Evaluating the effects of hypoxic storage on platelet function and health using a novel storage system.

BACKGROUND: Thousands of units of whole blood (WB) and blood components are transfused daily to treat trauma patients. Improved methods for blood storage are critical to support trauma-related care. The Hemanext ONE® system offers a unique method for hypoxic storage of WB, with successfully demonstrated storage of clinically viable RBCs. This work evaluated the system for the storage of WB, focusing on platelet health and function. STUDY DESIGN AND METHODS: WB was collected from healthy donors and processed through the Hemanext ONE® system. Hemoglobin oxygen saturation (HbSO2) levels of WB were depleted to 10%, 20%, or 30% of total HbSO2 and then stored in PVC bags sealed in oxygen-impermeable bags (except for normoxic control) with samples collected on days 1, 7, and 14 post-processing. Flow cytometry assessed the activation and apoptosis of platelets. Clot dynamics were assessed based on aggregometry and thromboelastography assays, as well as thrombin generation using a calibrated-automated thrombogram method. RESULTS: Hypoxic storage conditions were maintained throughout the storage period. Hypoxia triggered increased lactate production, but pH changes were negligible compared to normoxic control. Storage at 10% HbSO2 had a significant impact on platelet function, resulting in increased activation and reduced clot formation and aggregation. These effects were less significant at 20% and 30% HbSO2. DISCUSSION: This study indicates that platelets are sensitive to hypoxic storage and suffer significant metabolic and functional deterioration when stored at or below 10% HbSO2.

Still-face effect in domestic dogs: comparing untrained with trained and animal assisted interventions dogs.

The still-face effect has been extensively studied in human infants and comprises the reduction in affiliative behaviors and increased stress that occurs after a sudden interruption of social interaction with a caregiver. Domestic dogs (Canis familiaris) are model candidates for showing this effect, as they form deep bonds with their owners and interspecific social interaction is reinforcing to them. The aim of these studies was to assess if companion dogs exhibit the still-face effect and whether prior experiences during ontogeny modulate this effect. To this end, Study 1 compared dogs with different levels of training (untrained, intermediate, and advanced), while Study 2 assessed dogs that participated in Animal Assisted Interventions (AAIs) and companion dogs (CDs). The procedure was carried out virtually and comprised three phases lasting 1 min: interaction, still-face (the owner turned suddenly indifferent), and reunion (the interaction was resumed). Dogs exhibited a decrease in proximity to and contact with the owner, as well as an increase in begging and stress behaviors during the still-face phase. Moreover, this was not observed in a control condition in which the interaction continued in the same way during all three phases, discarding alternative explanations for these changes. These results show that dogs experience a still-face effect in a similar way to infants, highlighting the value interspecific social interaction has for dogs. Nevertheless, the absence of differences according to their training level or participation in AAIs suggests this is a robust phenomenon, which appears to be less susceptible to the influences of ontogenetic experiences.

[Dental care during SARS-CoV-2 pandemic]. / SARS-CoV-2 en atención odontológica: vías de transmisión y sus consideraciones en la práctica clínica.

We analyze the transmission routes, possible viral reservoirs in the oral cavity and considerations about dental care of SARS-CoV-2 virus infection. We also analyze the protocols required before and after a dental procedure, aiming to increase the awareness of dentists about the importance of virus spread prevention among health care workers and patients. The evaluation of symptoms associated with SARS- CoV-2 such as fever, fatigue, dry cough, myalgia, dyspnea, and the inquiry about possible contacts with infected people is of utmost importance. The tongue and oral mucosa are important viral reservoirs and the transmission of the virus occurs primarily by saliva droplets. Therefore, elective dental care should be postponed, attending only dental emergencies during this period, incorporating the use of protective personal equipment (PPE) and using manual instruments to prevent the production of aerosols.

Low-dose curcuminoid-loaded in dextran nanobubbles can prevent metastatic spreading in prostate cancer cells.

Preventing recurrences and metastasis of prostate cancer after prostatectomy by administering adjuvant therapies is quite a controversial issue. In addition to effectiveness, absence of side effects and long term toxicity are mandatory. Curcuminoids (Curc) extracted with innovative techniques and effectively loaded by polymeric nanobubbles (Curc-NBs) satisfy such requirements. Curc-NBs showed stable over 30 d, were effectively internalized by tumor cells and were able to slowly release Curc in a sustained way. Significant biological effects were detected in PC-3 and DU-145 cell lines where Curc-NBs were able to inhibit adhesion and migration, to promote cell apoptosis and to affect cell viability and colony-forming capacity in a dose-dependent manner. Since the favourable effects are already detectable at very low doses, which can be reached at a clinical level, the actual drug concentration can be visualized and monitored by US or MRI, Curc-NBs can be proposed as an effective adjuvant theranostic tool.

Is previous experience important for inhibitory control? A comparison between shelter and pet dogs in A-not-B and cylinder tasks.

This study compares the performance of two groups of dogs with different levels of social interaction with humans, shelter and pet dogs, in two inhibitory control tasks. (1) In the A-not-B task, dogs were required to resist searching for food in a previously rewarded location, and (2) in the cylinder task, dogs were required to resist approaching visible food directly in favor of a detour reaching response. Our first aim was to evaluate the importance of learning and ontogeny in performing inhibitory tasks. Also, we assessed whether there is a correlation between the two tasks by comparing performance in the same subjects. Results showed significant differences between shelter and pet dogs in the A-not-B task, with poorer performance in shelter dogs. However, no differences were found in the cylinder task. The poorer performance of shelter dogs might be related to their infrequent interaction with humans, which reduces the chances to learn to inhibit certain behaviors. This result would highlight the importance of ontogeny in developing that ability. On the other hand, no correlations were found between the two tasks, which contributes information to the debate about the context specificity of inhibitory control in dogs.

Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins.

Trefoil factors are effector molecules in gastrointestinal tract physiology. Each one improves healing of the gastrointestinal tract. Trefoil factors may be grouped into three classes: the gastric peptides (TFF1), spasmolytic peptide (TFF2) and intestinal trefoil factor (TFF3). Significant amounts of TFF3 are present in human breast milk. Previously, we have reported that trefoil factor 3 isolated from human breast milk produces down regulation of cytokines and promotes human beta defensins expression in intestinal epithelial cells. This study aimed to determine the molecular mechanism involved. Here we showed that the presence of TFF3 strongly correlated with protease activated receptors 2 (PAR-2) activation in human intestinal cells. Intracellular calcium ((Ca2+)i)mobilization was induced by the treatment with: 1) TFF3, 2) synthetic PAR-2 agonist peptide. The co-treatment with a synthetic PAR-2 antagonist peptide and TFF3 eliminates the latter's effect. Additionally, we demonstrated the existence of interactions among TFF3 and PAR-2 receptors through far Western blot and co-precipitation. Finally, down regulation of PAR-2 by siRNA resulted in a decrease of TFF3 induced intracellular (Ca2+)i mobilization, cytokine regulation and defensins expression. These findings suggest that TFF3 activates intestinal cells through PAR-2 (Fig. 4, Ref. 19).

Effect of weight maintenance or gain in a 10 years period over telomere length, sirtuin 1 and 6 expression and carotid intima media thickness.

BACKGROUND: Lack of weight gain throughout adult life could mimic the beneficial effects of energy restriction in humans. The present study aimed to assess the effects of weight stability or gain, over a period of 10 years, on telomere length, sirtuin 1 and 6 expression, and carotid intima media thickness. METHODS: We studied 148 healthy adults (age range 20-59 years; 101 females) who had an objective record of their weight 10 years before. They were classified as weight losers, weight maintainers, weight gainers and extreme weight gainers. A fasting blood sample was obtained for routine laboratory and isolation of peripheral blood mononuclear cells, to extract DNA and RNA, and to measure telomere length and sirtuin 1 and 6 expression, respectively. Carotid intima media thickness was measured by ultrasound. Body composition was measured by Dual-energy X-ray absorptiometry. RESULTS: In the 10-year period, 24 participants lost weight (17 females), 65 maintained weight (41 females), 25 gained weight (15 females) and 34 were extreme weight gainers (28 females). Female weight gainers had a higher body mass index, waist circumference, total body fat and homeostatic model assessment insulin resistance. Male weight gainers had a higher hip circumference and total body fat. No differences in telomere length, sirtuin 1 expression and carotid intima media thickness were observed between weight gainers and maintainers. CONCLUSIONS: No effect of weight maintenance or gain was observed on metabolic and vascular markers of ageing.

High fever following postpartum administration of sublingual misoprostol.

