Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.

• MeSH
• Chondrocytes * metabolism   MeSH
• Ferroptosis * physiology   MeSH
• Glucosephosphate Dehydrogenase metabolism   MeSH
• Glucose metabolism   MeSH
• Mice MeSH
• Oxidation-Reduction MeSH
• Oxidative Stress * MeSH
• Pentose Phosphate Pathway * MeSH
• Reactive Oxygen Species * metabolism   MeSH
• Protein Folding * MeSH
• Unfolded Protein Response MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Humans MeSH
• Neurotoxicity Syndromes * etiology   prevention & control   MeSH
• Neuroinflammatory Diseases MeSH
• Organophosphates MeSH
• Organophosphate Poisoning * drug therapy   prevention & control   MeSH
• Reactive Oxygen Species MeSH
• Seizures MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Colorectal cancer (CRC) is one of the most deaths causing diseases worldwide. Several risk factors including hormones like insulin and insulin like growth factors (e.g., IGF-1) have been considered responsible for growth and progression of colon cancer. Though there is a huge advancement in the available screening as well as treatment techniques for CRC. There is no significant decrease in the mortality of cancer patients. Moreover, the current treatment approaches for CRC are associated with serious challenges like drug resistance and cancer re-growth. Given the severity of the disease, there is an urgent need for novel therapeutic agents with ideal characteristics. Several pieces of evidence suggested that natural products, specifically medicinal plants, and derived phytochemicals may serve as potential sources for novel drug discovery for various diseases including cancer. On the other hand, cancer cells like colon cancer require a high basal level of reactive oxygen species (ROS) to maintain its own cellular functions. However, excess production of intracellular ROS leads to cancer cell death via disturbing cellular redox homeostasis. Therefore, medicinal plants and derived phytocompounds that can enhance the intracellular ROS and induce apoptotic cell death in cancer cells via modulating various molecular targets including IGF-1 could be potential therapeutic agents. Alkaloids form a major class of such phytoconstituents that can play a key role in cancer prevention. Moreover, several preclinical and clinical studies have also evidenced that these compounds show potent anti-colon cancer effects and exhibit negligible toxicity towards the normal cells. Hence, the present evidence-based study aimed to provide an update on various alkaloids that have been reported to induce ROS-mediated apoptosis in colon cancer cells via targeting various cellular components including hormones and growth factors, which play a role in metastasis, angiogenesis, proliferation, and invasion. This study also provides an individual account on each such alkaloid that underwent clinical trials either alone or in combination with other clinical drugs. In addition, various classes of phytochemicals that induce ROS-mediated cell death in different kinds of cancers including colon cancer are discussed.

• MeSH
• Alkaloids * therapeutic use   MeSH
• Hormones therapeutic use   MeSH
• Insulin-Like Growth Factor I MeSH
• Humans MeSH
• Colonic Neoplasms * drug therapy   metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

OBJECTIVE: The onset of new conduction abnormalities requiring permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) is still a relevant adverse event. The main objective of this registry was to identify modifiable procedural risk factors for an improved outcome (lower rate of PPI) after TAVI in patients at high risk of PPI. METHODS: Patients from four European centres receiving a balloon-expandable TAVI (Edwards SAPIEN 3/3 Ultra) and considered at high risk of PPI (pre-existing conduction disturbance, heavily calcified left ventricular outflow tract or short membranous septum) were prospectively enrolled into registry. RESULTS: A total of 300 patients were included: 42 (14.0%) required PPI after TAVI and 258 (86.0%) did not. Patients with PPI had a longer intensive care unit plus intermediate care stay (65.7 vs 16.3 hours, p<0.001), general ward care stay (6.9 vs 5.3 days, p=0.004) and later discharge (8.6 vs 5.0 days, p<0.001). Of the baseline variables, only pre-existing right bundle branch block at baseline (OR 6.8, 95% CI 2.5 to 18.1) was significantly associated with PPI in the multivariable analysis. Among procedure-related variables, oversizing had the highest impact on the rate of PPI: higher than manufacturer-recommended sizing, mean area oversizing as well as the use of the 29 mm valve (OR 3.4, 95% CI 1.4 to 8.5, p=0.008) all were significantly associated with PPI. Rates were higher with the SAPIEN 3 (16.1%) vs SAPIEN 3 Ultra (8.5%), although not statistically significant but potentially associated with valve sizing. Implantation depth and postdelivery balloon dilatation also tended to affect PPI rates but without a statistical significance. CONCLUSION: Valve oversizing is a strong procedure-related risk factor for PPI following TAVI. The clinical impact of the valve type (SAPIEN 3), implantation depth, and postdelivery balloon dilatation did not reach significance and may reflect already refined procedures in the participating centres, giving attention to these avoidable risk factors. TRIAL REGISTRATION NUMBER: NCT03497611.

• MeSH
• Aortic Valve Stenosis * surgery   MeSH
• Cardiac Pacing, Artificial adverse effects   methods   MeSH
• Pacemaker, Artificial * MeSH
• Humans MeSH
• Registries MeSH
• Risk Factors MeSH
• Heart Valve Prosthesis * adverse effects   MeSH
• Transcatheter Aortic Valve Replacement * adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Research Support, Non-U.S. Gov't MeSH

In response to the emergence of drug resistance and limited therapeutic options, researchers are in action to look for more effective and sustainable antimicrobial practices. Over few years, novel nanoparticles are proving to be potent and promising for effectively dealing with ever- evolving microbial pathogens and diseases. In the present investigation, antibacterial and anti-biofilm efficiencies of zinc ferrite nanoparticles (ZnFe2O4 NPs) are explored against opportunistic pathogens Klebsiella pneumoniae (K. pneumoniae). Results of the present study demonstrate that the ZnFe2O4 NPs endow an excellent antibacterial efficiency with a maximum zone of inhibition i.e.16 mm. The reactive oxygen species (ROS)-induced bacterial damage is caused by the ZnFe2O4 NPs. Subsequently, intracellular cytoplasmic leakage of sugar and protein confirms their ability to disturb the membrane integrity of bacteria. This study also demonstrates the prominent efficiency of ZnFe2O4 NPs in an anti-biofilm study by inhibiting biofilm formation up to 81.76% and reducing mature biofilm up to 56.22% at 75 μg/mL the minimum inhibitory concentration value. Therapeutic possibilities of the ZnFe2O4 NPs in antimicrobial applications are discussed which are helpful to overcome the challenges associated with biofilm infectivity.

• MeSH
• Anti-Bacterial Agents pharmacology   therapeutic use   MeSH
• Anti-Infective Agents * pharmacology   MeSH
• Bacteria metabolism   MeSH
• Biofilms MeSH
• Sugars pharmacology   MeSH
• Klebsiella pneumoniae MeSH
• Microbial Sensitivity Tests MeSH
• Nanoparticles * MeSH
• Reactive Oxygen Species metabolism   MeSH
• Ferric Compounds MeSH
• Zinc pharmacology   MeSH
• Publication type
• Journal Article MeSH

Distributed cutaneous tissue blood volume oscillations contain information on autonomic nervous system (ANS) regulation of cardiorespiratory activity as well as dominating thermoregulation. ANS associated with low-frequency oscillations can be quantified in terms of frequencies, amplitudes, and phase shifts. The relative order between these faculties may be disturbed by conditions colloquially termed 'stress'. Photoplethysmography imaging, an optical non-invasive diagnostic technique provides information on cutaneous tissue perfusion in the temporal and spatial domains. Using the cold pressure test (CPT) in thirteen healthy volunteers as a well-studied experimental intervention, we present a method for evaluating phase shifts in low- and intermediate frequency bands in forehead cutaneous perfusion mapping. Phase shift changes were analysed in low- and intermediate frequency ranges from 0.05 Hz to 0.18 Hz. We observed that time waveforms increasingly desynchronised in various areas of the scanned area throughout measurements. An increase of IM band phase desynchronization observed throughout measurements was comparable in experimental and control group, suggesting a time effect possibly due to overshooting the optimal relaxation duration. CPT triggered an increase in the number of points phase-shifted to the reference that was specific to the low frequency range for phase-shift thresholds defined as π/4, 3π/8, and π/2 rad, respectively. Phase shifts in forehead blood oscillations may infer changes of vascular tone due to activity of various neural systems. We present an innovative method for the phase shift analysis of cutaneous tissue perfusion that appears promising to assess ANS change processes related to physical or psychological stress. More comprehensive studies are needed to further investigate the reliability and physiological significance of findings.

• MeSH
• Autonomic Nervous System MeSH
• Photoplethysmography * methods   MeSH
• Skin * blood supply   MeSH
• Humans MeSH
• Perfusion MeSH
• Reproducibility of Results MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The frequencies of adverse outcomes associated with male reproductive health, including infertility and testicular cancer, are increasing. These adverse trends are partially attributed to increased exposure to environmental agents such as endocrine-disrupting chemicals (EDCs). This study addresses effects on EDCs on adjacent prepubertal Sertoli TM4 cells, specifically on 1) testicular gap junctional intercellular communication (GJIC), one of the hallmarks of non-genotoxic carcinogenicity, 2) GJIC building blocks connexins (Cx), and 3) mitogen-activated protein kinases MAPKs. We selected eight representatives of EDCs: organochlorine chemicals such as pesticides dichlorodiphenyltrichloroethane, lindane, methoxychlor, and vinclozolin, industrial chemicals bisphenol A and 2,2',4,4',5,5'-hexachlorobiphenyl, and components of personal care products, triclocarban and triclosan. EDCs rapidly dysregulated GJIC in Sertoli TM4 cells mainly via MAPK p38 and/or Erk1/2 pathways by the intermediate hyper- or de-phosphorylation of Cx43 (Ser368, Ser282) and translocation of Cx43 from the plasma membrane, suggesting disturbed intracellular trafficking of Cx43 protein. Surprisingly, EDCs did not rapidly activate MAPK Erk1/2 or p38; on the contrary, TCC and TCS decreased their activity (phosphorylation). Our results indicate that EDCs might disrupt testicular homeostasis and development via testicular GJIC, junctional and non-junctional functions of Cx43 and MAPK-signaling pathways in Sertoli cells.

• MeSH
• Endocrine Disruptors * metabolism   MeSH
• Phosphorylation MeSH
• Connexin 43 genetics   metabolism   MeSH
• Humans MeSH
• Gap Junctions metabolism   MeSH
• Cell Communication MeSH
• Testicular Neoplasms * metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH

Three genetically determined enzyme defects of purine de novo synthesis (PDNS) have been identified so far in humans: adenylosuccinate lyase (ADSL) deficiency, 5-amino-4-imidazole carboxamide-ribosiduria (AICA-ribosiduria), and deficiency in bifunctional enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS). Clinical signs of these defects are mainly neurological, such as seizures, psychomotor retardation, epilepsy, autistic features, etc. This work aims to describe the metabolic changes of CRISPR-Cas9 genome-edited HeLa cells deficient in the individual steps of PDNS to better understand known and potential defects of the pathway in humans. High-performance liquid chromatography coupled with mass spectrometry was used for both targeted and untargeted metabolomic analyses. The statistically significant features from the untargeted study were identified by fragmentation analysis. Data from the targeted analysis were processed in Cytoscape software to visualize the most affected metabolic pathways. Statistical significance of PDNS intermediates preceding deficient enzymes was the highest (p-values 10 × 10-7-10 × 10-15) in comparison with the metabolites from other pathways (p-values of up to 10 × 10-7). Disturbed PDNS resulted in an altered pool of adenine and guanine nucleotides. However, the adenylate energy charge was not different from controls. Different profiles of acylcarnitines observed among deficient cell lines might be associated with a specific enzyme deficiency rather than global changes related to the PDNS pathway. Changes detected in one-carbon metabolism might reduce the methylation activity of the deficient cells, thus affecting the modification state of DNA, RNA, and proteins.

• Publication type
• Journal Article MeSH

The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin-silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

• Publication type
• Journal Article MeSH

PURPOSE: Excessive exposure of skin to solar radiation is associated with greatly increased production of reactive oxygen and nitrogen species (ROS, RNS) resulting in oxidative stress (OS), inflammation, immunosuppression, the production of matrix metalloproteinase, DNA damage and mutations. These events lead to increased incidence of various skin disorders including photoaing and both non-melanoma and melanoma skin cancers. The ultraviolet (UV) part of sunlight, in particular, is responsible for structural and cellular changes across the different layers of the skin. Among other effects, UV photons stimulate oxidative damage to biomolecules via the generation of unstable and highly reactive compounds. In response to oxidative damage, cytoprotective pathways are triggered. One of these is the pathway driven by the nuclear factor erythroid-2 related factor 2 (Nrf2). This transcription factor translocates to the nucleus and drives the expression of numerous genes, among them various detoxifying and antioxidant enzymes. Several studies concerning the effects of UV radiation on Nrf2 activation have been published, but different UV wavelengths, skin cells or tissues and incubation periods were used in the experiments that complicate the evaluation of UV radiation effects. CONCLUSIONS: This review summarizes the effects of UVB (280-315 nm) and UVA (315-400 nm) radiation on the Nrf2 signaling pathway in dermal fibroblasts and epidermal keratinocytes and melanocytes. The effects of natural compounds (pure compounds or mixtures) on Nrf2 activation and level as well as on Nrf2-driven genes in UV irradiated human skin fibroblasts, keratinocytes and melanocytes are briefly mentioned as well.HighlightsUVB radiation is a rather poor activator of the Nrf2-driven pathway in fibroblastsUVA radiation stimulates Nrf2 activation in dermal fibroblastsEffects of UVA on the Nrf2 pathway in keratinocytes and melanocytes remain unclearLong-term Nrf2 activation in keratinocytes disturbs their normal differentiationPharmacological activation of Nrf2 in the skin needs to be performed carefully.

• MeSH
• NF-E2-Related Factor 2 metabolism   MeSH
• Keratinocytes MeSH
• Skin metabolism   MeSH
• Humans MeSH
• Reactive Oxygen Species MeSH
• Signal Transduction * MeSH
• GA-Binding Protein Transcription Factor MeSH
• Ultraviolet Rays * adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH