Functional properties of edible insects: a systematic review.

Consumption of edible insects has been widely suggested as an environmentally sustainable substitute for meat to reduce greenhouse gas emissions. However, the novel research field for edible insects relies on the content of bioactive ingredients and on the ability to induce a functional effect in humans. The goal of this manuscript is to review the available body of evidence on the properties of edible insects in modulating oxidative and inflammatory stress, platelet aggregation, lipid and glucose metabolism and weight control. A search for literature investigating the functional role of edible insects was carried out in the PubMed database using specific keywords. A total of 55 studies, meeting inclusion criteria after screening, were divided on the basis of the experimental approach: in vitro studies, cellular models/ex vivo studies or in vivo studies. In the majority of the studies, insects demonstrated the ability to reduce oxidative stress, modulate antioxidant status, restore the impaired activity of antioxidant enzymes and reduce markers of oxidative damage. Edible insects displayed anti-inflammatory activity reducing cytokines and modulating specific transcription factors. Results from animal studies suggest that edible insects can modulate lipid and glucose metabolism. The limited number of studies focused on the assessment of anti-coagulation activity of edible insects makes it difficult to draw conclusions. More evidence from dietary intervention studies in humans is needed to support the promising evidence from in vitro and animal models about the functional role of edible insect consumption.

Endoparasites of the European Hare (Lepus Europaeus) (Pallas, 1778) in Central Italy.

Brown hare (Lepus europaeus) populations in Europe have declined through decades due to several, but not clear yet, factors. Parasite infections and diseases are some of the causes that directly affected the survival and breeding rates of animal population. A study on the endoparasites of 70 hares (37 hunted free-living hares, and 33 bred on farms hares) was performed between 2015 - 2017 in the province of Grosseto (central Italy), an area where the impact of parasites in the hare population has never been investigated. During necroscopic analysis of hunted hares the following helminthes were found: Trichostrongylus retortaeformis (87.1 %), Passalurus ambiguus (12.9 %) and Andrya spp. (6.4 %) in the intestinal tract, Protostrongylus cuniculorum (8.3 %) in lungs and Dicrocoelium dendriticum (16.7 %) in livers. The prevalences of the intestinal helminthes in bred hares were: 12.1 % for Passalurus ambiguus and 3 % for Trichostrongylus retortaeformis. The coprological analysis showed prevalences of 64.9 % for coccidia in the 37 hunted hares and 45.5 % in the 33 bred hares. The relationship between the intensities of parasitic infections and body weight was evaluated. The results of the present study in the Grosseto area indicate that free-living hares have few species of parasites and that the intensities of parasitic infection did not affect their general condition and health, suggesting that endoparasites played no detectable role in the dynamics of this hare population.

Chemical research on red pigments after adverse reactions to tattoo.

Currently, the incidence of tattooing is on the rise compared to the past, especially among adolescents, and it leads to the urgency of monitoring the security status of tattooing centers, as well as to inform people about the risks of tattoo practice. In our clinical experience, 20% of tattooed patients presented adverse reactions, like allergic contact dermatitis, psoriasis with Koebner's phenomena and granulomatous reactions, with the latter most prevalent and most often related to red pigment. Adverse reactions to tattoo pigments, especially the red one, are well known and described in literature. Great attention has to be focused on the pigments used, especially for the presence of new substances, often not well known. For this reason, we decided to perform a study on 12 samples of red tattoo ink, obtained by patients affected by different cutaneous reactions in the site of tattoo, to analyze their chemical composition.

Dietary non-enzymatic antioxidant capacity and the risk of myocardial infarction: a case-control study in Italy.

BACKGROUND AND AIMS: Oxidative processes have been related to atherosclerosis, but there is scanty information on the role of dietary antioxidants in the prevention of acute myocardial infarction (AMI). METHODS AND RESULTS: The relationship between non-enzymatic antioxidant capacity (NEAC) and the risk of nonfatal AMI was investigated in a case-control study conducted in Milan, Italy, between 1995 and 2003. Cases were 760 patients below 75 years with a first episode of AMI and controls were 682 patients admitted to hospitals for acute conditions, who completed an interviewer-administered food frequency questionnaire, tested for validity and reproducibility. NEAC (excluding coffee) was measured using Italian food composition tables in terms of ferric reducing-antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) and total radical-trapping antioxidant parameter (TRAP). The odds ratios (OR) of AMI, and the corresponding 95% confidence intervals (CI), were obtained by multiple logistic regression models including terms for main risk factors of AMI and total energy intake. NEAC was inversely related with the risk of AMI. The ORs for the highest quintile compared with the lowest one were 0.41 (95% CI, 0.27-0.63) for FRAP, 0.42 (95% CI, 0.27-0.65) for TEAC and 0.41 (95% CI, 0.27-0.62) for TRAP, with significant trends in risk. The inverse relationship was apparently stronger in women and in subjects aged ≥ 60 years. CONCLUSIONS: Our results support a favorable role of dietary NEAC in the prevention of AMI, and encourage a high consumption of fruit and vegetables and a moderate consumption of wine and whole cereals.

