The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.

Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family.

The Role of Plant Lectins in the Cellular and Molecular Processes of Skin Wound Repair: An Overview.

There is increasing pressure for innovative methods to treat compromised and difficult-to-heal wounds. Consequently, new strategies are needed for faster healing, reducing infection, hydrating the wound, stimulating healing mechanisms, accelerating wound closure, and reducing scar formation. In this scenario, lectins present as good candidates for healing agents. Lectins are a structurally heterogeneous group of glycosylated or non-glycosylated proteins of non-immune origin, which can recognize at least one specific monosaccharide or oligosaccharide specific for the reversible binding site. Cell surfaces are rich in glycoproteins (glycosidic receptors) that potentially interact with lectins through the number of carbohydrates reached. This lectin-cell interaction is the molecular basis for triggering various changes in biological organisms, including healing mechanisms. In this context, this review aimed to (i) provide a comprehensive overview of relevant research on the potential of vegetable lectins for wound healing and tissue regeneration processes and (ii) discuss future perspectives.

Omega-3 pleiad: The multipoint anti-inflammatory strategy.

Omega 3 (ω3) fatty acids have been described since the 1980s as promising anti-inflammatory substances. Prostaglandin and leukotriene modulation were exhaustively explored as the main reason for ω3 beneficial outcomes. However, during the early 2000s, after the human genome decoding advent, the nutrigenomic approaches exhibited an impressive plethora of ω3 targets, now under the molecular point of view. Different G protein-coupled receptors (GPCRs) recognizing ω3 and its derivatives appear to be responsible for blocking inflammation and insulin-sensitizing effects. A new class of ω3-derived substances, such as maresins, resolvins, and protectins, increases ω3 actions. Inflammasome disruption, the presence of GPR120 on immune cell surfaces, and intracellular crosstalk signaling mediated by PPARγ compose the last discoveries regarding the multipoint anti-inflammatory targets for this nutrient. This review shows a detailed mechanistic proposal to understand ω3 fatty acid action over the inflammatory environment in the background of several chronic diseases.

Multi-scale mechanobiological model for skeletal muscle hypertrophy.

Skeletal muscle adaptation is correlated to training exercise by triggering different signaling pathways that target many functions; in particular, the IGF1-AKT pathway controls protein synthesis and degradation. These two functions regulate the adaptation in size and strength of muscles. Computational models for muscle adaptation have focused on: the biochemical description of signaling pathways or the mechanical description of muscle function at organ scale; however, an interrelation between these two models should be considered to understand how an adaptation in muscle size affects the protein synthesis rate. In this research, a dynamical model for the IGF1-AKT signaling pathway is linked to a continuum-mechanical model describing the active and passive mechanical response of a muscle; this model is used to study the impact of the adaptive muscle geometry on the protein synthesis at the fiber scale. This new computational model links the signaling pathway to the mechanical response by introducing a growth tensor, and links the mechanical response to the signaling pathway through the evolution of the protein synthesis rate. The predicted increase in cross sectional area (CSA) due to an 8 weeks training protocol excellently agreed with experimental data. Further, our results show that muscle growth rate decreases, if the correlation between protein synthesis and CSA is negative. The outcome of this study suggests that multi-scale models coupling continuum mechanical properties and molecular functions may improve muscular therapies and training protocols.

Membrane Rigidity and Phosphatidic Acid (PtdOH) Signal: Two Important Events in Acinetobacter guillouiae SFC 500-1A Exposed to Chromium(VI) and Phenol.

The remodeling of membrane lipids is a mechanism that allows microorganisms to survive in unfavorable environments such as industrial effluents, which often contain inorganic and organic pollutants, like chromium and phenol. In the present work, we evaluated the effect of Cr(VI) and phenol on the membrane of Acinetobacter guillouiae SFC 500-1A, a bacterial strain isolated from tannery sediments where such pollutants can be found. The presence of lipid kinases and phospholipases and the changes in their activities under exposure to these pollutants were determined. Cr(VI) and Cr(VI) + phenol caused the membrane to become more rigid for up to 16 h after exposure. This could be due to an increase in cardiolipin (Ptd2 Gro) and a decrease in phosphatidylethanolamine (PtdEtn), which are indicative of more order and rigidity in the membrane. Increased phospholipase A activity (PLA, EC 3.1.1.4) could be responsible for the decrease in PtdEtn levels. Moreover, our results indicate that Cr(VI) and Cr(VI) + phenol trigger the phosphatidic acid (PtdOH) signal. The finding of significantly increased phosphatidylinositol-4-phosphate (PtdIns-4-P) levels means this is likely achieved via PtdIns-PLC/DGK. This report provides the first evidence that A. guillouiae SFC 500-1A is able to sense Cr(VI) and phenol, transduce this signal through changes in the physical state of the membrane, and trigger lipid-signaling events.

