Biological Activities of Lactose-Derived Prebiotics and Symbiotic with Probiotics on Gastrointestinal System.

Lactose-derived prebiotics provide wide ranges of gastrointestinal comforts. In this review article, the probable biochemical mechanisms through which lactose-derived prebiotics offer positive gastrointestinal health are reported along with the up-to-date results of clinical investigations; this might be the first review article of its kind, to the best of our knowledge. Lactose-derived prebiotics have unique biological and functional values, and they are confirmed as 'safe' by the Food and Drug Administration federal agency. Medical practitioners frequently recommend them as therapeutics as a pure form or combined with dairy-based products (yoghurt, milk and infant formulas) or fruit juices. The biological activities of lactose-derived prebiotics are expressed in the presence of gut microflora, mainly probiotics (Lactobacillus spp. in the small intestine and Bifidobacterium spp. in the large intestine). Clinical investigations reveal that galacto-oligosaccharide reduces the risks of several types of diarrhea (traveler's diarrhea, osmotic diarrhea and Clostridium difficile associated relapsing diarrhea). Lactulose and lactosucrose prevent inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Lactulose and lactitol reduce the risk of hepatic encephalopathy. Furthermore, lactulose, galacto-oligosaccharide and lactitol prevent constipation in individuals of all ages. It is expected that the present review article will receive great attention from medical practitioners and food technologists.

Biological Activities of Lactose-Based Prebiotics and Symbiosis with Probiotics on Controlling Osteoporosis, Blood-Lipid and Glucose Levels.

Lactose-based prebiotics are synthesized by enzymatic- or microbial- biotransformation of lactose and have unique functional values. In this comprehensive review article, the biochemical mechanisms of controlling osteoporosis, blood-lipid, and glucose levels by lactose-based prebiotics and symbiosis with probiotics are reported along with the results of clinical investigations. Interaction between lactose-based prebiotics and probiotics reduces osteoporosis by (a) transforming insoluble inorganic salts to soluble and increasing their absorption to gut wall; (b) maintaining and protecting mineral absorption surface in the intestine; (c) increasing the expression of calcium-binding proteins in the gut wall; (d) remodeling osteoclasts and osteoblasts formation; (e) releasing bone modulating factors; and (f) degrading mineral complexing phytic acid. Lactose-based prebiotics with probiotics control lipid level in the bloodstream and tissue by (a) suppressing the expressions of lipogenic- genes and enzymes; (b) oxidizing fatty acids in muscle, liver, and adipose tissue; (c) binding cholesterol with cell membrane of probiotics and subsequent assimilation by probiotics; (d) enzymatic-transformations of bile acids; and (e) converting cholesterol to coprostanol and its defecation. Symbiosis of lactose-based prebiotics with probiotics affect plasma glucose level by (a) increasing the synthesis of gut hormones plasma peptide-YY, glucagon-like peptide-1 and glucagon-like peptide-2 from entero-endocrine L-cells; (b) altering glucose assimilation and metabolism; (c) suppressing systematic inflammation; (d) reducing oxidative stress; and (e) producing amino acids. Clinical investigations show that lactose-based prebiotic galacto-oligosaccharide improves mineral absorption and reduces hyperlipidemia. Another lactose-based prebiotic, lactulose, improves mineral absorption, and reduces hyperlipidemia and hyperglycemia. It is expected that this review article will be of benefit to food technologists and medical practitioners.

Metabolic Syndrome and Biotherapeutic Activity of Dairy (Cow and Buffalo) Milk Proteins and Peptides: Fast Food-Induced Obesity Perspective-A Narrative Review.

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article.

Optimization of Conditions for Microwave-Assisted Extraction of Polyphenols from Olive Pomace of Zutica Variety: Waste Valorization Approach.

Olive pomace is a by-product of olive oil production that is toxic to the environment. The purpose of this study was to evaluate the methods of olive pomace valorization through the implementation of novel technology, the so-called microwave-assisted extraction process. To determine the total polyphenol content (TPC) and antioxidant activity (AA), polyphenol extraction using MAE was performed. Response surface methodology was used to determine the best extraction conditions, whereby the effects of three factors, solid ratio (g/50 mL), time (s), and power (W), were measured. The ferric reducing antioxidant power (FRAP) method was used to assess AA, whereas the spectrophotometric Folin-Ciocalteu (FC) method was used to determine TPC. The highest TPC of 15.30 mg of gallic acid equivalents per gram of dried weight (mg GAE/gdw) was generated after 105 s at 450 W, with a solid concentration of 1 g/50 mL, while the maximum AA was 10 mg of ascorbic acid equivalents per gram of dried weight (mg AAE/gdw). Numerical optimization revealed that 800 W, 180 s, and 1 g/50 mL were the best conditions for obtaining maximum TPC and AA.

