Modulation Of Protein Levels Research Articles

Silibinin promotes healing in spinal cord injury through anti-ferroptotic mechanisms.

Pre-clinical animal experiment. In this study, we investigated therapeutic effects of silibinin in a spinal cord injury (SCI) model. In SCI, loss of cells due to secondary damage mechanisms exceeds that caused by primary damage. Ferroptosis, which is iron-dependent non-apoptotic cell death, is shown to be influential in the pathogenesis of SCI. The study was conducted as an in vivo experiment using a total of 78 adult male/female Sprague Dawley rats. Groups were as follows: Sham, SCI, deferoxamine (DFO) treatment, and silibinin treatment. There were subgroups with follow-up periods of 24 h, 72 h, and 6 weeks in all groups. Malondialdehyde (MDA), glutathione (GSH), and Fe2+ levels were measured by spectrophotometry. Glutathione peroxidase-4 (GPX4), ferroportin (FPN), transferrin receptor (TfR1), and 4-hydroxynonenal (4-HNE)-modified protein levels were assessed by Western blotting. Functional recovery was assessed using Basso-Beattie-Bresnahan test. Silibinin achieved significant suppression in MDA and 4-HNE levels compared to the SCI both in 72-h and 6 weeks group (p < 0.05). GSH, GPX4, and FNP levels were found to be significantly higher in the silibinin 24 h, 72 h, and 6 weeks group compared to corresponding SCI groups (p < 0.05). Significant reduction in iron levels was observed in silibinin treated rats in 72 h and 6 weeks group (p < 0.05). Silibinin substantially suppressed TfR1 levels in 24 h and 72 h groups (p < 0.05). Significant difference among recovery capacities was observed as follows: Silibinin > DFO > SCI (p < 0.05). Impact of silibinin on iron metabolism and lipid peroxidation, both of which are features of ferroptosis, may contribute to therapeutic activity. Within this context, our findings posit silibinin as a potential therapeutic candidate possessing antiferroptotic properties in SCI model. Therapeutic agents capable of effectively and safely mitigating ferroptotic cell death hold the potential to be critical points of future clinical investigations.

A multilevel investigation to reveal the regulatory mechanism of lignin accumulation in juice sac granulation of pomelo

Granulation of juice sacs is a physiological disorder, which affects pomelo fruit quality. Here, the transcriptome and ubiquitinome of the granulated juice sacs were analyzed in Guanxi pomelo. We found that lignin accumulation in the granulated juice sacs was regulated at transcription and protein modification levels. In transcriptome data, we found that the genes in lignin biosynthesis pathway and antioxidant enzyme system of the granulated juice sacs were significantly upregulated. However, in ubiquitinome data, we found that ubiquitinated antioxidant enzymes increased in abundance but the enzyme activities decreased after the modification, which gave rise to reactive oxygen species (ROS) contents in granulated juice sacs. This finding suggests that ubiquitination level of the antioxidant enzymes is negatively correlated with the enzyme activities. Increased H2O2 is considered to be a signaling molecule to activate the key gene expressions in lignin biosynthesis pathway, which leads to the lignification in granulated juice sacs of pomelo. This regulatory mechanism in juice sac granulation of pomelo was further confirmed through the verification experiment using tissue culture by adding H2O2 or dimethylthiourea (DMTU). Our findings suggest that scavenging H2O2 and other ROS are important for reducing lignin accumulation, alleviating juice sac granulation and improving pomelo fruit quality.