OBJECTIVE: To explore what triggers an elevated body temperature of > or =40.0 degrees C in some women given misoprostol, a prostaglandin E1 analogue, for postpartum haemorrhage (PPH). DESIGN: Post hoc analysis. SETTING: One tertiary-level hospital in Quito, Ecuador. POPULATION: A cohort of 58 women with a fever of above 40 degrees C following treatment with sublingual misoprostol (800 micrograms) for PPH. METHODS: Side effects were documented for 163 Ecuadorian women given sublingual misoprostol to treat their PPH. Women's body temperatures were measured, and if they had a fever of > or =40.0 degrees C, measurements were taken hourly until the fever subsided. Temperature trends were analysed, and the possible physiological mechanisms by which postpartum misoprostol produces a high fever were explored. MAIN OUTCOME MEASURES: The onset, duration, peak temperatures, and treatments administered for cases with a high fever. RESULTS: Fifty-eight of 163 women (35.6%) treated with misoprostol experienced a fever of > or =40.0 degrees C. High fevers followed a predictable pattern, often preceded by moderate/severe shivering within 20 minutes of treatment. Body temperatures peaked 1-2 hours post-treatment, and gradually declined over 3 hours. Fevers were transient and did not lead to any hospitalisation. Baseline characteristics were comparable among women who did and did not develop a high fever, except for known previous PPH and time to placental expulsion. CONCLUSIONS: An unexpectedly high rate of elevated body temperature of > or =40.0 degrees C was documented in Ecuador following sublingually administered misoprostol. It is unclear why temperatures > or =40.0 degrees C occurred with a greater frequency in Ecuador than in other study populations using similar treatment regimens for PPH. Pharmacogenetic studies may shed further light on variations in individuals' responses to misoprostol.

Oxytocin effects on gazing at the human face in retriever dogs.

Oxytocin is a neurohormone involved in domestic dogs' socio-cognitive abilities which appears to be key in the display of gazing behavior as a communicative signal. However, differential effects of oxytocin have been reported in various tasks according to the dogs' breed. In the present study, we evaluated the effect of the intranasal administration of oxytocin on gazing towards the human face in Golden and Labrador Retrievers. This was assessed during a learning task in which dogs had to gaze at the human face in order to receive food that was visible but inaccessible. Results indicate that only intact dogs who received oxytocin exhibited an increase in gazing behavior, while no differences were observed for neutered dogs. This effect could be related to an interaction between oxytocin and steroid hormones in intact dogs. These findings highlight the importance of including modulating factors, such as breed and neutered status, when studying the mechanisms of oxytocin.

The Mexican consensus on non-cardiac chest pain. / Consenso mexicano sobre dolor torácico no cardiaco.

INTRODUCTION: Non-cardiac chest pain is defined as a clinical syndrome characterized by retrosternal pain similar to that of angina pectoris, but of non-cardiac origin and produced by esophageal, musculoskeletal, pulmonary, or psychiatric diseases. AIM: To present a consensus review based on evidence regarding the definition, epidemiology, pathophysiology, and diagnosis of non-cardiac chest pain, as well as the therapeutic options for those patients. METHODS: Three general coordinators carried out a literature review of all articles published in English and Spanish on the theme and formulated 38 initial statements, dividing them into 3 main categories: (i)definitions, epidemiology, and pathophysiology; (ii)diagnosis, and (iii)treatment. The statements underwent 3rounds of voting, utilizing the Delphi system. The final statements were those that reached >75% agreement, and they were rated utilizing the GRADE system. RESULTS AND CONCLUSIONS: The final consensus included 29 statements. All patients presenting with chest pain should initially be evaluated by a cardiologist. The most common cause of non-cardiac chest pain is gastroesophageal reflux disease. If there are no alarm symptoms, the initial approach should be a therapeutic trial with a proton pump inhibitor for 2-4weeks. If dysphagia or alarm symptoms are present, endoscopy is recommended. High-resolution manometry is the best method for ruling out spastic motor disorders and achalasia and pH monitoring aids in demonstrating abnormal esophageal acid exposure. Treatment should be directed at the pathophysiologic mechanism. It can include proton pump inhibitors, neuromodulators and/or smooth muscle relaxants, psychologic intervention and/or cognitive therapy, and occasionally surgery or endoscopic therapy.

Magnetization switching in high-density magnetic nanodots by a fine-tune sputtering process on a large-area diblock copolymer mask.