The effect of physical stimuli on the expression level of key elements in mitochondrial biogenesis.

Proper mitochondrial function is crucial for intact cellular homeostasis. Mitochondrial dysfunction is clearly involved in the pathogenesis of most neurodegenerative- and age-related chronic disorders. The aim of this study is to stimulate cellular production of important compounds of mitochondrial biogenesis, namely in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)- and Sirtuin (SIRT)-systems. We studied the effect of cold challenge and training on the mRNA expression levels of some compounds of these systems in different brain areas of mice. With regard to the PGC-system, the mRNA levels of the full- and N-truncated isoforms, and those of the two promoters (brain-specific, reference) were measured. In case of Sirtuins, the mRNA levels of SIRT1 and SIRT3-M1/M2/M3 were assessed. We found the following expression level alterations: cooling resulted in the elevation of cortical SIRT3-M1 levels and the decrease of cerebellar SIRT3-M3 levels after 200 min. 900 min of cold exposure resulted in the reduction of cortical SIRT1 and striatal SIRT3-M1 levels. A prominent elevation could be observed in the levels of all PGC-1α isoforms in the cerebellum after 12 days of training. The 12 days of exercise resulted in increased cerebellar SIRT3-M1 and SIRT3-M2 mRNA levels as well. Although the efficacy of cooling core body and brain temperature is questionable, we found that training exerted a clear effect. The cause of the prominent cerebellar elevation of PGC-, and Sirtuin isoforms could be an increase in synaptic plasticity between Purkinje cells, which facilitates better motor coordination and more precise movement integration. We propose that these systems may serve as promising targets for future therapeutic studies in neurodegenerative diseases.

Non-motor Behavioral Alterations of PGC-1α-Deficient Mice - A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression.

Dysfunction of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) has been linked to various neurodegenerative and neuropsychiatric disorders; however, reports on psychic behavioral alterations on PGC-1α-deficient animals are sparse. The present study revisited prior observations of anxiety-related, depression-related, and hippocampal memory-related observations having been made on different PGC-1α-deficient murine strains, in a large-scale analysis on whole-body full-length (FL-)PGC-1α-deficient mice. The examinations were performed on animals covering a wide age range enrolled from both sexes, and included paradigms such as the open-field, elevated plus maze, light-dark box, tail suspension test, and spatial recognition two-trial Y-maze. The findings revealed no signs of previously reported anxiety-like behavior, but revealed an unexpected phenotype with decreased anxiety behavior consistent throughout different paradigms, with slight male preponderance. This was associated with despair-like anhedonic behavior, consistent with that reported previously, but did not associate with either peripheral or brain alterations in kynurenic acid synthesis, which was previously proposed. Though male FL-PGC-1α-deficient mice tended to perform poorer in the hippocampus-based spatial learning paradigm, the genotype overall was not associated with impairment in spatial memory, contradicting with prior observations. None of the observed alterations deteriorated with age, similarly to motor alterations as reported previously. The most likely contributors of this peculiar phenotype are discussed, with clinicopathological correlations drawn. Being the first to address these behavioral domains within the same PGC-1α-deficient strain, our findings extend the knowledge about the complex in vivo effect of PGC-1α dysfunction and add important notes to research in the field of PGC-1α in connection with neuropsychiatric disorders.

Effect of MPTP on mRNA expression of PGC-1α in mouse brain.

The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Besides the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). Achieving neuroprotection via CNS-targeted pharmacological stimulation is limited due to poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option. The current study aimed to examine of how the expression levels of FL-, NT-, CNS- and reference PGC-1α isoforms change in different brain regions following various 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment regimens, including chronic low-dose treatment for preconditioning. Ninety minutes following the acute treatment regimen, the expression levels of FL-, NT- and CNS-PGC-1α isoforms increased significantly in the striatum, cortex and cerebellum. However, this elevation diminished 7days following the last MPTP injection in the acute treatment regimen. The chronic low-dose administration of MPTP, which did not cause significant toxic effects in light of the relatively unaltered dopamine levels, did not result in any significant change of PGC-1α expression. The elevation of PGC-1α levels following acute treatment may demonstrate a short-term compensatory mechanism against mitochondrial damage induced by the complex I inhibitor MPTP. However, drug-induced preconditioning by chronic low-dose MPTP seems not to induce protective responses via the PGC-1α system.