Guarana (Paullinia cupana) as a potential tool for mesenchymal stromal cells priming in regenerative medicine.

Mesenchymal stromal cells (MSCs) have therapeutic potential due to their abilities of differentiation, immunomodulation, and migration to injured tissues, potentiating such effects when cells are activated. Guarana (Paullinia cupana) is a tropical plant species found in South America that is known for its antioxidant, stimulant, and cicatricial effects. The guarana extract is composed of many substances and caffeine is the main component. The objective was to evaluate the effects of guarana and caffeine on MSCs. After the initial characterization, MSCs were treated with Paullinia cupana (10, 100, and 1000 µg/mL) or caffeine (0.4, 4, and 40 µg/mL) for 24 h. MSCs treatment with 1000 µg/mL guarana increased cell polarity, viability, cell migration to chemoattractant, antioxidant potential, and liberation of extracellular vesicles (EVs), while it reduced the levels of autophagy. MSCs treated with 100 and 1000 µg/mL guarana or 40 µg/mL caffeine showed a decrease of cell proliferation. No treatment affected the cellular area and cell cycle of MSCs. The study shows in vitro evidence that guarana could be a promising alternative for activating MSCs to promote better cellular products for future clinical therapies.

A study survey on molnupiravir treatment in COVID-19 patients at home in Ninh Thuan province, Vietnam.

OBJECTIVE: Molnupiravir (MOV) is an oral antiviral drug that received use authorization in Vietnam for the treatment of mild COVID-19 (F0). There was a need to develop alternative approaches that allowed patients to access medication, decongest hospitals, clinics, and facilities, and protect people from infection. During the COVID-19 crisis, the Ninh Thuan Health Authorities implemented the home delivery of medication by community health workers. This study conducted in collaboration with two important Italian entities [the Aldo Moro University of Bari City and the 118 Department of Territorial Emergency System (118 SET) of Taranto City] aimed to evaluate the implementation of home delivery F0 treatment package assessing the rate of infection recovering during the coronavirus pandemic in Ninh Thuan province, Vietnam. PATIENTS AND METHODS: A convergent mixed methods research, based on a longitudinal study with quantitative research and qualitative assessments, evaluated four implementation outcomes: the feasibility, fidelity, coverage, sustainability, and effectiveness of the initiative. Data sources included routinely collected data, a telephonic survey of patients, an analysis of set-up and recurrent costs, as well as descriptive exploratory qualitative and quantitative analysis. RESULTS: After taking the MOV for 5 days, only 35 out of the initial 400 F0 patients remained positive, while 365 patients (91.2%) were negative (CT≥30). Whilst, the successful rate after using the drug during the course accounted for 99.85% and 100% after the entire treatment course, without any death. After 5 days of taking the drug, a positive test result (CT<30) was associated with age group ≥60 (OR=2.7) and comorbidities (OR=3.0) (p<0.05) compared to negative and positive results (CT≥30). Negative factors impacting F0 at home include a shortage of healthcare workers, inadequate supply of thermometers and SpO2 meters, and insufficient financial support for healthcare workers. CONCLUSIONS: MOV caused a reduction in the risk of hospitalization or death in mild COVID-19 patients, and molnupiravir was also found to be well tolerated and safe without any major adverse events during the administration period.

Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: evidence for a mechanism of antioxidant tuning.

BACKGROUND AND AIMS: The intake of antioxidant-rich foods may increase the blood levels of non enzymatic antioxidant capacity (NEAC). NEAC takes into account all antioxidants from food and synergistic effects between them. We examined the effect of a 1-year intervention with Mediterranean diet on plasma NEAC and assessed whether it was related to baseline NEAC levels. METHODS AND RESULTS: Five hundred sixty-four participants at high cardiovascular risk were randomly selected from the PREDIMED (Prevención con DIeta MEDiterránea) Study, a large 3-arm randomized clinical trial. Blood NEAC levels were measured at baseline and after 1-year of dietary intervention with 1) a Mediterranean diet supplemented with virgin olive oil (MED + VOO); 2) a Mediterranean diet supplemented with nuts (MED + nuts), or 3) a control low-fat diet. Plasma NEAC was analyzed using FRAP (ferric reducing antioxidant potential) and TRAP (total radical-trapping antioxidant parameter) assays. Plasma FRAP levels increased after 1-year of intervention with MED + VOO [72.0 µmol/L (95% CI, 34.2-109.9)] and MED + nuts [48.9 µmol/L (24.3-73.5)], but not after the control low-fat diet [13.9 µmol/L (-11.9 to 39.8)]. Participants in the lowest quartile of plasma FRAP at baseline significantly increased their levels after any intervention, while those in the highest quartile decreased. Similar results occurred with TRAP levels. CONCLUSIONS: This study shows that a 1-year of MED diet intervention increases plasma TAC level in subjects at high risk for cardiovascular disease. Moreover, the effectiveness of dietary supplementation with antioxidants may be related to baseline levels of plasma NEAC.

Dietary quercetin intake and risk of gastric cancer: results from a population-based study in Sweden.

BACKGROUND: To study the impact of the dietary antioxidant quercetin on risk of gastric adenocarcinoma. PATIENTS AND METHODS: Using data from a large Swedish population-based case-control study of gastric cancer (505 cases and 1116 controls), we studied the association between quercetin and risk of anatomic (cardia/noncardia) and histological (intestinal and diffuse) subtypes of gastric cancer. RESULTS: We found strong inverse associations between quercetin and the risk of noncardia gastric adenocarcinoma, with an adjusted odds ratio (OR) of 0.57 (95% confidence interval 0.40-0.83) for the highest quintile (≥11.9 mg) of daily quercetin intake relative to the lowest quintile of intake (<4 mg quercetin/day), supported by a significant decreasing linear trend (P value < 0.001). Similar findings were observed for the intestinal and diffuse subtype. For cardia cancer, we found a less evident and nonsignificant inverse relationship. The protection of quercetin appeared to be stronger among female smokers, with the OR leveled of at values <0.2 in quintiles 3-5 (>6 mg quercetin/day). CONCLUSIONS: High dietary quercetin intake is inversely related to the risk of noncardia gastric adenocarcinoma, and the protection appears to be particularly strong for women exposed to oxidative stress, such as tobacco smoking.

Adrenal ganglioneuroma incidentally discovered in a patient with dysuria: a case report.

A case of adrenal ganglioneuroma incidentally discovered during an abdominal ultrasound examination in a 26 year-old woman patient with recurrent episodes of dysuria. After a diagnostic work-up with laboratory and abdomen CT scan, the patient uderwent a laparotomic removal of the adrenal lesion. Histopathological examination of the adrenal mass confirmed the diagnosis.

Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice.

In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia.

Analytical techniques to recognize inclusion complexes formation involving monoterpenes and cyclodextrins: A study case with (-) borneol, a food ingredient.

Monoterpenes are non-polar secondary metabolites widely used by industry due to their excellent therapeutic, food-ingredient and cosmetic properties. However, their low solubility in water limits their use. In this sense, cyclodextrins (CDs) have been widely used to solve these technological challenges. Thus, this study aims to use (-)-borneol as a monoterpene model to prepare inclusion complexes between ß-CD and hydroxypropyl-ß-CD (HP-ß-CD) through different ways and characterize them in order to choose the best inclusion method to improve physicochemical properties of monoterpenes. To achieve this goal, the samples were prepared by physical mixture (PM), paste complex (PA) and freeze-drying complex (FD) and then, extensively characterized by thermal analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy, size particle, X-ray diffraction and nuclear magnetic resonance. The physicochemical results showed that freeze-drying was more effective to form inclusion complexes between (-)-borneol with both CDs. This research highlights the importance of recognizing the best method to prepare inclusion complexes, including food additives as (-)-borneol, to achieve better results in food preparations.

dLLME-µSPE extraction coupled to HPLC-ESI-MS/MS for the determination of F2α-IsoPs in human urine.

