Selective Extraction of Piceatannol from Passiflora edulis by-Products: Application of HSPs Strategy and Inhibition of Neurodegenerative Enzymes.

Passiflora edulis by-products (PFBP) are a rich source of polyphenols, of which piceatannol has gained special attention recently. However, there are few studies involving environmentally safe methods for obtaining extracts rich in piceatannol. This work aimed to concentrate piceatannol from defatted PFBP (d-PFBP) by means of pressurized liquid extraction (PLE) and conventional extraction, using the bio-based solvents selected with the Hansen solubility parameters approach. The relative energy distance (Ra) between solvent and solute was: Benzyl Alcohol (BnOH) < Ethyl Acetate (EtOAc) < Ethanol (EtOH) < EtOH:H2O. Nonetheless, EtOH presented the best selectivity for piceatannol. Multi-cycle PLE at 110 °C was able to concentrate piceatannol 2.4 times more than conventional extraction. PLE exhibited a dependence on kinetic parameters and temperature, which could be associated with hydrogen bonding forces and the dielectric constant of the solvents. The acetylcholinesterase (AChE) and lipoxygenase (LOX) IC50 were 29.420 µg/mL and 27.682 µg/mL, respectively. The results reinforce the demand for processes to concentrate natural extracts from food by-products.

Telomerase activation in the treatment of aging or degenerative diseases: a systematic review.

Telomeres are protective structures that are shortened during the lifetime, resulting in aging and degenerative diseases. Subjects experiencing aging and degenerative disorders present smaller telomeres than young and healthy ones. The size of these structures can be stabilized by telomerase, an enzyme which is inactive in adult tissues but functional in fetal and newborn tissues and adult testes and ovaries. The aim of this study was to perform a systematic review to evaluate the effect of telomerase activation in the treatment of degenerative and aging disorders. We accomplished the search using the Pubmed interface for papers published from September 1985 to April 16th, 2020. We found twenty one studies that matched our eligibility criteria. I concluded that telomerase is probably a potential and safe treatment for aging and degenerative diseases, demonstrating neither side effects nor risk of cancer in the selected studies. Further studies in humans are needed to confirm safety and efficiency of this treatment.

The Impact of Purinergic System Enzymes on Noncommunicable, Neurological, and Degenerative Diseases.

Evidences show that purinergic signaling is involved in processes associated with health and disease, including noncommunicable, neurological, and degenerative diseases. These diseases strike from children to elderly and are generally characterized by progressive deterioration of cells, eventually leading to tissue or organ degeneration. These pathological conditions can be associated with disturbance in the signaling mediated by nucleotides and nucleosides of adenine, in expression or activity of extracellular ectonucleotidases and in activation of P2X and P2Y receptors. Among the best known of these diseases are atherosclerosis, hypertension, cancer, epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The currently available treatments present limited effectiveness and are mostly palliative. This review aims to present the role of purinergic signaling highlighting the ectonucleotidases E-NTPDase, E-NPP, E-5'-nucleotidase, and adenosine deaminase in noncommunicable, neurological, and degenerative diseases associated with the cardiovascular and central nervous systems and cancer. In conclusion, changes in the activity of ectonucleotidases were verified in all reviewed diseases. Although the role of ectonucleotidases still remains to be further investigated, evidences reviewed here can contribute to a better understanding of the molecular mechanisms of highly complex diseases, which majorly impact on patients' quality of life.

New Views on the Misconstrued: Executioner Caspases and Their Diverse Non-apoptotic Roles.

Initially characterized for their roles in apoptosis, executioner caspases have emerged as important regulators of an array of cellular activities. This is especially true in the nervous system, where sublethal caspase activity has been implicated in axonal pathfinding and branching, axonal degeneration, dendrite pruning, regeneration, long-term depression, and metaplasticity. Here we examine the roles of sublethal executioner caspase activity in nervous system development and maintenance, consider the mechanisms that locally activate and restrain these potential killers, and discuss how their activity be subverted in neurodegenerative disease.

Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes.

Human kallikrein-related peptidases (KLKs) are a subgroup of serine proteases that participate in proteolytic pathways and control protein levels in normal physiology as well as in several pathological conditions. Their complex network of stimulatory and inhibitory interactions may induce inflammatory and immune responses and contribute to the neoplastic phenotype through the regulation of several cellular processes, such as proliferation, survival, migration, and invasion. This family of proteases, which includes one of the most useful cancer biomarkers, kallikrein-related peptidase 3 or PSA, also has a protective effect against cancer promoting apoptosis or counteracting angiogenesis and cell proliferation. Therefore, they represent attractive therapeutic targets and may have important applications in clinical oncology. Despite being intensively studied, many gaps in our knowledge on several molecular aspects of KLK functions still exist. This review aims to summarize recent data on their involvement in different processes related to health and disease, in particular those directly or indirectly linked to the neoplastic process.

Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications.

Protein disulfide isomerases (PDIs) are a family of foldases and chaperones primarily located at the endoplasmic reticulum that catalyze the formation and isomerization of disulfide bonds thereby facilitating protein folding. PDIs also perform important physiological functions in protein quality control, cell death, and cell signaling. Protein misfolding is involved in the etiology of the most common neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, Prion-related disorders, among others. Accumulating evidence indicate altered expression of PDIs as a prominent and common feature of these neurodegenerative conditions. Here we overview most recent advances in our understanding of the possible functional contribution of PDIs to neurodegeneration, depicting a complex and poorly understood scenario. Possible therapeutic benefits of targeting PDIs in a disease context and their use as biomarkers are discussed.

Monoamino oxidase a: an interesting pharmacological target for the development of multi-target QSAR.

