticles (NHS) with a size of 14.3 ± 0.2 nm (Ag14) and 100.0 ± 11.0 nm (AG100), stabilized with gum acacia and for comparison , those of Ag2SO4 (silver ions). In the same range of concentrations . All substances were suspended or dissolved in drinking water.The results showed that the NPS had genotoxic and cytotoxic effects that made them unsuitable to improve the quality of drinking water. Effects of genome instability determined by the frequency of dividing cells with micronuclei and nucleoplasmic bridges, as well as inhibition of mitotic activity, decrease of proliferative activity and increasing duration of the cell cycle came down in series of Ag2SO4 >> Ag100 >> Ag14. However, frequency rise of asymmetric 3-nucleated cells due to aneuploidy induction was the most characteristic of Ag14 particles.

Mesenchymal stem and progenitor cells of rats' bone marrow under chronic action of ionizing radiation

to define functioning characteristics of mesenchymal stem and progenitor cells of rats' bone marrow under prolonged action of ionizing radiation as a result of 90Sr incorporation. We applied the model of Wistar rats' internal irradiation with 90Sr radionuclide and per formed the in vitro cultivation of their bone marrow mesenchymal cells. Colony forming efficiency in the in vitro cell culture was determined, as well as the possibility of these cells to form feeder layers and to support rat bone mar row hematopoietic cells in the culture of diffusion chambers in vitro. We established that chronic action of incorporated 90Sr radionuclide induced considerable decrease in proliferative activity of mesenchymal stem cells comparing to control, as well as the inhibition of the capability to prolonged support of hematopoietic processes in vitro by their feeder layers.Thus, bone marrow mesenchymal stem cells and their closest progeny - progenitor cells were characterized by rather high radiosensitivity under the influence of ionizing radiation, which was revealed in considerable decline of their functional activity in cell culture in vitro comparing to control indices as a result of irradiation.

The role of partial androgen deficiency in aging men in the development of benign prostatic hyperplasia and prostate cancer

AbstractOnce people reach 35-40 years, they have a decrease in their pool of pluripotent stem cells, and show a violation of tissue renewal, a decrease in the number of cell-producers of testosterone (Leidig cells) and a reduction in testosterone circulating in the blood. Partial androgen deficiency in aging men violates division and differentiation of androgen-dependent cells and increases the risk for development of benign prostatic hyperplasia and prostate cancer. The recovery of testosterone production and regeneration helps make a decrease in proliferative activity, and the rehabilitation of regulation of androgen-dependent cells of the prostate and other tissues and organs, as well as reduce insulin resistance among older men.

Immunomorphology of oral lichen planus

The article is devoted to immunohistochemical study of reticular and erosive forms of oral lichen planus. Morphological examination of the reticular form revealed the increased number of Langerhans cells (CD1a), mast cells (CD25) and T lymphocytes (CD4, CD8, CD16) in the oral epithelium. Activation of these cells leads to the secretion of TNF-α and destruction of basal keratinocytes, which manifests as a focal reduction of intercellular protein expression of E-cadherin. Destruction of basal keratinocytes in a reticular form of oral lichen planus is accompanied by a significant decrease in proliferative activity of the basal cell layer (21.7±10.2%) compared with normal mucosa (33.6±7.0%), p=0.0045. In erosive form along with the above changes IgG and C3d complement's elements are revealed, which confirms the activation of immune complex mechanisms in the erosion area.

Testicular histomorphometry and the proliferative and apoptotic activities of the seminiferous epithelium in Syrian hamster (Mesocricetus auratus) during regression owing to short photoperiod.