Oxidative stress is a pathological condition characterized by an imbalance between body's antioxidant defenses and oxidizing agents, resulting in damage of endogenous molecules. These products can be used as markers of oxidative conditions; in particular, isoprostanes (IsoPs) come from the reaction of arachidonic acid with reactive oxygen species (ROS) and are currently defined as gold markers of oxidative stress in urine. Our main goal was the development of a reliable analytical method for the determination and quantification of the IsoPs in human urine by dispersive Liquid-Liquid Micro Extraction (dLLME) coupled with micro Solid Phase Extraction (µSPE) clean-up and HPLC-MS/MS analysis. The selected compounds are present in very small concentration in urine, furthermore, due to relevant matrix effect, they are challenging for ESI-MS/MS analysis. This approach provided selectivity and sensitivity for 8-isoprotaglandine F2α (8-iso-PGF2α), the "gold" OS marker, together with the main isomers. dLLME extraction allowed a significant enrichment factor and µSPE clean-up provided the removal of ion-suppressing compounds from the sample resulting in low matrix effect. The chromatographic separation was also challenging as the target compounds possess very similar chemical characteristics, so experimental conditions were carefully tuned. The reported method represents a useful tool for the detection of IsoPs in urine taking advantage of the combination of dLLME extraction and µSPE clean-up; overall recoveries were above 50 % and matrix effects were ≤15 %, with LOQs ranging between 0.020 and 0.060 ng mL-1. The procedure is easy to use and rapid allowing the removal of interfering compounds and matrix effect maintaining a highly sensitive determination.

Inflammatory disease processes and interactions with nutrition.

Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain omega-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (omega-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are required.

Severe acute multineuropathy in Churg-Strauss syndrome in a patient with a history of melanoma.

We describe the clinicopathologic features of a 69-year-old man affected with acute onset Churg-Strauss syndrome with major peripheral nerve involvement. At admission the patient presented a one-week history of distal upper-limb asymmetrical paresthesias. Asthma had been present since the age of 55 and treated with leukotriene receptor antagonists (LTAs, Montelukast) for a few years. Multiple pulmonary infiltrates had been diagnosed during follow-up for melanoma. During hospitalization he showed rapidly progressive weakness worsening within a few hours; cerebrospinal fluid analysis, cervical MRI, head CT scan, nerve conduction studies and peripheral nerve and skeletal muscle biopsies were performed. Blood analysis showed leukocytosis and marked eosinophilia; p-ANCA were positive. Sural nerve biopsy showed a marked loss of myelinated fibers, thrombosed vessels surrounded by mononuclear and eosinophilic cells, necrotizing and hyaline degeneration. Eosinophilic infiltrates were shown in May-Grunwald-Giemsa stained sections. The eosinophils mostly occupied the outer zone of the adventitia at the margin of the active lesion. Perivascular cellular infiltrates within the epineurium were immunoreactive for T-lymphocytes and macrophages. Strong HLA-DR immunostaining was present in the perineurium and membrane attack complex deposition was present in a few endoneurial capillaries. Muscle biopsy showed neurogenic changes and one vessel surrounded by mononuclear cells. After a few days of corticosteroid therapy leukocytosis and eosinophilia normalized and the patient's clinical features stabilized.

A new high-throughput method to make a quality control on tattoo inks.

Nowadays, practice of tattooing is very common worldwide and, along with this increasing trend, there is also an increased risk of adverse reactions to tattoo pigments that are well known and described in literature. Previous studies have reported that cutaneous and allergic reactions to a particular pigment can manifest in several ways (allergic contact dermatitis and photo-allergic dermatitis). In this paper, a new high-throughput method is presented, in order to achieve a new system for the quality control on tattoo inks based on chromatographic-spectroscopic approach. The samples, twenty-one tattoo inks and three permanent makeup, comprised the following colors: black inks, yellow, blue, green, white, pink and various shades of red (pigment that gives many allergic responses) were analyzed through the combination of chromatographic and spectroscopic techniques, the HPTLC-Raman. In particular, Raman technique has been chosen because of its high sensitivity towards the inorganic and organic pigments, main constituents of tattoo inks. Moreover, the advantage of this hyphenated technique is to overcome the problem of analysing the complex mixture of tattoo inks, allowing to obtain a Raman spectrum of each single component, isolated by chromatographic separation. This approach aims at developing a powerful instrument to establish the nature of tattoo inks and substances that could be cause adverse reactions in tattooed patients.

Guarana (Paullinia cupana) as a potential tool for mesenchymal stromal cells priming in regenerative medicine

Mesenchymal stromal cells (MSCs) have therapeutic potential due to their abilities of differentiation, immunomodulation, and migration to injured tissues, potentiating such effects when cells are activated. Guarana (Paullinia cupana) is a tropical plant species found in South America that is known for its antioxidant, stimulant, and cicatricial effects. The guarana extract is composed of many substances and caffeine is the main component. The objective was to evaluate the effects of guarana and caffeine on MSCs. After the initial characterization, MSCs were treated with Paullinia cupana (10, 100, and 1000 μg/mL) or caffeine (0.4, 4, and 40 μg/mL) for 24 h. MSCs treatment with 1000 μg/mL guarana increased cell polarity, viability, cell migration to chemoattractant, antioxidant potential, and liberation of extracellular vesicles (EVs), while it reduced the levels of autophagy. MSCs treated with 100 and 1000 μg/mL guarana or 40 μg/mL caffeine showed a decrease of cell proliferation. No treatment affected the cellular area and cell cycle of MSCs. The study shows in vitro evidence that guarana could be a promising alternative for activating MSCs to promote better cellular products for future clinical therapies.