C-di-AMP determines the hierarchical organization of bacterial RCK proteins

In bacteria, intracellular K+ is involved in the regulation of membrane potential, cytosolic pH, and cell turgor as well as in spore germination, environmental adaptation, cell-to-cell communication in biofilms, antibiotic sensitivity, and infectivity. The second messenger cyclic-di-AMP (c-di-AMP) has a central role in modulating the intracellular K+ concentration in many bacterial species, controlling transcription and function of K+ channels and transporters. However, our understanding of how this regulatory network responds to c-di-AMP remains poor. We used the RCK (Regulator of Conductance of K+) proteins that control the activity of Ktr channels in Bacillus subtilis as a model system to analyze the regulatory function of c-di-AMP with a combination of in vivo and in vitro functional and structural characterization. We determined that the two RCK proteins (KtrA and KtrC) are neither physiologically redundant or functionally equivalent. KtrC is the physiologically dominant RCK protein in the regulation of Ktr channel activity. In explaining this hierarchical organization, we found that, unlike KtrA, KtrC is very sensitive to c-di-AMP inactivation and lack of c-di-AMP regulation results in RCK protein toxicity, most likely due to unregulated K+ flux. We also found that KtrC can assemble with KtrA, conferring c-di-AMP regulation to the functional KtrA/KtrC heteromers and potentially compensating KtrA toxicity. Altogether, we propose that the central role of c-di-AMP in the control of the K+ machinery, by modulating protein levels through gene transcription and by regulating protein activity, has determined the evolutionary selection of KtrC as the dominant RCK protein, shaping the hierarchical organization of regulatory components of the K+ machinery.

Dysregulation and antimetastatic function of circLRIG1 modulated by miR-214-3p/LRIG1 axis in bladder carcinoma

CircLRIG1, a newly discovered circRNA, has yet to have its potential function and biological processes reported. This study explored the role of circLRIG1 in the development and progression of bladder carcinoma and its potential molecular mechanisms. Techniques such as qRT-PCR, Western blot, various cellular assays, and in vivo models were used to investigate mRNA and protein levels, cell behavior, molecular interactions, and tumor growth. The results showed that both circLRIG1 and LRIG1 were significantly reduced in bladder carcinoma tissues and cell lines. Low circLRIG1 expression was associated with poor patient prognosis. Overexpressing circLRIG1 inhibited bladder carcinoma cell growth, migration, and invasion, promoted apoptosis, and decreased tumor growth and metastasis in vivo. Importantly, circLRIG1 was found to sponge miR-214-3p, enhancing LRIG1 expression, and its overexpression also modulated protein levels of E-cadherin, N-cadherin, Vimentin, and LRIG1. Similar effects were observed with LRIG1 overexpression. Notably, a positive correlation was found between circLRIG1 and LRIG1 expression in bladder carcinoma tissues. Additionally, the tumor-suppressing effect of circLRIG1 was reversed by overexpressing miR-214-3p or silencing LRIG1. The study concludes that circLRIG1 suppresses bladder carcinoma progression by enhancing LRIG1 expression via sponging miR-214-3p, providing a potential strategy for early diagnosis and treatment of bladder carcinoma.

A chemical magnet: Approaches to guide precise protein localization

Small molecules that chemically induce proximity between two proteins have been widely used to precisely modulate protein levels, stability, and activity. Recently, several studies developed novel strategies that employ heterobifunctional molecules that co-opt shuttling proteins to control the spatial localization of a target protein, unlocking new potential within this domain. Together, these studies lay the groundwork for novel targeted protein relocalization modalities that can rewire the protein circuitry and interactome to influence biological outcomes.

Effect of Herniarin on Cell Viability, Cell Cycle, and Erk Protein Levels in Different Stages of Bladder Cancer Cells.

This study examines the potential of herniarin from tarragon, as an agent with multifaceted effects on bladder cancer cells and investigates herniarin's impact on cell viability, migration, cell cycle regulation, apoptosis induction, and Erk signaling pathways in bladder cancer cell lines, including RT-112 (grade 1, non-invasive), HTB9 (grade 2, invasive), and HT1376 (grade 3, invasive), through comprehensive in vitro experiments. The compound causes cell cycle arrest at distinct phases in different cell lines: G1/S arrest in RT112 cells, G2/M arrest in HTB9 cells, and S phase arrest in HT1376 cells. Furthermore, herniarin induces caspase-mediated apoptosis in various cell lines and simultaneously modulates protein levels of apoptotic and anti-apoptotic proteins, indicating its potential as a therapeutic agent. Herniarin's influence also extends to Erk signaling, a crucial pathway that regulates cell growth and differentiation. In conclusion, this study reveals herniarin's potential as a versatile agent in the treatment of bladder cancer.