During the non-breeding season some animals exhibit testicular atrophy, decreased testicular weight and reduced seminiferous tubule diameter accompanied by depletion of the seminiferous epithelium. Some cellular factors involved in this depletion are changes in germ cell proliferation and apoptosis. In the Syrian hamster this depletion has been studied histologically and in terms of the involvement of proliferation and apoptosis in the seminiferous epithelium of fully regressed testes. The objectives of this study included the histomorphometrical characterization of the testis and the determination of the proliferative and apoptotic activity of germ cells in the seminiferous epithelium during testicular regression owing to short photoperiod. The study was performed using conventional light microscopy (hematoxylin and eosin), proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labelling staining, image analysis software, and transmission electron microscopy in three established regression groups: mild regression (MR), strong regression (SR), and total regression (TR). Morphometrically a gradual decrease in total tubular area and in the testicular, tubular, and epithelial volumes was observed during testicular regression. Interstitial and luminal volumes decreased from the MR group onwards. The tubular length decreased from MR to SR. As regards spermatogonial proliferation, only an initial decrease in proliferative activity was observed, whereas apoptotic germ cell activity increased throughout regression. The number of germ cells studied decreased throughout the process of testicular regression. In conclusion, testicular regression in Syrian hamster comprises two histomorphometrical phases, the first involving a decrease in seminiferous tubular diameter and volume and the second involving shortening of the seminiferous tubule and a decrease in interstitial volume. At the cellular level, there is an initial decrease in proliferation and increase in apoptosis involving all germ cells. At the end of regression, the proliferative and apoptotic activities of the spermatogonia recover the values observed prior to regression in preparation for recrudescence.

Bumetanide-induced NKCC1 inhibition attenuates oxygen–glucose deprivation-induced decrease in proliferative activity and cell cycle progression arrest in cultured OPCs via p-38 MAPKs

The Na–K–Cl co-transporter 1 (NKCC1; a member of the cation-chloride co-transporter family) mediates the coupled movement of Na+ and/or K+ with Cl− across the plasma membrane of cells (Haas and Forbush, 2000, Annu. Rev. Physiol., 62, 515–534; Russell, 2000, Physiol. Rev., 80, 211–276). Although it acts as an important regulator of cell volume, secretion, and modulator of cell apoptosis and proliferation (Chen et al., 2005, J. Cereb. Blood Flow Metab., 25, 54–66; Kahle et al., 2008, Nat. Clin. Pract. Neurol., 4, 490–503; Kidokoro et al., 2014, Am. J. Physiol. Ren. Physiol., 306, F1155–F1160; Wang et al., 2011, Cell. Physiol. Biochem., 28, 703–714), NKCC1׳s effects on oligodendrocyte precursor cells (OPCs) have not been characterized. The aim of this study was to investigate whether and to what extent inhibition of NKCC1 alters oxygen glucose deprivation (OGD)-induced cell cycle progression. In the present study, we demonstrated that inhibition of NKCC1 with bumetanide attenuates the decrease in OGD-induced DNA synthesis in cultured OPCs. Western blots showed that NKCC1 inhibition led to an increased expression of cyclin D1, CDK 4, and cyclin E in OGD-treated cells. Furthermore, our results showed bumetanide attenuated the decrease in OGD-induced proliferation and arrest of cell cycle progression via the P-38 MAPK signaling cascade. Thus, NKCC1 plays important roles in the proliferation of OPCs under OGD-induced stress.

Decreased Expression of Stem Cell Markers by Simvastatin in 7,12-dimethylbenz(a)anthracene (DMBA)–induced Breast Cancer

Simvastatin, a competitive inhibitor of HMG-CoA reductase widely used in the treatment and prevention of hyperlipidemia-related diseases, has recently been associated to in vitro anticancer stem cell (CSC) actions. However, these effects have not been confirmed in vivo. To assess in vivo anti-CSC effects of simvastatin, female Sprague-Dawley rats with 7,12-dimethyl-benz(a)anthracene (DMBA)-induced mammary cancer and control animals were treated for 14 days with either simvastatin (20 or 40 mg/kg/day) or soybean oil (N = 60). Tumors and normal breast tissues were removed for pathologic examination and immunodetection of CSC markers. At 40 mg/kg/day, simvastatin significantly reduced tumor growth and the expression of most CSC markers. The reduction in tumor growth (80%) could not be explained solely by the decrease in CSCs, since the latter accounted for less than 10% of the neoplasia (differentiated cancer cells were also affected). Stem cells in normal, nonneoplastic breast tissues were not affected by simvastatin. Simvastatin was also associated with a significant decrease in proliferative activity but no increase in cell death. In conclusion, this is the first study to confirm simvastatin anti-CSC actions in vivo, further demonstrating that this effect is specific for neoplastic cells, but not restricted to CSCs, and most likely due to inhibition of cell proliferation.