Ordered magnetic nanodot arrays with extremely high density provide unique properties to the growing field of nanotechnology. To overcome the size limitations of conventional lithography, a fine-tuned sputtering deposition process on mesoporous polymeric template fabricated by diblock copolymer self-assembly is herein proposed to fabricate uniform and densely spaced nanometer-scale magnetic dot arrays. This process was successfully exploited to pattern, over a large area, sputtered Ni80Fe20 and Co thin films with thicknesses of 10 and 13 nm, respectively. Carefully tuned sputter-etching at a suitable glancing angle was performed to selectively remove the magnetic material deposited on top of the polymeric template, producing nanodot arrays (dot diameter about 17 nm). A detailed study of magnetization reversal at room temperature as a function of sputter-etching time, together with morphology investigations, was performed to confirm the synthesis of long-range ordered arrays displaying functional magnetic properties. Magnetic hysteresis loops of the obtained nanodot arrays were measured at different temperatures and interpreted via micromagnetic simulations to explore the role of dipole-dipole magnetostatic interactions between dots and the effect of magnetocrystalline anisotropy. The agreement between measurements and numerical modelling results indicates the use of the proposed synthesis technique as an innovative process in the design of large-area nanoscale arrays of functional magnetic elements.

Calmodulin antagonism and growth-inhibiting activity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells.

The triphenylethylene antiestrogen tamoxifen has been shown previously to inhibit both calmodulin and protein kinase C activities, which are involved in the control of cell proliferation. We have studied the effect of several derivatives of the triphenylethylene antiestrogen family on the inhibition of both calmodulin-dependent cyclic adenosine 3':5'-monophosphate-phosphodiesterase activity and proliferation of breast cancer cells cultured with 0.5 microM estradiol in order to prevent interaction of these drugs with the estrogen receptor. We have observed that hydroxylation of the triphenylethylene molecule significantly decreases its ability to inhibit the calmodulin-dependent phosphodiesterase activity in vitro. Furthermore, the growth-inhibiting activity of several antiestrogens and other calmodulin antagonists [R24571, trifluoperazine, N-(6-aminohexyl)-5-chloronaphthalene-1-sulfonamide, and N-(6-aminohexyl)-1-naphthalenesulfonamide] correlated with their antagonistic effects on calmodulin activity. The level of activity was determined as follows: R24571 greater than tamoxifen = N-demethyltamoxifen = nafoxidine greater than 4-hydroxytamoxifen greater than 3,4-dihydroxytamoxifen = trifluoperazine greater than N-(6-aminohexyl)-5-chloronaphthalene-1-sulfononamide greater than metabolite A greater than N-(6-aminohexyl)-1-naphthalenesulfonamide. On the other hand both protein kinase C-activating and -inhibiting drugs (phorboltetradecanoate-13-acetate and tamoxifen, respectively) have a synergistic inhibitory effect on the growth of MCF-7 cells. Our data suggest that antiestrogen interactions with calmodulin and not protein kinase C may play a role in mediating the drug-induced estrogen-independent inhibition of breast cancer cell growth.

4-Hydroxynonenal, a product of cellular lipid peroxidation, which modulates c-myc and globin gene expression in K562 erythroleukemic cells.

Several studies point to the existence of an inverse correlation between cellular lipid peroxidation and both cell proliferation and neoplastic transformation. Here, we show that 4-hydroxynonenal (HNE) concentrations close to the level found in normal cells (in the range of 1 and 3 microM) can specifically induce changes in the expression of c-myc and gamma-globin mRNA in K562 cells, without inducing any toxic effects or affecting cell viability. Since we have determined that K562 cells have undetectable levels of endogenous lipid peroxidation, all these effects can be assigned to the exogenous HNE treatment. After a 1-h treatment with 1 microM HNE, c-myc mRNA levels decrease transiently during the first 4 h, rebounding later to higher levels, and normalizing to basal expression after 4 days. Run-on experiments show a transient transcriptional block 20 min after HNE treatment and subsequent posttranscriptional regulation. According to S1 mapping, mRNA changes are exerted on c-myc transcripts initiated from both the principal constitutive start sites (P1 and P2). gamma-Globin mRNA levels concomitantly increase 3- to 4-fold, but no significant changes of housekeeping gene expression are observed. On the basis of these results it appears that the restoration in human erythroleukemic K562 cells of HNE concentrations closer to the level in normal cells can modulate the expression of specific genes.