High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries.

Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.

Assessment of oxidative stress and protein modification in essential hypertensive subjects

&#x0D; &#x0D; Hypertension has been identified to be the leading cause of cardiovascular disease and premature death worldwide due to its numerous comorbidities and associated risk of damage to vital body organs like the brain, heart and kidneys. The aim of this study was to determine the level of protein modifications and oxidative stress of hypertensive patients. One hundred and fourteen (114) participants were recruited for this study comprising 81 subjects with essential hypertension and 33 control (non- hypertensive) subjects. Body Mass Index (BMI) was calculated, systolic and diastolic blood pressure(SBP and DBP) readings were taken using digital sphygmomanometer, glutathione peroxidase (GPx) and carbonyl (CO) group was estimated using ELISA, while protein sulfhydryl (SH) group was estimated using colorimetric assay. The results obtained showed that BMI of treated hypertensive patients was significantly decreased (p&lt;0.0001) compared with control. Systolic and diastolic blood pressure was significantly increased when treated patients were compared with control (p&lt;0.0001). GPx and SH groups of treated hypertensive patients was significantly increased (p&lt;0.0001) in treated hypertensive patients as compared to control. The study concludes that protein modification occurs as a result of oxidative stress resulting in reduced levels of glutathione peroxidase which could be a risk factor associated with the development of essential hypertension These findings could help in designing quality diagnostic strategies and effective treatment and management approach for better clinical outcomes.

Controlling protein stability with SULI, a highly sensitive tag for stabilization upon light induction

Optogenetics tools for precise temporal and spatial control of protein abundance are valuable in studying diverse complex biological processes. In the present study, we engineer a monomeric tag of stabilization upon light induction (SULI) for yeast and zebrafish based on a single light-oxygen-voltage domain from Neurospora crassa. Proteins of interest fused with SULI are stable upon light illumination but are readily degraded after transfer to dark conditions. SULI shows a high dynamic range and a high tolerance to fusion at different positions of the target protein. Further studies reveal that SULI-mediated degradation occurs through a lysine ubiquitination-independent proteasome pathway. We demonstrate the usefulness of SULI in controlling the cell cycle in yeast and regulating protein stability in zebrafish, respectively. Overall, our data indicate that SULI is a simple and robust tool to quantitatively and spatiotemporally modulate protein levels for biotechnological or biomedical applications.

Ubiquitin‐dependent regulation of MYC: A promising therapeutic target

Ubiquitin‐dependent regulation of MYC: A promising therapeutic target

E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology.

Ubiquitination is a key post-translational modification of proteins, affecting the regulation of multiple cellular processes. Cells are equipped with over 600 ubiquitin orchestrators, called E3 ubiquitin ligases, responsible for directing the covalent attachment of ubiquitin to substrate proteins. Due to their regulatory role in cells, significant efforts have been made to discover ligands for E3 ligases. The recent emergence of the proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) modalities has further increased interest in E3 ligases as drug targets. This perspective focuses on how fragment based lead discovery (FBLD) methods have been used to discover new ligands for this important target class. In some cases these efforts have led to clinical candidates; in others, they have provided tools for deepening our understanding of E3 ligase biology. Recently, FBLD-derived ligands have inspired the design of PROTACs that are able to artificially modulate protein levels in cells.

