In this study, we aimed to determine the relative effectiveness of common dietary polyphenols or the isoquinoline alkaloid berberine in protecting against molecular mechanisms underlying ...non-alcoholic fatty liver disease (NAFLD) involving changes to cellular lipid metabolism and bioenergetics. In a model of steatosis using HepG2 hepatocytes, exposure of the cells to 1.5 mM oleic acid (OA) for 24 h caused steatosis and distorted cell morphology, induced the expression of mRNA for enzymes that are involved in lipogenesis and fatty acid oxidation (
and
), and impaired indices of aerobic energy metabolism (
mRNA expression, mitochondrial membrane potential (MMP), and galactose-supported ATP production). Co-treatment with 10 µM of selected polyphenols all strongly protected against the steatosis and changes in cell morphology. All polyphenols, except cyanidin, inhibited the effects on
and
and further increased
expression, suggesting a shift toward increased β-oxidation. Resveratrol, quercetin, catechin, and cyanidin, however not kuromanin or berberine, ameliorated the decreases in MMP and galactose-derived ATP. Berberine was unique in worsening the decrease in galactose-derived ATP. In further investigations of the mechanisms involved, resveratrol, catechin, and berberine increased SIRT1 enzyme activity and p-AMPKα
protein, which are involved in mitochondrial biogenesis. In conclusion, selected polyphenols all protected against steatosis with similar effectiveness, however through different mechanisms that increased aerobic lipid metabolism and mitochondrial function.
Dietary polyphenols act in cancer prevention and may inhibit carcinogenesis. A possible mitochondrial mechanism for carcinogen-induced neoplastic transformation and chemoprevention by polyphenols, ...however, is largely unexplored. Using the Bhas 42 cell model of carcinogen-induced neoplastic transformation, we investigated benzoapyrene (BaP) along with different polyphenols for their effects on mitochondrial content and function, and on mitochondrial and intracellular ROS generation. Bhas 42 cells were either co-treated with 5 μM polyphenol starting 2 h before exposure to 4 μM BaP for 24 or 72 h, or pre-treated with polyphenol for 24 h and removed prior to BaP exposure. Exposure to BaP decreased mitochondrial content (by 46% after 24 h and 30% after 72 h), decreased mitochondrial membrane potential and cellular ATP, and increased generation of mitochondrial superoxide and intracellular ROS. Polyphenol co-treatments protected against the decreased mitochondrial content, with resveratrol being the most effective (increasing the mitochondrial content after 72 h by 75%). Measurements after 24 h of mRNA for mitochondria-related proteins and of SIRT1 enzyme activity suggested an involvement of increased mitochondrial biogenesis in the polyphenol effects. The polyphenol co-treatments also ameliorated BaP-induced deficits in mitochondrial function (most strongly resveratrol), and increases in generation of mitochondrial superoxide and intracellular ROS. Notably, 24 h pre-treatments with polyphenols strongly suppressed subsequent BaP-induced increases, after 24 and 72 h, in mitochondrial superoxide and intracellular ROS generation, with resveratrol being the most effective. In conclusion, the results support a mechanism for BaP carcinogenesis involving impaired mitochondrial function and increased mitochondria-derived ROS, that can be ameliorated by dietary polyphenols. The evidence supports an increase in mitochondrial biogenesis behind the strong chemoprevention by resveratrol, and a mitochondrial antioxidant effect in chemoprevention by quercetin.
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•Benzoapyrene produces mitochondrial dysfunction and ROS generation in Bhas 42 fibroblasts.•Polyphenols protect, most effectively resveratrol and quercetin.•Mitochondrial and intracellular ROS correlate inversely with mitochondrial content.•Prior increased mitochondria by resveratrol protects from benzoapyrene ROS generation.•Results suggest a mitochondrial mechanism in preventing carcinogenesis.
Abstract Flavonoids have long been acknowledged for their unique antioxidant properties, and possess other activities that may be relevant to heart ischemia–reperfusion. They may prevent production ...of oxidants (e.g. by inhibition of xanthine oxidase and chelation of transition metals), inhibit oxidants from attacking cellular targets (e.g. by electron donation and scavenging activities), block propagation of oxidative reactions (by chain-breaking antioxidant activity), and reinforce cellular antioxidant capacity (through sparing effects on other antioxidants and inducing expression of endogenous antioxidants). Flavonoids also possess anti-inflammatory and anti-platelet aggregation effects through inhibiting relevant enzymes and signaling pathways, resulting ultimately in lower oxidant production and better re-establishment of blood in the ischemic zone. Finally, flavonoids are vasodilatory through a variety of mechanisms, one of which is likely interaction with ion channels. These multifaceted activities of flavonoids raise their utility as possible therapeutic interventions to ameliorate ischemia–reperfusion injury.