With the significant increase of life expectancy of populations in societies today, the importance of the discovery of drugs associated with neurodegenerative diseases has emerged. Therefore, neurodegenerative diseases are an important topic in Medicinal Chemistry. Although drug discovery is considered a complex and slow process, new approaches and methods have been developed with the intention of finding new chemical entities in more efficient ways. This work provides a review of virtual methodologies applied in drug discovery and especially a new model for the prediction of MAO-A inhibitors using a multi-target QSAR methodology. This model involves a mixed approach containing simple descriptors based on atom-centered fragments and functional groups (DRAGON) and topological substructural molecular design descriptors (MODESLAB). This unified multi-species QSAR model was validated through a virtual screening of a new series of oxoisoaporphine derivatives, taking into account the information in the calculated fragmental contributions. Therefore, this method represents a useful tool for the in silico screening of MAO-A inhibitors.

Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-ß prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes.

Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-ß (GSK3-ß) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-ß and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-ß active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in ß-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-ß. Thus, GSK3-ß seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection.

Silencing of CDK5 as potential therapy for Alzheimer's disease.

Neurodegeneration is one of the greatest public health challenges for the 21st century. Among neurodegenerative diseases, Alzheimer's disease (AD) is the most prevalent and best characterized. Nevertheless, despite the large investment in AD research, currently there is no effective therapeutic option. In the present review, we highlight a novel alternative, which takes advantage of the biotechnological outbreak deployed by the discovery of the RNA interference-based gene silencing mechanism, and its application as a tool for neurodegeneration treatment. Here, we highlight cyclin-dependent kinase 5 (CDK5) as a key candidate target for therapeutic gene silencing. Unlike other members of the cyclin-dependent kinase family, CDK5 does not seem to play a crucial role in cell cycle regulation. By contrast, CDK5 participates in multiple functions during nervous system development and has been established as a key mediator of Tau hyperphosphorylation and neurofibrillary pathology, thus serving as an optimal candidate for targeted therapy in the adult nervous system. We propose that the use of RNA interference for CDK5 silencing presents an attractive and specific therapeutic alternative for AD and perhaps against other tauopathies.

Cerebellar degeneration in cattle grazing Solanum bonariense ("Naranjillo") in Western Uruguay.

Cattle in western Uruguay that were eating Solanum bonariense developed periodic episodes of ataxia, hypermetria, hyperesthesia, head and thoracic limb extension, opisthotonus, nystagmus, and falling to the side or backward. Similar clinical signs were experimentally reproduced in cattle by administration of S. bonariense via rumen cannula at a dose of 1,024 g/kg body mass. No significant gross lesions were observed in field cases or experimentally induced cases. Spontaneous and induced histologic lesions were similar and included vacuolation, degeneration, and loss of Purkinje cells. Axonal spheroids, microcavitations, and other changes of wallerian-type degeneration in cerebellar white matter were also observed. Ultrastructural changes included increased number of electron-dense residual storage bodies in membrane-bound vesicles in affected Purkinje cells, and similar vesicles and mitochondria in axonal spheroids. No histologic lesions were detected in the other examined tissues. The Purkinje-cell swelling and vacuolation with subsequent cerebellar degeneration are suggestive of Purkinje-cell specific toxin that produces abnormal lysosome function and cell specific axonal transport. This is the first report of S. bonariense toxicity.

Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.

In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata. These plants contain a class of powerful, lipophilic complex I inhibitors, the annonaceous acetogenins. To determine the neurotoxic potential of these substances, we administered annonacin, the major acetogenin of A. muricata, to rats intravenously with Azlet osmotic minipumps (3.8 and 7.6 mg per kg per day for 28 days). Annonacin inhibited complex I in brain homogenates in a concentration-dependent manner, and, when administered systemically, entered the brain parenchyma, where it was detected by matrix-associated laser desorption ionization-time of flight mass spectrometry, and decreased brain ATP levels by 44%. In the absence of evident systemic toxicity, we observed neuropathological abnormalities in the basal ganglia and brainstem nuclei. Stereological cell counts showed significant loss of dopaminergic neurones in the substantia nigra (-31.7%), and cholinergic (-37.9%) and dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones (-39.3%) in the striatum, accompanied by a significant increase in the number of astrocytes (35.4%) and microglial cells (73.4%). The distribution of the lesions was similar to that in patients with atypical parkinsonism. These data are compatible with the theory that annonaceous acetogenins, such as annonacin, might be implicated in the aetiology of Guadeloupean parkinsonism and support the hypothesis that some forms of parkinsonism might be induced by environmental toxins.

Influencia de mecanismos colinergicos nos processos neurodegenerativos relacionados a formacao de amiloide e a fosforilacao da proteina TAU / Cholinergic mechanisms influence in neurodegenerative process related to amyloid formation and phosphorylation of TAU protein

Na doenca de Alzheimer (DA), os principais eventos associados a neurodegeneracao sao a formacao de placas senis e de emaranhados neurofibrilares. Estes fenomenos relacionam-se respectivamente a deposicao de beta-amiloide (Ab) e a alteracoes do estado de fosforilacao da proteina Tau. Esta e componente essencial dos microtubulos, onde se encontra em estado polimerizado. A estabilidade do polimero depende do grau de fosforilacao da Tau, tornando-se mais instavel quanto mais fosforilada a proteina. Consequentemente, a hiperfosforilacao da Tau relaciona-se com menor estabilidade do citoesqueleto, favorecendo a morte neuronal. O Ab e produzido pela clivagem da proteina precursora do amiloide (APP) por acao da enzima beta-secretase, em detrimento da acao mais fisiologica da alfa-secretase, que da origem ao fragmento APPs. As fibras de Ab tem diversos efeitos neurotoxicos, alem de ocorrerem associadamente a uma presumivel perda funcional do metabolito secretado APPs...