Specific alterations in riboproteomes composition of isonicotinic acid treated arabidopsis seedlings

Plants have developed strategies to deal with the great variety of challenges they are exposed to. Among them, common targets are the regulation of transcription and translation to finely modulate protein levels during both biotic and abiotic stresses. Increasing evidence suggests that ribosomes are highly adaptable modular supramolecular structures which remodel to adapt to stresses. Each Arabidopsis thaliana ribosome consists of approximately 81 distinct ribosomal proteins (RPs), each of which is encoded by two to seven genes. To investigate the identity of ribosomal proteins of the small subunit (RPS) and of the large subunit (RPL) as well as ribosomes-associated proteins, we analysed by LC/MS/MS immunopurified ribosomes from A. thaliana leaves treated with isonicotinic acid (INA), an inducer of plant innate immunity. We quantified a total of 2084 proteins. 165 ribosome-associated proteins showed increased abundance while 52 were less abundant. Of the 52 identified RPS (from a possibility of 104 encoding genes), 15 were deregulated. Similarly, from the 148 possible RPL, 80 were detected and 9 were deregulated. Our results revealed potential candidates involved in innate immunity that could be interesting targets for functional genomic studies.

Proteolysis Targeting Chimeras (PROTACs): A Perspective on Integral Membrane Protein Degradation.

Targeted protein degradation (TPD) is a promising therapeutic modality to modulate protein levels and its application promises to reduce the "undruggable" proteome. Among TPD strategies, Proteolysis TArgeting Chimera (PROTAC) technology has shown a tremendous potential with attractive advantages when compared to the inhibition of the same target. While PROTAC technology has had a significant impact in scientific research, its application to degrade integral membrane proteins (IMPs) is still in its beginnings. Among the 15 compounds having entered clinical trials by the end of 2021, only two targets are membrane-associated proteins. In this review we are discussing the potential reasons which may underlie this, and we are presenting new tools that have been recently developed to solve these limitations and to empower the use of PROTACs to target IMPs.

MicroRNA Expression Levels Change in Neonatal Patients During and After Exposure to Cardiopulmonary Bypass.

BackgroundThe systemic inflammation that occurs after exposure to cardiopulmonary bypass (CPB), which is especially severe in neonatal patients, is associated with poorer outcomes and is not well understood. In order to gain deeper insight into how exposure to bypass activates inflammatory responses in circulating leukocytes, we studied changes in microRNA (miRNA) expression during and after exposure to bypass. miRNAs are small noncoding RNAs that have important roles in modulating protein levels and function of cells.Methods and ResultsWe performed miRNA‐sequencing on leukocytes isolated from neonatal patients with CPB (n=5) at 7 time points during the process of CPB, including before the initiation of bypass, during bypass, and at 3 time points during the first 24 hours after weaning from bypass. We identified significant differentially expressed miRNAs using generalized linear regression models, and miRNAs were defined as statistically significant using a false discovery rate–adjusted P<0.05. We identified gene targets of these miRNAs using the TargetScan database and identified significantly enriched biological pathways for these gene targets. We identified 54 miRNAs with differential expression during and after CPB. These miRNAs clustered into 3 groups, including miRNAs that were increased during and after CPB (3 miRNAs), miRNAs that decreased during and after CPB (10 miRNAs), and miRNAs that decreased during CPB but then increased 8 to 24 hours after CPB. A total of 38.9% of the target genes of these miRNAs were significantly differentially expressed in our previous study. miRNAs with altered expression levels are predicted to significantly modulate pathways related to inflammation and signal transduction.ConclusionsThe unbiased profiling of the miRNA changes that occur in the circulating leukocytes of patients with bypass provides deeper insight into the mechanisms that underpin the systemic inflammatory response that occurs in patients after exposure to CPB. These data will help the development of novel treatments and biomarkers for bypass‐associated inflammation.

Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris.

The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.

Sulforaphane enhances Nrf2-mediated antioxidant responses of skeletal muscle induced by exhaustive exercise in HIIT mice