Increased load of electron donors (NADH and FADH2) originating from fat metabolism to the mitochondrial electron transport chain (ETC) results in increased ROS production due to leakage of electrons ...from complex I and III. These ROS further cause mitochondrial dysfunction and decrease mitochondrial content. Polyphenols improve the flow of electrons in the ETC possibly by inducing the expression of mitochondrial respiratory complex subunits and improving mitochondrial function leading to protection against the decline in mitochondrial membrane potential. Polyphenols also prevent induction of endoplasmic reticulum chaperones by palmitate, leading to lower expression of pro-apoptotic CHOP. By preventing the decline in ΔΨm and the expression of ER stress chaperones and CHOP, polyphenols may prevent apoptosis involved in the progression of NAFLD.
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•Palmitate increased hepatocyte ROS, mitochondrial dysfunction and ER stress.•Functional food-relevant polyphenols all prevented steatosis and decreased intracellular ROS.•Polyphenols prevented a large increase in iNOS mRNA expression.•Some polyphenols helped preserve mitochondrial content and membrane potential.•Quercetin most effectively attenuated ER stress.
Polyphenol-rich functional foods have shown promise in ameliorating NAFLD but the relative effectiveness and mechanisms of different polyphenols are largely unknown. In a model of steatosis using HepG2 hepatocytes exposed to palmitic acid, we investigated the effect of selected polyphenols (resveratrol, quercetin, catechin, cyanidin, kuromanin) and berberine. Exposure to palmitic acid produced steatosis and intracellular ROS production, which were prevented by all of the polyphenols and berberine, at 10 µM. Palmitic acid produced a 245% increase in mRNA for inducible nitric oxide synthase (iNOS) that was almost completely prevented by all of the polyphenols (but not by berberine). Most of the polyphenols also partially inhibited palmitic acid-induced increases in markers of endoplasmic reticulum stress, and decreases in mitochondrial content and mitochondrial membrane potential. In conclusion, the polyphenols all similarly prevented steatosis, ROS generation and iNOS induction, and protected against ER stress and mitochondrial impairment.
Near-continuous measurements of hydroxyl radical (OH) reactivity in the urban background atmosphere of central London during the summer of 2012 are presented. OH reactivity behaviour is seen to be ...broadly dependent on air mass origin, with the highest reactivity and the most pronounced diurnal profile observed when air had passed over central London to the east, prior to measurement. Averaged over the entire observation period of 26 days, OH reactivity peaked at ∼ 27 s−1 in the morning, with a minimum of ∼ 15 s−1 during the afternoon. A maximum OH reactivity of 116 s−1 was recorded on one day during morning rush hour. A detailed box model using the Master Chemical Mechanism was used to calculate OH reactivity, and was constrained with an extended measurement data set of volatile organic compounds (VOCs) derived from a gas chromatography flame ionisation detector (GC-FID) and a two-dimensional GC instrument which included heavier molecular weight (up to C12) aliphatic VOCs, oxygenated VOCs and the biogenic VOCs α-pinene and limonene. Comparison was made between observed OH reactivity and modelled OH reactivity using (i) a standard suite of VOC measurements (C2–C8 hydrocarbons and a small selection of oxygenated VOCs) and (ii) a more comprehensive inventory including species up to C12. Modelled reactivities were lower than those measured (by 33 %) when only the reactivity of the standard VOC suite was considered. The difference between measured and modelled reactivity was improved, to within 15 %, if the reactivity of the higher VOCs (⩾ C9) was also considered, with the reactivity of the biogenic compounds of α-pinene and limonene and their oxidation products almost entirely responsible for this improvement. Further improvements in the model's ability to reproduce OH reactivity (to within 6 %) could be achieved if the reactivity and degradation mechanism of unassigned two-dimensional GC peaks were estimated. Neglecting the contribution of the higher VOCs (⩾ C9) (particularly α-pinene and limonene) and model-generated intermediates increases the modelled OH concentrations by 41 %, and the magnitude of in situ ozone production calculated from the production of RO2 was significantly lower (60 %). This work highlights that any future ozone abatement strategies should consider the role that biogenic emissions play alongside anthropogenic emissions in influencing London's air quality.
Air quality on the east coast of Peninsular Malaysia is influenced by local
anthropogenic and biogenic emissions as well as marine air masses from the
South China Sea and aged emissions transported ...from highly polluted East
Asian regions during the winter monsoon season. An atmospheric observation
tower has been constructed on this coastline at the Bachok Marine Research Station. Daily PM2.5 samples were collected from
the top of the observation tower over a 3-week period, and ion chromatography
was used to make time-resolved measurements of major atmospheric ions present
in aerosol. SO42- was found to be the most dominant ion present
and on average made up 66 % of the total ion content. Predictions of
aerosol pH were made using the ISORROPIA II
thermodynamic model, and it was estimated that the aerosol was highly acidic,
with pH values ranging from −0.97 to 1.12. A clear difference in aerosol
composition was found between continental air masses originating from
industrialised regions of East Asia and marine air masses predominantly
influenced by the South China Sea. For example, elevated SO42-
concentrations and increased Cl− depletion were observed when
continental air masses that had passed over highly industrialised regions of
East Asia arrived at the measurement site. Correlation analyses of the ionic
species and assessment of ratios between different ions provided an insight
into common sources and formation pathways of key atmospheric ions, such as
SO42-, NH4+ and C2O42-. To our
knowledge, time-resolved measurements of water-soluble ions in PM2.5 are
virtually non-existent in rural locations on the east coast of Peninsular
Malaysia. Overall this dataset contributes towards a better understanding of
atmospheric composition in the Maritime Continent, a region of the tropics
that is vulnerable to the effects of poor air quality, largely as a result of
rapid industrialisation in East Asia.
OH, HO2, total and partially speciated RO2, and OH reactivity (kOH′) were measured during the July 2015 ICOZA (Integrated Chemistry of OZone in the Atmosphere) project that took place at a coastal ...site in north Norfolk, UK. Maximum measured daily OH, HO2 and total RO2 radical concentrations were in the range 2.6–17 × 106, 0.75–4.2 × 108 and 2.3–8.0 × 108 molec. cm−3, respectively. kOH′ ranged from 1.7 to 17.6 s−1, with a median value of 4.7 s−1. ICOZA data were split by wind direction to assess differences in the radical chemistry between air that had passed over the North Sea (NW–SE sectors) and that over major urban conurbations such as London (SW sector). A box model using the Master Chemical Mechanism (MCMv3.3.1) was in reasonable agreement with the OH measurements, but it overpredicted HO2 observations in NW–SE air in the afternoon by a factor of ∼ 2–3, although slightly better agreement was found for HO2 in SW air (factor of ∼ 1.4–2.0 underprediction). The box model severely underpredicted total RO2 observations in both NW–SE and SW air by factors of ∼ 8–9 on average. Measured radical and kOH′ levels and measurement–model ratios displayed strong dependences on NO mixing ratios, with the results suggesting that peroxy radical chemistry is not well understood under high-NOx conditions. The simultaneous measurement of OH, HO2, total RO2 and kOH′ was used to derive experimental (i.e. observationally determined) budgets for all radical species as well as total ROx (i.e. OH + HO2 + RO2). In NW–SE air, the ROx budget could be closed during the daytime within experimental uncertainty, but the rate of OH destruction exceeded the rate of OH production, and the rate of HO2 production greatly exceeded the rate of HO2 destruction, while the opposite was true for RO2. In SW air, the ROx budget analysis indicated missing daytime ROx sources, but the OH budget was balanced, and the same imbalances were found with the HO2 and RO2 budgets as in NW–SE air. For HO2 and RO2, the budget imbalances were most severe at high-NO mixing ratios, and the best agreement between HO2 and RO2 rates of production and destruction rates was found when the RO2 + NO rate coefficient was reduced by a factor of 5. A photostationary-steady-state (PSS) calculation underpredicted daytime OH in NW–SE air by ∼ 35 %, whereas agreement (∼ 15 %) was found within instrumental uncertainty (∼ 26 % at 2σ) in SW air. The rate of in situ ozone production (P(Ox)) was calculated from observations of ROx, NO and NO2 and compared to that calculated from MCM-modelled radical concentrations. The MCM-calculated P(Ox) significantly underpredicted the measurement-calculated P(Ox) in the morning, and the degree of underprediction was found to scale with NO.
Breast cancer represents a critical global health issue, accounting for a substantial portion of cancer-related deaths worldwide. Metastasis, the spread of cancer cells to distant organs, is the ...primary cause of approximately 90% of breast cancer-related fatalities. Despite advances in cancer treatment, conventional chemotherapeutic drugs often encounter resistance and demonstrate limited efficacy against metastasis. Natural products have emerged as promising sources for innovative cancer therapies, with curcumin being one such example. However, despite its therapeutic potential, curcumin exhibits several limitations. Analogous compounds possessing enhanced bioavailability, potency, or specificity offer a promising avenue for overcoming these challenges and demonstrate potent anti-tumor activities. Our study investigates the antimetastatic potential of the curcumin analog NC2603 in breast cancer cells, utilizing BT-20 cells known for their migratory properties. Cell viability assessments were performed using the MTT reduction method, while migration inhibition was evaluated through scratch and Transwell migration assays. Transcriptome analysis via next-generation sequencing was employed to elucidate gene modulation and compound mechanisms, with subsequent validation using RT-qPCR. The IC50 of NC2603 was determined to be 3.5 μM, indicating potent inhibition of cell viability, and it exhibited greater specificity for BT-20 cells compared with non-cancerous HaCaT cells, surpassing the efficacy of doxorubicin. Notably, NC2603 demonstrated superior inhibition of cell migration in both scratch and Transwell assays compared with curcumin. Transcriptome analysis identified 10,620 modulated genes. We validated the expression of six: EGR3, ATF3, EMP1, SOCS3, ZFP36, and GADD45B, due to their association with migration inhibition properties. We hypothesize that the curcumin analog induces EGR3 expression, which subsequently triggers the expression of ATF3, EMP1, SOCS3, ZFP36, and GADD45B. In summary, this study significantly advances our comprehension of the intricate molecular pathways involved in cancer metastasis, while also examining the mechanisms of analog NC2603 and underscoring its considerable potential as a promising candidate for adjuvant therapy.
Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast ...cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide for drug development, and aiming to enhance treatment specificity and efficacy. Natural compounds, such as curcumin, offer a diverse array of chemical structures with promising therapeutic potential. Despite curcumin's benefits, challenges like poor solubility and rapid metabolism have spurred the exploration of analogs. Here, we evaluated the efficacy of the curcumin analog NC2603 to induce cell cycle arrest in MCF-7 breast cancer cells and explored its molecular mechanisms. Our findings reveal potent inhibition of cell viability (IC50 = 5.6 μM) and greater specificity than doxorubicin toward MCF-7 vs. non-cancer HaCaT cells. Transcriptome analysis identified 12,055 modulated genes, most notably upregulation of
and downregulation of
, implicating
-mediated regulation of proliferation and cell cycle genes. We hypothesize that the curcumin analog by inducing
expression and repressing
, triggers the expression of
, which in turn downregulates the expression of many important genes of proliferation and the cell cycle. These insights advance our understanding of curcumin analogs' therapeutic potential, highlighting not just their role in treatment, but also the molecular pathways involved in their activity toward breast cancer cells.
The use of dietary supplements is high among athletes and non-athletes alike, as well as able-bodied individuals and those with impairments. However, evidence is lacking in the use of dietary ...supplements for sport performance in a para-athlete population (e.g., those training for the Paralympics or similar competition). Our objective was to examine the literature regarding evidence for various sport supplements in a para-athlete population. A comprehensive literature search was conducted using PubMed, SPORTDiscus, MedLine, and Rehabilitation and Sports Medicine Source. Fifteen studies met our inclusion criteria and were included in our review. Seven varieties of supplements were investigated in the studies reviewed, including caffeine, creatine, buffering agents, fish oil, leucine, and vitamin D. The evidence for each of these supplements remains inconclusive, with varying results between studies. Limitations of research in this area include the heterogeneity of the subjects within the population regarding functionality and impairment. Very few studies included individuals with impairments other than spinal cord injury. Overall, more research is needed to strengthen the evidence for or against supplement use in para-athletes. Future research is also recommended on performance in para-athlete populations with classifiable impairments other than spinal cord injuries.
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