Efeitos in vitro da cafeína na cartilagem de crescimento de ratos

Objective To evaluate the in vitro effetcs of caffeine on proliferation, apoptosis a nd gene transcripts expression of chondrogenic differentiation in growth cartilage. Methods The cartilaginous epiphyses of femurs of newborn rats, which were divided into two subgroups: treated with caffeine and control group, both observed over the time periods of 0, 7, 14 and 21 days. The cartilaginous epiphyses of femurs of each subgroup and each time span were subjected to histomorphometric, immunohistochemical analysis, Tunel technique and RT-PCR in real time. Results The decrease in proliferative activity and the increase of apoptotic chondroblasts at 21 days were found regardless of the subgroup. However, the decrease in cell proliferation caused by caffeine was lower than in the control group and significantly increased the expression of gene transcripts for chondrogenic differentiation, represented by Sox-9 and Runx-2. However, the in vitro culture with caffeine revealed antagonistic effects: despite the positive effect on chondroblasts proliferation and differentiation, caffeine increased apoptosis, characterized by increased expression of caspase 3 and of the number of cells undergoing apoptosis (p<0.05). Conclusion Caffeine presents antagonistic effects in vitro on growth cartilage, increasing the proliferation, differentiation and cell apoptosis. Experimental Study.

Use of Epothilone B (Patupilone) in Refractory Lymphoma and Advanced Solid Tumors in Dogs

The epothilones are microtubule-stabilizing agents with promising antitumor effect in refractory and metastatic tumors in humans. The toxicity profile is considered more favorable than in taxanes. The safety of epothilone B (patupilone) has not been evaluated in tumor-bearing dogs. To evaluate the inhibition of proliferation in canine tumor cells after patupilone treatment. To assess toxicity profile and maximally tolerated dose of patupilone in dogs with refractory tumors. Twenty client-owned dogs with various malignancies. Prospective clinical study. The inhibition of proliferation was assessed with a proliferation assay in vitro in canine hemangiosarcoma and lymphoma cell lines. Dogs received patupilone IV once a week for 2 treatments (= 1 treatment cycle). Dose was escalated with 3 dogs per cohort and 20% increments. Adverse effects were graded according to the VCOG-CTCAE v1.0. Both canine cell lines were sensitive to patupilone with approximately 50% decrease in proliferative activity at 0.2-1 nM. In vivo, dose-limiting adverse effects occurred at 3.3 mg/m(2); main adverse effects were diarrhea, anorexia, vomiting, and nausea. Neither neutropenia nor peripheral neuropathy was observed. Maximally tolerated dose for 2 patupilone administrations once weekly IV is 2.76 mg/m(2). Three per 11 dogs receiving more than 1 treatment cycle showed partial remission in the short period of observation. Canine tumor cells show inhibition of proliferation to patupilone in vitro. Clinically, a dose of 2.76 mg/m(2) IV is well tolerated in dogs with spontaneously occurring tumors.