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is the master regulator of antioxidant defenses. High-intensity interval training (HIIT) has been proposed as a time-efficient training program and has become a substantial component of modern training program. In the present study, we evaluated the effects of sulforaphane (SFN), a dietary isothiocyanate derived from cruciferous vegetables and a potent Nrf2 activator, on Nrf2-mediated antioxidant defense responses of skeletal muscle induced by exhaustive exercise in HIIT mice. Male C57BL/6J mice were randomly allocated into control group, HIIT group, and HIIT pretreated with SFN (HIIT+SFN) group. On the third day after completion of a 6-weeks HIIT protocol, an exhaustive treadmill test was conducted in all mice. Mice were intraperitoneally injected with SFN (HIIT+SFN group) or PBS (HIIT and control mice) 4 times in 3 days prior to the exhaustive treadmill test. The results indicated that the 6-weeks HIIT protocol did not increase the antioxidative capacity of skeletal muscle during exhaustive exercise. Importantly, SFN treatment improved antioxidative capacity of skeletal muscle in response to the acute exhaustive exercise by increasing mRNA and nucleoprotein expression of Nrf2 and these genes involved in antioxidant generation and decreasing blood creatine kinase (CK) and 4-hydroxy-2-nonenal (4-HNE)-modified protein levels in the HIIT mice.

Decoupling the Transcriptional and Translational Roles of Core Binding Factor Beta to Identify Novel Therapeutic Targets in Osteosarcoma

Core binding factor beta (CBFβ) functions as a binding partner to the RUNX family of DNA binding transcription factors (RUNX1‐3) and acts as a transcriptional co‐activator by allosterically increasing their DNA binding. According to The Cancer Genome Atlas Program (TCGA) and Genotype‐Tissue Expression (GTEx) datasets, high CBFβ expression is correlated with poor disease‐free and overall survival across 17 cancer types, including sarcomas. Of particular interest to osteosarcoma (OS) research is the interaction of CBFβ with RUNX2, the master regulator of bone growth and differentiation, also dysregulated in aggressive OS and implicated in chemoresistance. Recent research supports a non‐canonical role of CBFβ as a regulator of protein translation initiation. In breast cancer cells, this translation‐associated activity occurs via interactions with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and allows CBFβ to influence translation of hundreds of mRNA transcripts. Binding of CBFβ to hnRNPK or RUNX1 appears mutually exclusive, suggesting possible competition between these two roles.We hypothesized that CBFβ plays a role in the translation of RUNX2 and RUNX2‐target gene mRNAs in OS and that disruption of this role may result in an antitumor effect. The intertwined nature of the two roles of CBFβ hampers study of each in OS. Thus, we aimed to decouple them to identify which presents the most viable therapeutic target in OS.Using CRISPR/Cas9 we generated a CBFβ knockout (KO) U2OS cell line and evaluated RUNX2 protein and mRNA levels via western blot (WB) and qRT‐PCR, respectively. Cycloheximide chase assay and proteasome inhibition were used to evaluate RUNX2 stability and degradation, respectively. Interactions between CBFβ and RUNX2 or hnRNPK were assessed via co‐immunoprecipitation. Site‐directed mutagenesis (SDM) of CBFβ and transfection of U2OS CBFβ KO cells with FLAG tagged CBFβ mutants was used to prevent RUNX2‐CBFβ interaction. WB was used to evaluate changes in subcellular CBFβ localization. Global, as well as protein‐specific, changes in de novo protein synthesis were evaluated using the Click‐IT system. Finally, in silico modeling was used to design a peptide that mimics a 10 amino acid sequence on RUNX2 in the CBFβ binding interface, which was then evaluated in vitro using a recombinant RUNX2‐CBFβ pulldown assay.Our results demonstrate that loss of CBFβ leads to reduced RUNX2 protein expression without changes in RUNX2 mRNA levels. RUNX2 protein half‐life is not reduced in CBFβ nor does proteasome inhibition rescue RUNX2 protein levels. CBFβ interacts with hnRNPK in OS cells, and through this binding may perform a role in oncoprotein translation in OS, specifically modulating protein levels of RUNX2. SDM of CBFβ identified important residues for RUNX2 binding, which when targeted via a peptide resulted in a nearly 50% reduction in CBFβ and RUNX2 interaction. Ribosome footprinting combined with RNAseq and immunoprecipitation‐mass spectrometry utilizing WT U2OS, CBFβ mutants and peptide‐inhibited cells will provide further information on the translational role of CBFβ and potential therapeutic targets in OS.

