BACKGROUND AND OBJECTIVE: The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy. METHODS: Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data. KEY FINDINGS AND LIMITATIONS: Twenty-five patients (54%) had a response (
- Publication type
- Journal Article MeSH
The viscoelastic properties of biological membranes are crucial in controlling cellular functions and are determined primarily by the lipids' composition and structure. This work studies these properties by varying the structure of the constituting lipids in order to influence their interaction with high-density lipoprotein (HDL) particles. Various fluorescence-based techniques were applied to study lipid domains, membrane order, and the overall lateral as well as the molecule-internal glycerol region mobility in HDL-membrane interactions (i.e., binding and/or cargo transfer). The analysis of interactions with HDL particles and various lipid phases revealed that both fully fluid and some gel-phase lipids preferentially interact with HDL particles, although differences were observed in protein binding and cargo exchange. Both interactions were reduced with ordered lipid mixtures containing cholesterol. To investigate the mechanism, membranes were prepared from single-lipid components, enabling step-by-step modification of the lipid building blocks. On a biophysical level, the different mixtures displayed varying stiffness, fluidity, and hydrogen bond network changes. Increased glycerol mobility and a strengthened hydrogen bond network enhanced anchoring interactions, while fluid membranes with a reduced water network facilitated cargo transfer. In summary, the data indicate that different lipid classes are involved depending on the type of interaction, whether anchoring or cargo transfer.
- Publication type
- Journal Article MeSH
Immersive Virtual Reality (iVR) presents a promising avenue for treating acrophobia through Virtual Reality Exposure Therapy (VRET). This paper explores the current state of VRET for acrophobia, identifying significant technological and practical barriers that limit its effectiveness and hinder widespread adoption. Key challenges include the need for more advanced and realistic user experiences, and for the integration of biofeedback mechanisms. Additionally, the role of therapists remains crucial, as therapist-led VRET sessions demonstrate better outcomes compared to automated interventions. The potential of Collaborative Immersive Virtual Environments (CIVEs) to enhance VRET by simulating real-life interactions and improving patient-therapist engagement is also discussed. Future research should focus on developing comprehensive guidelines for CIVE design and evaluating integrated VRET and CIVE systems for treating phobias, including acrophobia. Addressing these issues will enhance the therapeutic experience, making VRET a more effective and accessible tool for treating acrophobia.
- Publication type
- Journal Article MeSH
Colorectal cancer is influenced by genetic mutations, lifestyle factors, and diet, particularly high fat intake, which raises bile acid levels in the intestinal lumen. This study hypothesized that bile acids contribute to tumorigenesis by disrupting ion transport and ATPase activity in the intestinal mucosa. The effects of 3-sulfo-taurolithocholic acid (TLC-S) on ATPase activity were investigated in colorectal cancer samples from 10 patients, using adjacent healthy tissue as controls, and in rodent liver function. ATPase activity was measured spectrophotometrically by determining inorganic phosphorus (Pi) in postmitochondrial fractions. Ca2+ dynamics were assessed in isolated mouse hepatocytes with fluorescence imaging, and rat liver mitochondria were studied using polarographic methods to evaluate respiration and oxidative phosphorylation. TLC-S increased Na+/K+ ATPase activity by 1.5 times in colorectal cancer samples compared to controls (p ≤ 0.05). In healthy mucosa, TLC-S decreased Mg2+ ATPase activity by 3.6 times (p ≤ 0.05), while Mg2+ ATPase activity in cancer tissue remained unchanged. TLC-S had no significant effect on Ca2+ ATPase activity in healthy colon mucosa but showed a trend toward decreased activity in cancer tissue. In rat liver, TLC-S decreased Ca2+ ATPase and Na+/K+ ATPase activities while increasing basal Mg2+ ATPase activity (p ≤ 0.05). Additionally, TLC-S induced cytosolic Ca2+ signals in mouse hepatocytes, partially attenuated by NED-19, an NAADP antagonist (p ≤ 0.05). TLC-S also reduced the V3 respiration rate of isolated rat liver mitochondria during α-ketoglutarate oxidation. These findings suggest that TLC-S modulates ATPase activity differently in cancerous and healthy colon tissues, playing a role in colorectal cancer development. In rat liver, TLC-S affects mitochondrial activity and ATPase function, contributing to altered cytosolic calcium levels, providing insight into the mechanistic effects of bile acids on colorectal cancer and liver function.
- Publication type
- Journal Article MeSH
Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.
- MeSH
- Guanylyl Cyclase C Agonists therapeutic use pharmacology MeSH
- Enzyme Activators therapeutic use pharmacology MeSH
- Antihypertensive Agents * therapeutic use pharmacology MeSH
- Cyclic GMP * metabolism MeSH
- Hypertension * drug therapy physiopathology MeSH
- Humans MeSH
- Nitric Oxide metabolism MeSH
- Soluble Guanylyl Cyclase * metabolism MeSH
- Signal Transduction drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The antioxidant activity of Scorzonera parviflora Jacq. roots were assessed by measuring their ability to scavenge ABTS and DPPH radicals. Bioactivity-guided fractionation was utilized to identify the compound(s) responsible for this activity. The most active phase, ethyl acetate, was isolated using column chromatography. The resulting fractions were then purified using preparative TLC on reverse phase and semi-preparative HPLC. The structures of the pure compounds were elucidated by spectral analysis (MS and 1H, 13C, 2D-NMR). Three undescribed phenolic acid derivatives, namely parvifloric acid A (1), B (2), and C (3), and one new sesquiterpene lactone, parviflorin (4) together with seven known compounds were isolated and identified as scopolin (5), scopoletin (6), caffeic acid (7), protocatechuic acid (8), 4,5-O-dicaffeoylquinic acid (9) 3,5-O-dicaffeoylquinic acid (10), and 3,5-O-dicaffeoylquinic acid methyl ester (11). Finally, the pure compounds obtained were tested to evaluate their antioxidant capacities, using ABTS and DPPH radical scavenging potencies. The highest activity was observed with 3,5-O-dicaffeoylquinic acid (10), followed by its methyl ester.
