Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.     

The Calcium-Dependent Protein Kinase TaCDPK27 Positively Regulates Salt Tolerance in Wheat

As essential calcium ion (Ca²⁺) sensors in plants, calcium-dependent protein kinases (CDPKs) function in regulating the environmental adaptation of plants. However, the response mechanism of CDPKs to salt stress is not well understood. In the current study, the wheat salt-responsive gene TaCDPK27 was identified. The open reading frame (ORF) of TaCDPK27 was 1875 bp, coding 624 amino acids. The predicted molecular weight and isoelectric point were 68.905 kDa and 5.6, respectively. TaCDPK27 has the closest relationship with subgroup III members of the CDPK family of rice. Increased expression of TaCDPK27 in wheat seedling roots and leaves was triggered by 150 mM NaCl treatment. TaCDPK27 was mainly located in the cytoplasm. After NaCl treatment, some of this protein was transferred to the membrane. The inhibitory effect of TaCDPK27 silencing on the growth of wheat seedlings was slight. After exposure to 150 mM NaCl for 6 days, the NaCl stress tolerance of TaCDPK27-silenced wheat seedlings was reduced, with shorter lengths of both roots and leaves compared with those of the control seedlings. Moreover, silencing of TaCDPK27 further promoted the generation of reactive oxygen species (ROS); reduced the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT); aggravated the injury to photosystem II (PS II); and increased programmed cell death (PCD) in wheat leaves under NaCl treatment, confirming that the TaCDPK27-silenced seedlings exhibited more NaCl injury than control seedlings. Taken together, the decrease in NaCl tolerance in TaCDPK27-silenced seedlings was due to excessive ROS accumulation and subsequent aggravation of the NaCl-induced PCD. TaCDPK27 may be essential for positively regulating salt tolerance in wheat seedlings.     

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.     

Genome-Wide Analysis of the Peptidase M24 Superfamily in Triticum aestivum Demonstrates That TaM24-9 Is Involved in Abiotic Stress Response

The peptidase M24 (Metallopeptidase 24, M24) superfamily is essential for plant growth, stress response, and pathogen defense. At present, there are few systematic reports on the identification and classification of members of the peptidase M24 proteins superfamily in wheat. In this work, we identified 53 putative candidate TaM24 genes. According to the protein sequences characteristics, these members can be roughly divided into three subfamilies: I, II, III. Most TaM24 genes are complex with multiple exons, and the motifs are relatively conserved in each sub-group. Through chromosome mapping analysis, we found that the 53 genes were unevenly distributed on 19 wheat chromosomes (except 3A and 3D), of which 68% were in triads. Analysis of gene duplication events showed that 62% of TaM24 genes in wheat came from fragment duplication events, and there were no tandem duplication events to amplify genes. Analysis of the promoter sequences of TaM24 genes revealed that cis-acting elements were rich in response elements to drought, osmotic stress, ABA, and MeJA. We also studied the expression of TaM24 in wheat tissues at developmental stages and abiotic stress. Then we selected TaM24-9 as the target for further analysis. The results showed that TaM24-9 genes strengthened the drought and salt tolerance of plants. Overall, our analysis showed that members of the peptidase M24 genes may participate in the abiotic stress response and provided potential gene resources for improving wheat resistance.     

Pivotal Role of Phytohormones and Their Responsive Genes in Plant Growth and Their Signaling and Transduction Pathway under Salt Stress in Cotton

The presence of phyto-hormones in plants at relatively low concentrations plays an indispensable role in regulating crop growth and yield. Salt stress is one of the major abiotic stresses limiting cotton production. It has been reported that exogenous phyto-hormones are involved in various plant defense systems against salt stress. Recently, different studies revealed the pivotal performance of hormones in regulating cotton growth and yield. However, a comprehensive understanding of these exogenous hormones, which regulate cotton growth and yield under salt stress, is lacking. In this review, we focused on new advances in elucidating the roles of exogenous hormones (gibberellin (GA) and salicylic acid (SA)) and their signaling and transduction pathways and the cross-talk between GA and SA in regulating crop growth and development under salt stress. In this review, we not only focused on the role of phyto-hormones but also identified the roles of GA and SA responsive genes to salt stress. Our aim is to provide a comprehensive review of the performance of GA and SA and their responsive genes under salt stress, assisting in the further elucidation of the mechanism that plant hormones use to regulate growth and yield under salt stress.     

Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO₂), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn²⁺) and oxidative stress (known as the “ROS hypothesis”) have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn²⁺ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn²⁺, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn²⁺ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH.     

GANAB and N-Glycans Substrates Are Relevant in Human Physiology,Polycystic Pathology and Multiple Sclerosis: A Review

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc₃Man₉GlcNAc₂ highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.     

Melatonin and the Brain–Heart Crosstalk in Neurocritically Ill Patients—From Molecular Action to Clinical Practice

Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain–heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.     

Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.     

The E3 Ligase GmPUB21 Negatively Regulates Drought and Salinity Stress Response in Soybean

E3-ubiquitin ligases are known to confer abiotic stress responses in plants. In the present study, GmPUB21, a novel U-box E3-ubiquitin ligase-encoding gene, was isolated from soybean and functionally characterized. The expression of GmPUB21, which possesses E3-ubiquitin ligase activity, was found to be significantly up-regulated by drought, salinity, and ABA treatments. The fusion protein GmPUB21-GFP was localized in the cytoplasm, nucleus, and plasma membrane. Transgenic lines of the Nicotiana benthamiana over-expressing GmPUB21 showed more sensitive to osmotic, salinity stress and ABA in seed germination and inhibited mannitol/NaCl-mediated stomatal closure. Moreover, higher reactive oxygen species accumulation was observed in GmPUB21 overexpressing plants after drought and salinity treatment than in wild-type (WT) plants. Contrarily, silencing of GmPUB21 in soybean plants significantly enhanced the tolerance to drought and salinity stresses. Collectively, our results revealed that GmPUB21 negatively regulates the drought and salinity tolerance by increasing the stomatal density and aperture via the ABA signaling pathway. These findings improved our understanding of the role of GmPUB21 under drought and salinity stresses in soybean.