Tolerance to delayed reward tasks in social and non-social contexts.

Domestic dogs have demonstrated striking social skills towards humans, however, there are few studies investigating impulsivity with delay-choice tasks in communicative contexts. In Study 1 we introduced a novel social delay-choice task in which subjects had to choose between one human cueing an immediate, low quality reward and another human signaling a delayed, high quality reward. In Study 2 we evaluated the tolerance to increasing delays using social and non-social cues. We also explored if more self-controlled dogs show any distinct behaviours during delays. Finally, we correlated all results with the Dog Impulsivity Assessment Scale (Wright et al., 2011). In Study 1 dogs reached an average maximum delay of 11.55s. In Study 2 that average was 52.14s with social cues and 40.2s with non-social, but differences were not significant. Tolerance to delays showed high interindividual variation. Dogs remained mostly standing and near the delayed experimenter in the social tasks although we could not to find any distinct coping strategies. No significant correlations were found between the delay reached and behaviours, neither with the scale. These results show the relevance of the parameters and methods used to investigate tolerance to delay of reinforcements. More investigations are required, especially an assessment of the same subjects performing the same tasks using different contexts.

Premature loss of muscle mass and function in type 2 diabetes.

INTRODUCTION: Muscle mass and function are among the most relevant factors that contribute to an optimal quality of life, and are strong predictors of mortality in the elderly. Loss of lean tissues and deterioration of muscle function have been described as one of the many complications of type 2 diabetes mellitus (DM2), but most studies do not isolate age as an intervening factor. AIM: To study whether adult DM2 patients up to 60years of age have decreased muscle mass and function compared with healthy non-diabetic (ND) subjects of similar age. METHODOLOGY: Appendicular fat-free mass (ApFFM) by dual X-ray absorptiometry (DEXA), handgrip strength (HS), quadriceps strength (QS), 12 min walking capacity (12MW) and the Timed Up and Go test (TUG) were measured in 100 DM2 patients and 39 ND controls. Muscle quality, or the ratio between lean mass and muscle strength of upper and lower limbs, and the functional limitations associated with pain and stiffness assessed according to the Western Ontario and McMaster Universities Arthrosis Index (WOMAC) were also recorded. Specific tests were performed to rule out microvascular diabetic complications (retinal and peripheral nerves), metabolic control, kidney function and vitamin D status and examine their association with ApFFM and function. RESULTS: ApFFM was significantly higher among DM2 female patients and lower among diabetic men. However opposite results were obtained when individual values were corrected for body mass index (BMI), specifically among women, who were more likely to be obese. As for muscle strength and global functionality tests, significantly better performances in TUG, 12MW, QS and HS were observed among ND subjects of both sexes. These differences prevailed even after excluding diabetic patients with microvascular complications as well as those with more than 10years of diabetes. Muscle quality was also significantly better among ND women. Higher scores of pain and stiffness in the WOMAC scale correlated with 12MW and TUG in both groups but did not correlate with ApFFM. CONCLUSIONS: We found a clear deterioration of lean mass and muscle functions among adult DM2 patients of up to 60years old, independent of length of disease, metabolic control, vitamin D status and presence of microvascular complications and pain.

YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

Skeletal muscle ceramide species in men with abdominal obesity.