BRAF V600E Mutations in Multiple Myeloma: Clinical and Therapeutic Implications

AbstractAbstract 4040 Background:Activating mutations of the serine/threonine kinase BRAF are observed in various solid and hematologic malignancies with the point mutation V600E being the most common. However, both frequency and relevance of the mutation differ greatly between entities. This year, a small molecule inhibitor specifically targeting V600E-mutated BRAF has been approved for metastatic melanoma. Recently, BRAF mutations in multiple myeloma (MM) have been reported by several groups in the context of next generation sequencing projects. However, the clinical relevance of these mutations remains unclear. Objective:We report on frequency and clinical characteristics of MM patients harboring the BRAF V600E mutation. Furthermore, first clinical data on treatment with vemurafenib in MM with BRAF V600E mutation is presented. Methods:A V600E-mutation specific monoclonal antibody was recently developed at our institution. We screened 338 tissue samples by immunohistochemistry (315 bone marrow, 23 soft tissue plasmocytoma) from 310 patients with monoclonal gammopathy collected at out center between April 1999 and May 2011. Positive results were verified by direct sequencing. Of 310 analyzed patients, 205 had symptomatic MM, 12 symptomatic light chain amyloidosis, 45 smoldering MM and 48 MGUS. MM subtypes comprised 174 IgG, 60 IgA, 55 Bence Jones, 14 IgM, 4 IgD, 1 biclonal, 4 asecretory. From 25 patients serial bone marrow samples or tissue from different compartments were available. Median age at biopsy was 61.4 years (range 29–87) and 244 samples were obtained at from newly diagnosed patients. Results:Six patients (2%) were positive for BRAF V600E mutation both by immunohistochemistry and by confirmatory sequencing. A brief overview of patient characteristics is shown in Table 1. Five patients received bortezomib-based first line treatment whereas one received conventional chemotherapy. Four patients underwent autologous transplantation. Interestingly, PFS after start of first-line treatment was relatively short with a median PFS of 10.5 months. Remarkably, four of these six patients developed extramedullary myeloma in their disease course (soft tissues in 2, CNS in 1, both soft tissues and CNS in 1). In two of these patients a re-biopsy after two and three lines of therapy, respectively, was available. In both cases the mutation remained present in all cells without signs of clonal evolution in regard to BRAF V600E.One of the BRAF V600E positive patients had relapsed with multiple soft tissue plasmocytomas after autologous transplantation followed by multiple treatment lines containing bortezomib, lenalidomide and bendamustine. After informed consent we started the patient on vemurafenib 480mg BID and increased the dosage to 720mg BID after one week. Vemurafenib was well tolerated and no grade III/IV adverse events were noted. Already after the first cycle (four weeks), a partial response was achieved according to IMWG and RECIST criteria for serological and radiological assessment, respectively. As assessed by immunohistochemistry, a dramatic decrease in proliferative activity (MIB-1) accompanied by a sharp increase in apoptosis, as well as loss of MAP kinase signaling (p-ERK) could be observed in tumor samples under treatment with vemurafenib. Conclusions:Immunhistochemistry is a rapid and reliable method for the detection of BRAF V600E and provides a useful tool especially if applied to entities with low mutation frequency, such as MM. In our cohort, however small, patients harboring the mutation show a conspicuous course of disease with a comparably short PFS and an unusually high frequency of extramedullary myeloma. Individualized treatment with vemurafenib seems feasible and rapid response was observed. A detailed follow-up of the clinical course will be presented at the meeting.Table 1Characterization of the six MM patients harboring BRAF mutation V600EAge [years]SexMM isotypeSalmon & Durie stageExtramedullary myeloma64femaleIgG lambdaIIIAsoft tissues47femaleIgG kappaIIIBsoft tissues, CNS45maleBJ kappaIA-58femaleIgA kappaIIIAsoft tissues76maleBJ kappaIIIA-56femaleBK kappaIIIACNS Disclosures:Off Label Use: Vemurafenib is a BRAF inhibitor FDA approved for treatment of metastatic melanoma.