Exhaustive acute exercise-induced ER stress is attenuated in IL-6-knockout mice.

The endoplasmic reticulum (ER) stress and inflammation relationship occurs at different levels and is essential for the adequate homeostatic function of cellular systems, becoming harmful when chronically engaged. Intense physical exercise enhances serum levels of interleukin 6 (IL-6). In response to a chronic exhaustive physical exercise protocol, our research group verified an increase of the IL-6 concentration and ER stress proteins in extensor digitorium longus (EDL) and soleus. Based on these results, we hypothesized that IL-6-knockout mice would demonstrate a lower modulation in the ER stress proteins compared to the wild-type mice. To clarify the relationship between exercise-induced IL-6 increased and ER stress, we studied the effects of an acute exhaustive physical exercise protocol on the levels of ER stress proteins in the skeletal muscles of IL-6-knockout (KO) mice. The WT group displayed a higher exhaustion time compared to the IL-6 KO group. After 1 h of the acute exercise protocol, the serum levels of IL-6 and IL-10 were enhanced in the WT group. Independent of the experimental group, the CHOP and cleaved caspase 12/total caspase 12 ratio in EDL as well as ATF6 and CHOP in soleus were sensitive to the acute exercise protocol. Compared to the WT group, the oscillation patterns over time of BiP in EDL and soleus as well as of peIF2-alpha/eIF2-alpha ratio in soleus were attenuated for the IL-6 KO group. In conclusion, IL-6 seems to be related with the ER stress homeostasis, once knockout mice presented attenuation of BiP in EDL and soleus as well as of pEiF2-alpha/EiF2-alpha ratio in soleus after the acute exhaustive physical exercise protocol.

The Mitogen-Activated Protein Kinase (MAPK) Pathway: Role in Immune Evasion by Trypanosomatids.

Leishmania spp. and Trypanosoma cruzi are the causative agents of leishmaniasis and Chagas disease, respectively, two neglected tropical diseases that affect about 25 million people worldwide. These parasites belong to the family Trypanosomatidae, and are both obligate intracellular parasites that manipulate host signaling pathways and the innate immune system to establish infection. Mitogen-activated protein kinases (MAPKs) are serine and threonine protein kinases that are highly conserved in eukaryotes, and are involved in signal transduction pathways that modulate physiological and pathophysiological cell responses. This mini-review highlights existing knowledge concerning the mechanisms that Leishmania spp. and T. cruzi have evolved to target the host's MAPK signaling pathways and highjack the immune response, and, in this manner, promote parasite maintenance in the host.

miRNA biogenesis: biological impact in the development of cancer.

microRNAs (miRNAs) are non coding RNAs with different biological functions and pathological implications. Given their role as post-transcriptional gene expression regulators, they are involved in several important physiological processes like development, cell differentiation and cell signaling. miRNAs act as modulators of gene expression programs in different diseases, particularly in cancer, where they act through the repression of genes which are critical for carcinogenesis. The expression level of mature miRNAs is the result of a fine mechanism of biogenesis, carried out by different enzymatic complexes that exert their function at transcriptional and post-transcriptional levels. In this review, we will focus our discussion on the alterations in the miRNA biogenesis machinery, and its impact on the establishment and development of cancer programs.

Ketogenic diets, mitochondria, and neurological diseases.

The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

Avaliação dos mecanismos envolvidos na inibição da proliferação e na indução da apoptose de linhagem leucêmica pelo óleo de sementes de Pterodon pubescens e suas frações/subfrações / Assessment of the mechanisms involved in inhibiting proliferation and inducing apoptosis of lineage leukemia by oil seed Pterodon pubescens and its fractions/subfractions

