Proteasome inhibition and ROS generation by 4-nerolidylcatechol induces melanoma cell death

Induction of apoptotic cell death in response to chemotherapy and other external stimuli has proved extremely difficult in melanoma, leading to tumor progression, metastasis formation and resistance to therapy. A promising approach for cancer chemotherapy is the inhibition of proteasomal activity, as the half‐life of the majority of cellular proteins is under proteasomal control and inhibitors have been shown to induce cell death programs in a wide variety of tumor cell types. 4‐Nerolidylcatechol (4‐NC) is a potent antioxidant whose cytotoxic potential has already been demonstrated in melanoma tumor cell lines. Furthermore, 4‐NC was able to induce the accumulation of ubiquitinated proteins, including classic targets of this process such as Mcl‐1. As shown for other proteasomal inhibitors in melanoma, the cytotoxic action of 4‐NC is time‐dependent upon the pro‐apoptotic protein Noxa, which is able to bind and neutralize Mcl‐1. We demonstrate the role of 4‐NC as a potent inducer of ROS and p53. The use of an artificial skin model containing melanoma also provided evidence that 4‐NC prevented melanoma proliferation in a 3D model that more closely resembles normal human skin.     

Spatial patterns of photosynthesis in thin- and thick-leaved epiphytic orchids: unravelling C3–CAM plasticity in an organ-compartmented way

Background and Aims

A positive correlation between tissue thickness and crassulacean acid metabolism (CAM) expression has been frequently suggested. Therefore, this study addressed the question of whether water availability modulates photosynthetic plasticity in different organs of two epiphytic orchids with distinct leaf thickness.

Methods

Tissue morphology and photosynthetic mode (C₃ and/or CAM) were examined in leaves, pseudobulbs and roots of a thick-leaved (Cattleya walkeriana) and a thin-leaved (Oncidium ‘Aloha’) epiphytic orchid. Morphological features were studied comparing the drought-induced physiological responses observed in each organ after 30 d of either drought or well-watered treatments.

Key Results

Cattleya walkeriana, which is considered a constitutive CAM orchid, displayed a clear drought-induced up-regulation of CAM in its thick leaves but not in its non-leaf organs (pseudobulbs and roots). The set of morphological traits of Cattleya leaves suggested the drought-inducible CAM up-regulation as a possible mechanism of increasing water-use efficiency and carbon economy. Conversely, although belonging to an orchid genus classically considered as performing C₃ photosynthesis, Oncidium ‘Aloha’ under drought seemed to express facultative CAM in its roots and pseudobulbs but not in its leaves, indicating that such photosynthetic responses might compensate for the lack of capacity to perform CAM in its thin leaves. Morphological features of Oncidium leaves also indicated lower efficiency in preventing water and CO₂ losses, while aerenchyma ducts connecting pseudobulbs and leaves suggested a compartmentalized mechanism of nighttime carboxylation via phosphoenolpyruvate carboxylase (PEPC) (pseudobulbs) and daytime carboxylation via Rubisco (leaves) in drought-exposed Oncidium plants.

Conclusions

Water availability modulated CAM expression in an organ-compartmented manner in both orchids studied. As distinct regions of the same orchid could perform different photosynthetic pathways and variable degrees of CAM expression depending on the water availability, more attention should be addressed to this in future studies concerning the abundance of CAM plants.     

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection

Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.     

Effect of vertebrate feces on the attraction of Culicoides (Diptera: Ceratopogonidae) in an Amazonian mangrove

Biting midges are of interest to public health because they play an important role as vectors of disease‐causing pathogens, as well as being a biting nuisance to humans and domestic animals. Although these insects are common in mangrove areas, they have not yet been studied in this ecosystem in the state of Maranhão (MA), Brazil. The objective of this study was to characterize the Culicoides community structure found in a mangrove swamp and verify if the use of vertebrate feces as bait interferes with their composition, richness, abundance, or seasonality. CDC light traps with vertebrate (chicken, ox, control, donkey, capuchin monkey and pig) feces baits were used to capture biting midges in a mangrove area of the Island of São Luís, MA. A total of 4,087 individuals representing 22 species of Culicoides were captured, the most abundant being C. (Oecacta) furens Poey (23.46%), C. (gr. Fluviatilis) leopoldoi Ortiz (21.58%), C. (Hoffmania) ignacioi Forattini (16.98%), C. (Hoffmania) maruim Lutz (13.85%), C. (Diphaomyia) iriartei Fox (10.57%), C. (Hoffmania) insignis Lutz (7.07%), and C. (gr. Limai) limai Barreto (3.03%). Species richness and abundance were higher when baits of capuchin monkey (15 species; 26.84% of the individuals) and pig (15; 25.3%) feces were used. The least attractive baits were donkey (12 species; 9.3%) and ox (nine species; 11.52%) feces. Biting midges were more abundant in the rainy season (67%), but richness was higher in the dry season (19 species). These results show that vertebrate feces may serve as olfactory cues and increase the attraction of biting midges to traps.     