Abstract 4329: Modulation of metastatic behavior in breast cancers harboring p53 mutations

Abstract The mutation of p53 generally occurs during the later stages of cancer and leads to the increased metastatic potential of triple negative (ER_/PR_/Her2_) breast cancer. The low survival rates of advanced metastatic cancer make it critical not only to understand the mechanisms underlying the functional implications of p53 mutation, but also to identify ways to regulate its impact in cancer cell physiology. We have previously described the design, synthesis, and evaluation of a stabilized α-helix of p53 (SAH-p53) capable of inhibiting the p53-HDM2 and p53-HDMX interactions in order to restore the functionality of p53. Despite having low expression of both HDM2 and HDMX and mutations in p53, SAH-p53 treatment of the triple negative breast cancer cell lines MDA-MB-231 and HS578T results in a modest decrease in proliferative activity. While mutant p53 is known to promote metastatic behavior of breast cancer cells, the propensity of triple negative breast cancer cells to migrate and invade through Matrigel in the presence of EGF was decreased by treatment with SAH-p53. The anti-proliferative and anti-migratory effects of SAH-p53 treatment are independent of each other, yet both are accompanied by an alteration in cell morphology that includes the loss of cell membrane integrity and actin cytoskeletal organization. The surface level of β1 integrin, which is typically kept constant by mutant p53, is decreased in the presence of SAH-p53, pointing to possible alterations in integrin recycling. SAH-p53 also causes a change in the localization of the adhesion protein and stem cell marker CD44. Moreover, it has been suggested that mutant p53 enhances invasive properties by interacting with and inhibiting isoforms of p63, which have been implicated in the regulation of cell adhesion. Treatment of the triple negative breast cancer cells with a stabilized α-helix of p63 showed a significant decrease in cell viability as well as an enhanced inhibition of migration when treated simultaneously with SAH-p53. Targeted therapy for triple negative breast cancer is currently very limited and patients must rely on standard chemotherapeutic regimens. These data show that the use of SAH-p53 and SAH-p63 peptides provides a novel avenue to study the molecular interactions that drive metastatic behavior originated by p53 gain-of-function mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4329. doi:1538-7445.AM2012-4329

Age‐related changes of the regeneration mode in the mouse peripheral olfactory system following olfactotoxic drug methimazole‐induced damage

We investigated age-related changes in the mode of regeneration in the mouse peripheral olfactory system after olfactotoxic drug-induced damage. Mice at postnatal ages of 10 days, 3 months, and 16 months were given an intraperitoneal injection of methimazole to produce damage in the olfactory neuroepithelium. The olfactory neuroepithelia were harvested and analyzed immunohistochemically at various postlesion timepoints, from 1 day through to 94 days, to investigate neuroepithelial cell proliferation, the time course of neuronal differentiation, the reconstitution of neuroepithelium, and the innervation of the olfactory bulb. Functional recovery was assessed using the vanillin avoidance behavioral test. The chronological pattern in the expression of Ki67, beta III tubulin, and olfactory marker protein, molecular markers for neuronal cell proliferation and differentiation, changed similarly among the different age groups. In contrast, the extent of neuroepithelial cell proliferation after injury decreased with age, and the final histological recovery of the olfactory neuroepithelium and the innervation of the olfactory bulb were significantly smaller in the 16-month-old group compared to the younger age groups. These results suggest that the age-related decline in the capacity of olfactory neuroepithelium to reconstitute neuroepithelium is associated with its age-related decrease in proliferative activity after the neuroepithelial injury rather than changes in the process of neuronal differentiation. In spite of these incomplete anatomical recoveries, 16-month-old mice regained the ability to avoid vanillin solution by 1 month postlesion, suggesting that the extent of anatomical epithelial damage is not necessarily proportional to the threshold of olfactory perception.

Вплив реній-платинової системи у вигляді наноліпосом на проліферативну активність ракових клітин

Decrease of proliferative activity of the cells of Guerin’s carcinoma T8 in the different conditions of administration of the Rhenium-Platinum anti-tumour system as nanolyposomes is shown. The Rhenium-Platinum anti-tumour system influenced on the morphological indices of tumour tissue. The cluster rhenium compounds reduced the indices of pathological mitoses 3.0–3.6 times in comparison with a control group. The amount of PCNA-positive cells under the Rhenium-Platinum system treatment went down by 82.5–84.5 %. The anti-tumour system led to the predominance of apoptotic cell death over the necrotic one. The most effective agent was the compound with cis-adamantan organic ligand cis-Re2(C10H15COO)2Cl4·2DMSO introducted on the 9th day.