BACKGROUND: Obesity is a risk factor for diabetes and its consequences, including accelerated ageing and mortality. The underlying factor could be accumulation of certain lipid moieties, such as ceramides (CER) and diacylgycerol (DAG) within muscle tissue, which are known to promote insulin resistance (IR), induce inflammation and oxidative injury, ultimately altering muscle function. AIM: First, to study the relationship between body composition and age (independent variables) with skeletal muscle accumulation of lipid species, oxidative injury and strength. Second, to analyze the relationship between muscle tissue metabolites and insulin resistance, inflammation and lymphocyte telomere length, the latter as an indicator of ageing. METHODOLOGY: The sample included 56 healthy sedentary males, scheduled for inguinal hernia surgery, aged 27 to 80 y. Each individual was subject to anthropometric measurements, body composition assessment through radiologic densitometry (DEXA), measurement of handgrip and quadriceps strength, serum biochemical parameters (lipoproteins, creatinine, high sensitivity C reactive protein [hsCRP], fasting and post glucose insulin and glucose concentrations for calculation of IR through the Matsuda and HOMA-IR indexes), and extraction of peripheral leukocytes for measurement of telomere length. During the surgical procedure, a sample of muscle tissue was obtained (anterior abdominal oblique) in order to measure CER and DAG (and sub species according to chain length and saturation) by mass spectrometry, 4 hydroxy-2-nonenal adducts (4-HNE) using electron microscopy immunohistochemistry, and carboxymethyl-lisine (CML) by immunohistochemistry, the latter as indicators of oxidative stress (OS). RESULTS: Body mass index (BMI) of twenty six individuals was > 25 k/m2, while BMI of 7 was > 30 k/m2. Overweight/obese individuals, did not exhibit differences in skeletal muscle lipid metabolites, however total CER and specific long chain CER sub-species (20 and 22 carbon) increased significantly among individuals with a central fat distribution (n = 14) as well as in glucose intolerant subjects (n =23). A negative association was found between mononuclear leukocyte telomere length and 20 and 22 carbon CER (rho = - 0.4 and -0.5 0 p < 0.05). Muscle strength was not associated with any of the measured muscle metabolites or markers of OS. A multiple regression analysis accepted central abdominal fat and telomere length as significant predictors of CER (R2 = 0.28). CONCLUSIONS: An association was found between accumulation of specific ceramide species in muscle tissue and abdominal obesity, glucose intolerance and shortening of leukocyte telomeres, although not with muscle oxidative injury or dysfunction.

SARS-CoV-2 en atención odontológica: vías de transmisión y sus consideraciones en la práctica clínica

We analyze the transmission routes, possible viral reservoirs in the oral cavity and considerations about dental care of SARS-CoV-2 virus infection. We also analyze the protocols required before and after a dental procedure, aiming to increase the awareness of dentists about the importance of virus spread prevention among health care workers and patients. The evaluation of symptoms associated with SARS- CoV-2 such as fever, fatigue, dry cough, myalgia, dyspnea, and the inquiry about possible contacts with infected people is of utmost importance. The tongue and oral mucosa are important viral reservoirs and the transmission of the virus occurs primarily by saliva droplets. Therefore, elective dental care should be postponed, attending only dental emergencies during this period, incorporating the use of protective personal equipment (PPE) and using manual instruments to prevent the production of aerosols.

Control of neoplastic cell proliferation and differentiation by restoration of 4-hydroxynonenal physiological concentrations.

Several studies point to the existence of an inverse correlation between cellular lipid peroxidation and both cell proliferation and neoplastic transformation. In anaplastic cell lines products of membrane lipid peroxidation are very low or undetectable. Furthermore numerous results demonstrate effect of lipid peroxidation products on central biochemical pathways and intracellular signalling at physiological concentrations. 4-hydroxynonenal (HNE) is one of the most active products of lipid peroxidation. The restoration of HNE physiological concentrations in neoplastic cells may inhibit cell proliferation and modulate cell re-differentiation. This review try to summarize and critically discuss the effects of physiological concentrations of HNE on normal and neoplastic cell line.

Inhibition of D1, D2, and A-cyclin expression in HL-60 cells by the lipid peroxydation product 4-hydroxynonenal.

4-Hydroxynonenal (HNE), a product of lipid peroxidation, is an highly reactive aldehyde that, at concentration similar to those found in normal cells, blocks proliferation and induces a granulocytic-like differentiation in HL-60 cells. These effects are accompained by a marked increase in the proportion G0/G1 cells. The mechanisms of HNE action were investigated by analyzing the expression of the cyclins and cyclin-dependent protein kinases (CDKs), controlling the cell cycle progression. Data obtained by exposing cells to dimethyl sulfoxide (DMSO) were used for comparison. 4-Hydroxynonenal downregulated both mRNA and protein contents of cyclins D1, D2, and A until 24 h from the treatments, whereas DMSO inhibited cyclin D1 and D2 expression until the end of experiment (2 days) and induces an increase of cyclin A until 1 day. Cyclins B and E, and protein kinase CDK2 and CDK4 expressions were not affected by HNE, whereas DMSO induced an increase of cyclin E, B, and CDK2 from 8 h to 1 day. These data are in agreement with previous results indicating a different time-course of accumulation in G0/G1 phases of cells treated with HNE and DMSO and suggest that the HNE inhibitory effect on proliferation and cell cycle progression may depend by the downregulation of D1, D2, and A cyclin expression.