Biology subjects

Tolstikov, V.

Publications and source records attributed to Tolstikov, V..

5 recordsLinked to original sources

bioRxiv2022

Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveal the potential role of ketogenesis to slow tumor growth: A secondary analysis of the CAPS2 diet trial

BackgroundSystemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown. MethodsTo identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT. ResultsLCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate. ConclusionThese results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.

cancer biology↗

bioRxiv2021

Identification and Validation of N-Acetylputrescine in Combination With Non-Canonical Clinical Features As a Parkinsons Disease Biomarker Panel

Parkinsons disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-5% of sporadic Parkinsons patients present with genetic abnormalities, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinsons disease, which highlights the critical need for biomarkers. There could be a significant clinical benefit to treating Parkinsons disease at the earliest stage and identify at-risk populations once disease-modifying treatments are available. In the present study, we prospectively collected and analyzed plasma samples from 201 Parkinsons disease patients and 199 age-matched non-diseased controls. Multiomic and Bayesian artificial intelligence analysis of molecular and clinical data identified the diagnostic utility of N-acetyl putrescine (NAP) in combination with smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements. The clinical and biomarker panel demonstrated an area under the curve, AUC = 0.9, positive predictive value, PPV = 0.91, and negative predictive value, NPV = 0.66 utilizing all four variables. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinsons disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.

neuroscience↗

bioRxiv2020

The effects of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer

Prostate cancer (PC) is the second most lethal cancer for men and metastatic PC is treated by androgen deprivation therapy (ADT). While effective, ADT has many metabolic side effects. Previously, serum metabolome analysis showed that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines while increased serum glucose. Since ADT reduced ketogenesis, we speculate that low-carbohydrate diets (LCD) may reverse many ADT-induced metabolic abnormalities in animals and humans. To test this possibility, we conducted a multi-center trial of PC patients initiating ADT randomized to no diet change (control) or LCD. We previously showed LCD led to significant weight loss, reduced fat mass, improved insulin resistance and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic effects, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD vs. control. We found androsterone sulfate was most consistently reduced by ADT, and was slightly further reduced by LCD. Contrastingly, LCD increased 3-hydroxybutyric acid and various acyl-carnitines, counteracting their reduction during ADT. LCD also reversed the ADT-reduced lactic acid, alanine and S-adenosyl Methionine (SAM), elevating glycolysis metabolites, amino acids and sulfur-containing metabolites. While the degree of ADT-reduced androsterone was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlation. However, many LCD-induced changes were seen at 3-but not 6-month, suggesting metabolic adaption. Together, LCD significantly reversed many ADT-induced metabolic changes while slightly enhancing androgen reduction. Future research is needed to confirm these findings and determine whether LCD can mitigate ADT-linked comorbidities and possibly delaying disease progression by further lowering androgens. Statement of translational relevanceProstate cancer (PC) is the most common non-skin cancer and second leading cause of cancer-related death in men. While androgen deprivation therapy (ADT) is the main treatment for metastatic PC, it has many metabolic side effects. Previous serum metabolome analysis of PC patients receiving ADT identified reduced ketogenesis. Therefore, low-carbohydrate diets (LCD), ketogenic in nature, may reverse many ADT-induced metabolic abnormalities. We conducted a 6-month multi-center trial of no diet change (control) vs. LCD in men initiating ADT. We found that LCD reversed many ADT-induced metabolic abnormalities while slightly further reducing androgen levels. Also, LCD disrupted the diabetogenic effects of ADT, but some effects seen at 3-month were lost at 6-month, suggesting metabolic adaptation to LCD. These data suggest the potential metabolic benefits of LCD with potential to enhance ADT efficacy. Larger studies testing whether LCDs mitigate metabolic side effects and slow disease progression are warranted given acceptable safety profiles, metabolic benefits, and possibly lowered androgens.

cancer biology↗

bioRxiv2020

Children Developing Celiac Disease Have a Distinct and Proinflammatory Gut Microbiota in the First 5 Years of Life

Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. To identify the role of gut microbes in CD onset, we performed a longitudinal study focusing on two important phases of gut microbiota development at ages 2.5 and 5 (n=16). We obtained samples from children who developed CD during or after the study (CD progressors) and age, sex, and HLA-matched healthy controls. CD progressors had a distinct gut microbiota composition and IgA-sequencing identified unique IgA targets in the gut. Three cytokines, one chemokine, and 19 plasma metabolites were significantly altered in CD progressors at age 5. Feeding C57BL/6J mice with taurodeoxycholic acid (TDCA), a 2-fold increased microbiota-derived metabolite in CD progressors, caused villous atrophy, increased intraepithelial lymphocytes (IELs), CD4+ T-cells, Natural Killer cells, and Qa-1 expression on T-cells while decreasing T-regulatory cells in IELs. Thus, TDCA drives inflammation in the small intestines that potentially contribute to the CD onset. HighlightsO_LICD progressors have a distinct gut microbiome composition compared to healthy controls in two important phases of gut microbiota development (age 2.5 and 5 years) C_LIO_LICD progressors have more IgA-coated bacteria in their gut at age 5 compared to healthy controls. Further, IgA-sequencing identified unique bacterial targets in CD progressors. C_LIO_LIThree plasma proinflammatory cytokines and a chemokine were increased in CD progressors years before diagnosis, indicating an early inflammatory response. C_LIO_LIWe identified 19 metabolites that are significantly altered in CD progress at age 5 and microbiota-derived TDCA increased two-fold. C_LIO_LITDCA treatment in B6 mice increased CD4+ cells and NK cells while decreasing CD8+ T-regulatory (Treg) cells. It also increased Qa-1 expression on immune cells. C_LI

microbiology↗

bioRxiv2018

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within the periphery and limbic brain regions contribute to depression symptomatology. Here, we utilized a mouse chronic stress model of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and prefrontal cortex) of susceptible, resilient, and unstressed control mice. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed pathway dysfunctions of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated MDD-like behaviors and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.

neuroscience↗