Age-Related Features of Expression of Cell Renewal Factors in the Intestinal Peyer’s Patches

Immunohistochemical study with markers of proapoptotic protein P53 and proliferation protein Ki-67 revealed an age-related decrease in proliferative activity of lymphocyte in the intestinal Peyer's patches and an increase in the ratio of apoptotic cells in humans. These changes aggravate atrophy and involution of the intestinal epithelium during aging.

Proliferation of normal and tumor cells in presence of serum of patients with breast carcinoma after phototherapy with visible and near infrared light

Simultaneous low-intensity visible (VIS) and near infrared (nIR) irradiation from laser and non-laser sources was used for treatment of complications developing in cancer patients after surgical tumor resection, chemo- and radiation therapy. However, the question remains about the impact of this physiotherapeutic method on proliferative activity of the patients' tumor cells and cells involved in wound healing, fibroblasts (FB) and keratinocytes (KC). In this paper, we studied the effect blood serum obtained from the patients with breast cancer after the course of irradiation with visible and NI light (480--3400 nm, 95 % polarization, 40 mW/cm2, 12 J/cm2) in postoperative period on the proliferative activity of primary cultures of human FB and KC, and of several human tumor cell lines (BT-474, HBL-100, Hs578T and A431). Seven-day course of phototherapy increase proliferation of FB (as compared to the initial level) and KC (as compared to postoperative level) by 22 and 28 %, respectively. The tumor cells BT-474, Hs578T and A431 showed statistically significant decrease in proliferative activity compared with the preoperative (initial) level by 31.5, 8.97 and 6.47%, respectively, whereas the cells BT-474, HBL-100, Hs578T and A431 also reduced their proliferative activity by 32,16, 8.65 and 6.26%, respectively, as compared with postperative level. The results obtained demonstrate the safety of the phototherapy with the visible and NI light for BC patients in the postoperative period.

Autophagy upregulation and loss of NF-κB in oxidative stress-related immunodeficient SAMP8 mice

Aged spleens from senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice 1 (SAMR1) were examined to determine whether sex or melatonin had an effect on oxidative stress-related immune impairments. We observed that the immunosenescence of SAMP8 mice was associated with a redox imbalance, leading to an age-related increase in oxidative damage, resulting from a decrease in antioxidant defense and protease activity. Moreover, increased apoptotic cell death, a decrease in proliferative activity and the loss of NF-κB activation were also related to the immunodeficiency seen in SAMP8 compared to SAMR1 mice. Females demonstrated higher oxidative stress-related alterations in the immune response, and subsequent, melatonin treatment provided the best protective effects. Pathways involved in autophagy were upregulated in SAMP8 as an adaptive response to oxidative stress, in an attempt to rescue the cell from increased apoptosis and age-related immunodeficiency. However, the NF-κB signaling and autophagic processes were unaffected by treatment with melatonin. Therefore, we propose a key role for NF-κB signaling and autophagy in the oxidative stress-related immunosenescent spleens of SAMP8 mice.

Two states of active spermatogenesis switch between reproductive and non‐reproductive seasons in the testes of the medaka, Oryzias latipes

Seasonal change in spermatogenesis was examined in the restricted spermatogonium-type testes of a teleost, Oryzias latipes. Histological observation revealed that the number of each stage of germ cells during most of the non-reproductive season, from October to January (O-J period) was nearly half of that during the reproductive season, from May to July (M-J period), except for type B spermatogonia (B-gonia), which was actually equal. As a result, the ratio of primary spermatocytes (P-cytes) to B-gonia was remarkably small in the O-J period. Despite the differences between both time periods, the proliferative activity of type A spermatogonia (A-gonia), B-gonia, or P-cytes was at a similar level in both periods. Moreover, in cultured testes treated with bromodeoxyuridine as a cell-lineage tracer, P-cytes differentiated to spermatids in 11-15 days in both M-J and O-J periods. These indicate that spermatogenesis is active in each period at a different state. In the spermatogenic testis, A-gonial proliferation was maintained by human follicle stimulating hormone/luteinizing hormone in culture. Whereas cell death of B-gonia and/or P-cytes gradually increased in the M-J period in spite of those cells being constant in population sizes. In transition to the O-J period, A-gonia and P-cytes first decreased, which was accompanied by a decrease in proliferative activity of A-gonia and relative increase of dead cells from B-gonia and/or P-cytes against live P-cytes. These suggest that A-gonial proliferation and cell death of B-gonia and/or P-cytes that is induced coordinately with B-gonial differentiation are critical for the spermatogenic control.

Gastroprotective Effect of Dalargin in Gastropathy due to Treatment with Nonsteroid Antiinflammatory Drugs

We studied the effect of dalargin and its analogue [Dala]2-leu-enkephalin on the gastric mucosa in indomethacin-receiving animals. Indomethacin treatment was followed by severe injury to the gastric mucosa, decrease in proliferative activity of the epithelium, and stimulation of free-radical processes in gastric tissues. Dalargin significantly decreased the area of erosive and ulcerative lesions, had a normalizing effect on proliferation of epithelial cells, and reduced the degree of oxidative stress. Administration of [Dala]2-leu-enkephalin did not improve the state of the gastric mucosa.

Dopaminergic regulation of granulocytopoiesis during cytostatic-induced myelosuppressions

The role of the dopaminergic system in the regulation of the granulocytic hemopoietic stem was studied after administration of cyclophosphamide and 5-fluorouracil. Dopamine in the central nervous system promotes the development of cytostatic-induced myelosuppressions. The inhibitory effect of dopaminergic structures on granulocytopoiesis after administration the fluoropyrimidine antimetabolite was of shorter duration compared to that observed in experiments with the alkylating agent. The inhibitory effect of brain dopamine is associated with a decrease in proliferative activity and differentiation of granulomonocytic precursors, prevention of hemopoietic islet formation, and impairment of secretion of colony-stimulating activity in adherent cells of the hemopoiesis-inducing microenvironment. Cyclophosphamide and 5-fluorouracil had different effects on the rate of hemopoietic tissue regeneration, which was related to specific interaction between distant regulatory structures and hemopoiesis-inducing microenvironment and differences in the influence of cytostatics on hemopoietic and stromal cells.

Lactate adversely affects the in vitro formation of endothelial cell tubular structures through the action of TGF-β1

When lactate accumulation in a tumor microenvironment reaches an average concentration of 10–20 mM, it tends to reflect a high degree of malignancy. However, the hypothesis that tumor-derived lactate has a number of partially adverse biological effects on malignant and tumor-associated host cells requires further evidence. The present study attempted to evaluate the impact of lactate on the process of angiogenesis, in particular on the formation of tubular structures. The endothelial cell (EC) network in desmoplastic breast tumors is primarily located in areas of reactive fibroblastic stroma. We employed a fibroblast–endothelial cell co-culture model as in vitro angiogenesis system normally producing florid in vitro tubule formation to analyze this situation. In contrast to previous studies, we found that lactate significantly reduces EC network formation in a dose-dependent manner as quantified by semi-automated morphometric analyses following immunohistochemical staining. The decrease in CD31-positive tubular structures and the number of intersections was independent of VEGF supplementation and became more pronounced in the presence of protons. The number of cells, primarily of the fibroblast population, was reduced but cell loss could not be attributed to a decrease in proliferative activity or pronounced apoptotic cell death. Treatment with 10 mM lactate was accompanied by enhanced mRNA expression and release of TGF-β1, which also shows anti-angiogenic activity in the model. Both TGF-β1 and lactate induced myofibroblastic differentiation adjacent to the EC tubular structures. The lactate response on the EC network was diminished by TGF-β1 neutralization, indicating a causal relationship between lactate and TGF-β1 in the finely tuned processes of vessel formation and maturation which may also occur in vivo within tumor tissue.