Detection and Molecular Characterization of <Emphasis Type=Italic>Yellow Fever Virus</Emphasis>, 2017, Brazil

At the end of 2016, Brazil experienced an unprecedented yellow fever (YF) outbreak. Clinical, molecular and ecological aspects of human and non-human primate (NHP) samples collected at the beginning of the outbreak are described in this study. Spatial distribution analyses demonstrated a strong overlap between human and NHP cases. Through molecular analyses, we showed that the outbreak had a sylvatic origin, caused by the South American genotype 1 YFV, which has already been shown to circulate in Brazil. As expected, the clusters of cases were identified in regions with a low vaccination coverage. Our findings highlight the importance of the synchronization of animal surveillance and health services to identify emerging YF cases, thereby promoting a better response to the vulnerable population.     

Synergy of Fresh and Accumulated Organic Matter to Bacterial Growth

The main goal of this research was to evaluate whether the mixture of fresh labile dissolved organic matter (DOM) and accumulated refractory DOM influences bacterial production, respiration, and growth efficiency (BGE) in aquatic ecosystems. Bacterial batch cultures were set up using DOM leached from aquatic macrophytes as the fresh DOM pool and DOM accumulated from a tropical humic lagoon. Two sets of experiments were performed and bacterial growth was followed in cultures composed of each carbon substrate (first experiment) and by carbon substrates combined (second experiment), with and without the addition of nitrogen and phosphorus. In both experiments, bacterial production, respiration, and BGE were always higher in cultures with N and P additions, indicating a consistent inorganic nutrient limitation. Bacterial production, respiration, and BGE were higher in cultures set up with leachate DOM than in cultures set up with humic DOM, indicating that the quality of the organic matter pool influenced the bacterial growth. Bacterial production and respiration were higher in the mixture of substrates (second experiment) than expected by bacterial production and respiration in single substrate cultures (first experiment). We suggest that the differences in the concentration of some compounds between DOM sources, the co-metabolism on carbon compound decomposition, and the higher diversity of molecules possibly support a greater bacterial diversity which might explain the higher bacterial growth observed. Finally, our results indicate that the mixture of fresh labile and accumulated refractory DOM that naturally occurs in aquatic ecosystems could accelerate the bacterial growth and bacterial DOM removal.     

Optimizing body contour in massive weight loss patients: the modified vertical abdominoplasty

In morbid obesity, contour deformities of the abdomen are common after bariatric surgery and radical weight loss. Traditional abdominoplasty techniques often fail to maximally improve body contour in these cases because adjacent sites such as the hip rolls and flanks are not treated, leaving the patient with large lateral tissue redundancies and dog-ears. In an attempt to solve these challenging problems, the authors present the modified vertical abdominoplasty technique, a single-stage procedure that involves a combined vertical and transverse approach in which an "en bloc" resection of the redundant tissues is performed without undermining, drainage, or reinforcement of the abdominal wall. The latter is only carried out when diastasis and/or hernias are present, and Marlex mesh may be utilized when indicated. In patients with simultaneous large umbilical hernias and/or excessively long stalks, neoumbilicoplasty is recommended. A significant improvement of abdominal contour was obtained in the vast majority of patients because the resection design offers simultaneous treatment of both vertical and transverse tissue redundancies in the abdomen and neighboring regions, with more harmonic results when compared with purely vertical or transverse approaches. The modified vertical abdominoplasty technique is an easy, fast, and reliable alternative for treating these patients, with less intraoperative bleeding, reduced overall cost, and low morbidity rates. In selected cases, the technique is capable of offering excellent results in terms of contouring and maximizes the overall outcome of treatment protocols for these patients, who can then be integrated into normal life with heightened self-esteem, happiness, and productivity.     

Influence of 5-HT1A agonist on the feeding behavior of Coturnix japonica (Galliformes: Aves).

In this study, we investigate the effect of serotonin receptor 5-HT1A stimulation on the feeding behavior of quails (Coturnix japonica). The administration of 5-HT1A agonist, 8-OH-DPAT (0.05 to 5.0 mg/Kg) dose-dependently inhibited the food intake in normally fed quails. Greater inhibition was attained with 5.0 mg/kg (0.93 +/- 0.21 g vs. 5.83 +/- 0.25 g, P < 0.05, 2 h after food offer). A comparable response was obtained from previously fasted quails. At end of 2 h, a higher dose of 8-OH-DPAT induced more intense hypophagy (1.59 +/- 0.41 g vs. 6.85 +/- 1.04 g, P < 0.0001). Previous treatment with the antagonist 5-HT1A/beta-adrenergic, propranolol, failed to block the inhibitory action of 8-OH-DPAT, but instead, intensified it (controls, 5.22 +/- 1.09 g; 8-OH-DPAT, 1.41 +/- 0.19 g; propranolol + 8-OH-DPAT, 0.44 +/- 0.25 g, P < 0.01, for all comparisons). The administration of an isolated higher dose of propranolol induced a hypophagic action (controls, 4.5 +/- 0.8 g vs. propranolol, 2.0 +/- 0.2 g, P < 0.01). Current outcomes suggest a possible role of 5-HT1A receptor on the feeding behavior of quails, as opposed to mammals. On the other hand, the intensified hypophagy induced by previous administration of propranolol raises the hypothesis of a beta-adrenergic excitatory mechanism that controls the feeding behavior of quails.