Do women >or=50 years of age need as much screening as women <50 years after they have had negative screening results?

To assess the adequacy of a routine screening to identify cervical intraepithelial neoplasia 2 or worse (CIN2+) in women over 50 years of age, a retrospective cohort was set in six Italian organised population-based screening programmes. In all, 287 330 women (1 714 550 person-years of observation, 1110 cases) screened at age 25-64, with at least two cytological screening tests, the first negative, were followed from their first negative smear until a biopsy proven CIN2+ lesion or their last negative smear. For women aged 25-49 and 50-64 years, crude and age-standardised detection rate (DR), cumulative risk (CR), adjusted hazard risk for number of previous negative screens, probability of false-positive CIN2+ after two or more smear tests were calculated. Detection rate is significantly lower over 50 years of age. Multivariable analysis shows a significant protective effect from four screening episodes (DR=0.70, 95% CI: 0.51-0.97); the effect of age >or=50 is 0.29 (95% CI: 0.24-0.35). The CR of CIN2+ is at least eightfold higher in women <50 (CR=2.06, 95% CI: 1.88-2.23) after one previous negative test than in women >or=50 years with four screens (CR=0.23, 95% CI: 0.00-0.46). Over 50 years of age, after four tests at least three false-positive cases are diagnosed for every true positive. Benefits arising from cytological screening is uncertain in well-screened older women.

Characterization of the Antioxidant Effects of γ-Oryzanol: Involvement of the Nrf2 Pathway.

γ-Oryzanol (ORY) is well known for its antioxidant potential. However, the mechanism by which ORY exerts its antioxidant effect is still unclear. In this paper, the antioxidant properties of ORY were investigated for its potential effects as a reactive oxygen and nitrogen species (ROS/RNS) scavenger and in activating antioxidant-promoting intracellular pathways utilizing the human embryonic kidney cells (HEK-293). The 24 h ORY exposure significantly prevented hydrogen peroxide- (H2O2-) induced ROS/RNS production at 3 h, and this effect was sustained for at least 24 h. ORY pretreatment also enhanced the activity of antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GPX). Interestingly, ORY induced the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation and upregulation of Nrf2-dependent defensive genes such as NAD(P)H quinone reductase (NQO1), heme oxygenase-1 (HO-1), and glutathione synthetase (GSS) at mRNA and protein levels in both basal condition and after H2O2 insult. Thus, this study suggested an intriguing effect of ORY in modulating the Nrf2 pathway, which is also involved in regulating longevity as well as age-related diseases.

Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice.

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice.

Distinct effects of Rac1 on differentiation of primary avian myoblasts.

Rho family GTPases have been implicated in the regulation of the actin cytoskeleton in response to extracellular cues and in the transduction of signals from the membrane to the nucleus. Their role in development and cell differentiation, however, is little understood. Here we show that the transient expression of constitutively active Rac1 and Cdc42 in unestablished avian myoblasts is sufficient to cause inhibition of myogenin expression and block of the transition to the myocyte compartment, whereas activated RhoA affects myogenic differentiation only marginally. Activation of c-Jun N-terminal kinase (JNK) appears not to be essential for block of differentiation because, although Rac1 and Cdc42 GTPases modestly activate JNK in quail myoblasts, a Rac1 mutant defective for JNK activation can still inhibit myogenic differentiation. Stable expression of active Rac1, attained by infection with a recombinant retrovirus, is permissive for terminal differentiation, but the resulting myotubes accumulate severely reduced levels of muscle-specific proteins. This inhibition is the consequence of posttranscriptional events and suggests the presence of a novel level of regulation of myogenesis. We also show that myotubes expressing constitutively active Rac1 fail to assemble ordered sarcomeres. Conversely, a dominant-negative Rac1 variant accelerates sarcomere maturation and inhibits v-Src-induced selective disassembly of I-Z-I complexes. Collectively, our findings provide a role for Rac1 during skeletal muscle differentiation and strongly suggest that Rac1 is required downstream of v-Src in the signaling pathways responsible for the dismantling of tissue-specific supramolecular structures.