Differential effects of 5-fluorouracil and oxaliplatin on autophagy in chemoresistant colorectal cancer cells.

Macroautophagy (hereafter autophagy) is one of the adaptive pathways that contribute to cancer cell chemoresistance. Despite the fact that autophagy can both promote and inhibit cell death, there is mounting evidence that in the context of anticancer treatment, it predominantly functions as a cell survival mechanism. Therefore, silencing of key autophagy genes emerges as a potent strategy to reduce chemoresistance. Though the importance of autophagy in chemoresistance is established, the changes in autophagy in the case of acquired chemoresistance are poorly understood. In this study, we aimed to determine the changes of autophagy in the cellular model of acquired chemoresistance of colorectal cancer cell lines HCT116 and SW620, induced by 5-fluorouracil (5-FU) or oxaliplatin (OxaPt) treatment, and determine the susceptible factors for autophagy inhibition. Our results demonstrate that in the context of autophagy, 5-FU and OxaPt have different effects on HCT116 and SW620 cell lines and their chemoresistant sublines. 5-FU inhibits autophagic flux, while changes in the flux after OxaPt treatment are cell type- and dose-dependent, inducing autophagy reduction or increase. The chemoresistant subline of HCT116 cells derived by OxaPt differs from the subline derived by 5-FU treatment - it responds to OxaPt by upregulating ATG7 protein level and autophagic flux, in contrast to downregulation in cells derived by 5-FU. Moreover, 5-FU and OxaPt treatments significantly modulate protein levels of core-autophagy proteins ATG7 and ATG12. The potential effects of 5-FU and OxaPt on ATG protein levels should be taken into account to reduce chemoresistance by applying small interferingRNAs, targeting ATG proteins.

α-Lipoic Acid, an Organosulfur Biomolecule a Novel Therapeutic Agent for Neurodegenerative Disorders: An Mechanistic Perspective

Lipoic acid (α-LA) (1,2-dithiolane3-pentanoic acid (C8H14O2S2) is also called thioctic acid with an oxidized (disulfide, LA) and a reduced (di-thiol: dihydro-lipoic acid, DHLA) form of LA. α-LA is a potent anti-oxidative agent that has a significant potential to treat neurodegenerative disorders. α-LA is both hydrophilic and hydrophobic in nature. It is widely distributed in plants and animals in cellular membranes and in the cytosol, which is responsible for LA's action in both the cytosol and plasma membrane. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the α-Lipoic acid for central nervous system diseases. Moreover, α-LA readily crosses the blood-brain barrier, which is a significant factor for CNS activities. The mechanisms of α-LA reduction are highly tissue-specific. α-LA produces its neuroprotective effect by inhibiting reactive oxygen species formation and neuronal damage, modulating protein levels, and promoting neurotransmitters and anti-oxidant levels. Hence, the execution of α-LA as a therapeutic ingredient in the therapy of neurodegenerative disorders is promising. Finally, based on evidence, it can be concluded that α-LA can prevent diseases related to the nervous system.

Probing the cumulative effects of unit operations and lactose to whey protein ratios on protein modifications in powdered model infant formula

The impact of lactose to whey protein ratio on processed-induced protein modifications was investigated in powdered model infant formula. Model samples were prepared with different lactose to whey protein ratios and different total protein concentrations; protein modifications were evaluated before, during and after processing. Lab-scale equipment was used to mimic commercial manufacturing, and a powdered young-child formula was included to elucidate cumulative effects of commercial unit operations. Maillard-related and structural protein modifications were affected differently by unit operations, both in model samples and commercial formula. Maillard reaction products (furosine, α-dicarbonyls and advanced glycation end products) increased with increased lactose content of model samples, whereas absence of lactose facilitated formation of disulphide-linked aggregates, lysinoalanine and lanthionine. The lowest level of protein modifications was observed at a 30:70 lactose to whey protein ratio, suggesting partial dry blending of lactose as a feasible approach to improve protein quality in powdered infant formula.