- MeSH
- Antioxidants * pharmacology isolation & purification chemistry MeSH
- Phytochemicals pharmacology isolation & purification MeSH
- Hydroxybenzoates * isolation & purification pharmacology chemistry MeSH
- Plant Roots * chemistry MeSH
- Molecular Structure MeSH
- Scorzonera * chemistry MeSH
- Sesquiterpenes pharmacology isolation & purification chemistry MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. METHODS: In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells' distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. RESULTS: Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).
- MeSH
- Cell Culture Techniques methods MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell * pathology metabolism MeSH
- Gels chemistry MeSH
- Collagen * chemistry pharmacology MeSH
- Humans MeSH
- Polyethylene Glycols * chemistry MeSH
- Receptors, CXCR4 metabolism MeSH
- Carboxymethylcellulose Sodium * chemistry pharmacology MeSH
- Cell Culture Techniques, Three Dimensional methods MeSH
- Tissue Scaffolds * chemistry MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND & OBJECTIVE: To analyze whether there is an association between pre-pregnancy lipid parameters and gestational diabetes mellitus (GDM) in women undergoing assisted reproductive technologies (ART), a group especially at risk for GDM, and if so, which parameter is associated the strongest. METHODS: Data was collected at the Reproductive and Genetic Hospital CITIC-Xiangya in Changsha, China from January 2017 to December 2018. The measured lipid parameters include LDL (low-density lipoprotein), HDL (high-density lipoprotein), TC (total cholesterol), and TG (triglycerides). RESULTS: 119 (15.5%) of the 767 patients developed GDM. On average, women who developed GDM were older, had a higher BMI, LDL, TC, and TG, and lower HDL. After adjusting for confounders, LDL and HDL showed a significant association with GDM (p < 0.05), but TC and TG did not. Binary LDL/HDL and TC/HDL ratios showed the strongest association with GDM incidence (OR 1.957 [95%CI 1.258-3.044] and 1.942 [1.243-3.034] respectively). Subgroup analysis showed that an elevated LDL/HDL ratio also increased GDM risk in subgroups with a typically lower prevalence of GDM, such as young women with a low BMI and low blood pressure. Both lipid ratios (LDL/HDL and TC/HD) show strong interactions with baseline age, fasting plasma glucose, and LH. CONCLUSIONS: In this cohort of Chinese women undergoing ART, pre-pregnancy LDL/HDL and TC/HDL were associated with GDM the strongest from the lipid parameters and could be useful to estimate GDM risk even before ART treatments and pregnancy. CLINICAL TRIAL NUMBER: NCT03503006 registered on the 21st of March 2018 (on clinicaltrials.gov). https://clinicaltrials.gov/study/NCT03503006?locStr=Changsha,%20Hunan,%20China&country=China&state=Hunan&city=Changsha&cond=ivf&rank=2 .
- MeSH
- Reproductive Techniques, Assisted * MeSH
- Cholesterol blood MeSH
- Adult MeSH
- Diabetes, Gestational * blood epidemiology diagnosis MeSH
- Cholesterol, HDL * blood MeSH
- Cholesterol, LDL blood MeSH
- Humans MeSH
- Risk Factors MeSH
- Pregnancy MeSH
- Triglycerides blood MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
- Geographicals
- China MeSH
Patients with alcohol use disorder (AUD) who seek treatment show highly variable outcomes. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.
- MeSH
- Alcoholism * drug therapy physiopathology MeSH
- Amino Acids MeSH
- Bridged Bicyclo Compounds, Heterocyclic * pharmacology MeSH
- Biomarkers MeSH
- Evoked Potentials drug effects MeSH
- Rats MeSH
- Disease Models, Animal * MeSH
- Prefrontal Cortex * drug effects physiopathology metabolism MeSH
- Psilocybin * pharmacology MeSH
- Receptors, Metabotropic Glutamate MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The diagnostic prevalence of autism spectrum disorders (ASD) shows boys to be more affected than girls. Due to this reason, there is a lack of research including and observing ASD girls. Present study was aimed to detect hormones of steroidogenesis pathway in prepubertal girls (n = 16) diagnosed with ASD and sex and age matched neurotypical controls (CTRL, n = 16). Collected plasma served for detection of conjugated and unconjugated steroids using gas chromatography tandem-mass spectrometry. We observed higher levels of steroids modulating ionotropic receptors, especially, GABAergic steroids and pregnenolone sulfate in ASD group. Concentration of many steroids throughout the pathway tend to be higher in ASD girls compared to CTRL. Pregnenolone and its isomers together with polar progestins and androstanes, i.e. sulfated steroids, were found to be higher in ASD group in comparison with CTRL group. Based on steroid product to precursor ratios, ASD group showed higher levels of sulfated/conjugated steroids suggesting higher sulfotransferase or lower steroid sulfatase activity and we also obtained data indicating lower activity of steroid 11β-hydroxylase compared to CTRL group despite higher corticosterone level observed in ASD. These findings need to be generalized in future studies to examine both genders and other age groups.
- MeSH
- Child MeSH
- Humans MeSH
- Gas Chromatography-Mass Spectrometry MeSH
- Autism Spectrum Disorder * metabolism MeSH
- Child, Preschool MeSH
- Pregnenolone * metabolism blood MeSH
- Steroids metabolism blood MeSH
- Case-Control Studies MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