Alterações no ciclo celular e desenvolvimento de tumor encontram-se intimamente ligados. Expressão inadequada e/ou mutações de quinases dependentes de ciclinas, ciclinas e inibidores de quinases dependentes de ciclinas têm sido descritas em vários tipos de cânceres. Portanto, a busca por novas molédulas que têm como alvo eventos em tal via bioquímica tem aumentado ao longo dos anos. Como as plantas são importantes fontes de novas potenciais drogas quimioterápicas, o estudo da fitoquímica, aliado às pesquisas farmacológicas, permite desvendar novas substâncias com potencial anti câncer. Embora efeitos antitumorais tenham sido demonstrados para extratos de Pterodon pubescens, os mecanismos que induzem estes efeitos ainda não estão esclarecidos. Portanto, o presente trabalho teve como objetivos subfracionar a fração hexano do extrato bruto de frutos de Pterodon pubescens, avaliar alguns mecanismos pelos quais a subfração mais ativa exerce seu efeito antiproliferativo sobre linhagem leucêmica (K562) e tentar identificar compostos envolvidos em tais efeitos. O extrato bruto (OPp) foi obtido por maceração em etanol e posteriormente foi feita uma partição líquido-liquido obtendo-se a fração Hexano (HEX). O subfracionamento por coluna de sílica da HEX resultou em oito subfrações, sendo que a subfração 5 (SF5) a que apresentou menor complexidade por cromatografia gasosa e maior efeito biológico. A citotoxicidade foi avaliada pelo método de redução do sal tetrazol (MTT) e a proliferação celular pela síntese de DNA e curva de crescimento. As fases do ciclo celular e a apoptose foram analisados por citometria de fluxo e a expressão do RNA mensageiro por RT-PCR. A expressão de proteína foi avaliada por Western blotting e a identificação de compostos por CG-EM e 13C-RMN. A SF5 exerceu efeito citotóxico maior do que o extrato bruto, fração HEX e as outras subfrações. Na síntese de DNA e curva de crescimento, a SF5 exerceu efeito inibitório tempo e concentração...

Alterations in the cell cycle and tumor development are closely connected. Inapropriated expression and/or mutations of cyclin dependet kinases, cyclins and cyclin kinase inhibitors have been described in many kinds of cancer. So, the search of new molecules that have such biochemical pathway as target has increased over the years. Since plants are important sources of new potential chemotherapic drugs, phytochemical studies combined to pharmacological investigations permit the discover of new substances with potential anti-cancer properties. Although anti tumor effects have been demonstrated for Pterodon pubescens extracts, its mechanisms are still obscure. Therefore, the aims of present work were to subfractionate the HEX fraction of Pterodon pubescens, evaluate some mechanisms by which the most active subfraction exerts its antiproliferative effect on leukemic cell line (K562) and try to elucidate compounds involved in such effects. The crude extract (PpO) was obtained by maceration in ethanol with further liquid-liquid partition yielding the Hexan fraction (HEX). The HEX subfractioning by silica column yielded 8 subfractions, being the subfraction 5 (SF5) that with minor complexity by gas chromatography and greater biological effect. The citotoxicity was evaluated by tetrazolium salt reduction (MTT) and cellular proliferation by DNA synthesis and growth curve. The cell cycle phases and apoptosis were analyzed by flow cytometry and messenger RNA expression by RT-PCR. The protein expression was evaluated by Western blotting and the identification of compounds by GC-MS and 13C-NMR. SF5 induced greater citotoxic effects when compared to crude extract, HEX fraction or the others subfractions. On DNA synthesis and growth curve, SF5 induced time and concentration dependent inhibiory effect, also greater than HEX fraction. The cell cycle analysis showed an increase of cells on G1 phase with consequently reduction of S and G2/M phases. SF5 inhibited the MAP...

La onda de calioo en células vegetaess / The Calcium Wave of Vegetable Cells

El calcio es un nutriente esencial para las plantas, se encuentra involucrado en procesos de desarrollo y de respuesta a factores bióticos y abióticos. Numerosas señales modifican la concentración de calcio en el citoplasma, núcleo, retículo endoplásmico o plastídios. El incremento del calcio en el citosol es rápidamente disminuido, pero en el lapso de incremento, se forman innumerables y complejas cascadas de señalización que conllevan a la respuesta celular. Este nota expone los mecanismos implicaciones de la entrada del calcio en las células vegetales.

Calcium is an essential nutrient for plants; it is involved in developmental processes and in responses to biotic and abiotic factors. Several signals that modify the calcium concentration in the cytoplasm, endoplasmic reticulum, nucleus and/or plastids have been observed. These changes in the calcium concentration in the cell interior are rapidly returned to basal levels, in the meantime, innumerable and complex signaling cascades. This note exposes the mechanisms of calcium transport through the cell membranes of the entrance of calcium in the plant cells.