Lack of age-related clinical progression in PGC-1α-deficient mice - implications for mitochondrial encephalopathies.

Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington's disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases.

High-dose 1,25-dihydroxyvitamin D supplementation elongates the lifespan of Huntington's disease transgenic mice.

Huntington's disease is an autosomal dominant progressive neurodegenerative disease, which results in a decreased quality of life and an early death. A high prevalence of vitamin D deficiency was first described in a 2013 study in patients with manifest Huntington's disease, where serum vitamin D level was found to be associated with motor capabilities of the patients. Our objective was to investigate the effect of a high-dose vitamin D3 supplementation on a transgenic mouse model of Huntington's disease. Our study was performed on N171-82Q Huntington's disease transgenic mice in age- and gender-matched groups. We collected data on the motor state and survival of the mice. The results demonstrate that though vitamin D3 had no effect on the motor performance of transgenic mice, but significantly increased the lifespan of transgenic animals (Kaplan-Meier survival curves: vehicle-supplemented group: 73 (67-94) days vs. vitamin D3-supplemented group: 101 (74-109) days, p=0.048 Mantel-Cox log rank test). Further investigations are needed to determine whether a neuroprotective or a general corroborative effect of vitamin D leads to the measured effect. Our findings support the potential influence of vitamin D deficiency on the disease course and propose that vitamin D may be an effective supplementary treatment to beneficially influence clinical features of Huntington's disease.

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease.

Experiments on human samples and on genetic animal models of Huntington's disease (HD) suggest that a number of neuroactive metabolites in the kynurenine (KYN) pathway (KP) of the tryptophan (TRP) catabolism may play a role in the development of HD. Our goal in this study was to assess the concentrations of TRP, KYN, kynurenic acid and 3-hydroxykynurenine (3-OHK) in the serum and brain of 5-month-old C57Bl/6 mice in the widely used 3-nitropropionic acid (3-NP) toxin model of HD. We additionally investigated the behavioral changes through open-field, rotarod and Y-maze tests. Our findings revealed an increased TRP catabolism via the KP as reflected by elevated KYN/TRP ratios in the striatum, hippocampus, cerebellum and brainstem. As regards the other examined metabolites of KP, we found only a significant decrease in the 3-OHK level in the cerebellum of the 3-NP-treated mice. The open-field and rotarod tests demonstrated that treatment with 3-NP resulted in a reduced motor ability, though this had almost totally disappeared a week after the last injection, similarly as observed previously in most murine 3-NP studies. The relevance of the alterations observed in our biochemical and behavioral analyses is discussed. We propose that the identified biochemical alterations could serve as applicable therapeutic endpoints in studies of drug effects on delayed-type neurodegeneration in a relatively fast and cost-effective toxin model of HD.

Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner.

WHAT IS KNOWN: There is an increasing number of studies demonstrating the direct effect of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant on the opioid system. The kappa opioid receptors (KORs) are well known to mediate depression- and anxiety-like behavior. Clinical studies on chronic rimonabant administration have revealed that rimonabant leads to a very similar pathophysiology, suggesting a potential impact of rimonabant on KORs. OBJECTIVES: Our objectives were to examine the putative effects of rimonabant on KOR ligand binding, G-protein activity, protein expression and how all these contribute to the development of depression- and anxiety-like behavior. RESULTS: In Chinese hamster ovary (CHO) cell membranes transfected with rat KOR (CHO-rKOR) rimonabant inhibited KOR agonist [3H]U69593 binding in the micromolar range in competition binding experiments and specifically reduced KOR basal activity at lower micromolar concentrations in [35S]GTPγS binding assays. Rimonabant significantly inhibited dynorphin (1-11)-induced [35S]GTPγS binding in micromolar range in CHO-rKOR cells, CB1 knockout (CB1 K.O.) and CB1/CB2 double knockout mouse forebrain membranes. A single dose of i.p. 0.1 mg/kg rimonabant significantly reduced dynorphin (1-11)-induced KOR G-protein activity and KOR protein expression levels 24 h following the administration in both wild type and CB1 K.O. mice forebrain. Furthermore, in elevated plus maze mice showed an anxiolytic-like effect upon rimonabant injection that could be reversed by 1 mg/kg KOR antagonist norbinaltorphimine. The anxiolytic-like effects were further confirmed with the light­dark box test. CONCLUSION: Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior.