Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury.

A poor diet can modify the intestinal microbiota, known as gut dysbiosis, which causes hepatocyte mitochondrial dysfunction through the release of endotoxins in the portal vein. Mitochondrial dysfunction in the liver leads to non-alcoholic fatty liver disease (NAFLD). Epidemiological evidence shows that most deaths from NAFLD are related to cardiovascular diseases (CVD) demonstrated by impaired vasodilatation as well as increased arterial stiffness, calcification, inflammation, and intimal-medial thickness. Therefore, the objective of our study was to investigate the potential of probiotic supplements to prevent a diet-induced mitochondrial dysfunction in hepatocytes. Apolipoprotein-E knockout mice—genetically modified animals that develop dyslipidemia—were placed in 3 diet groups including a control, western style (high in fats and carbohydrates), as well as a low-carbohydrate high-protein diet. Each group was then further divided in 3 subgroups based on the dose of probiotics administered, including a control, low (0.5 B/dose) and high (5 B/dose) dose of probiotics, for a total of 9 groups (n= 8-12 animals/group). The probiotic supplements contained a 1:1 ratio of Lactobacillus Helveticus and Bifidobacterium Bifidum . The bodyweight and water intake were monitored weekly. After 6 weeks, the liver mitochondria were analyzed by high resolution respirometry using a sequential substrate addition protocol (malate, octanoylcarnitine, ADP, glutamate, pyruvate, cytochrome C, succinate and FCCP) to investigate mitochondrial maximal respiration, leak, membrane damage and uncoupling. Our preliminary results show that the groups that received a high dose of probiotics gained less weight, had a higher respiration following the addition of ADP (a biomarker of complex V efficiency) and a lower respiration following FCCP (a biomarker of mitochondrial uncoupling), as compared to control. Supplements of probiotics could promote weight loss and prevent a diet-induced mitochondrial dysfunction in liver hepatocytes, an important risk factor for NAFLD and therefore, CVD. This project could translate into future research directions in preventative medicine, for example by investigating the potential of probiotics in the prevention of mitochondrial dysfunction in other organs, including the heart and the vascular system.

Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.

Tire wear particle leachate induces lipid metabolism disorders in Procambarus clarkii, leading to liver inflammation and mitochondrial dysfunction in hepatocytes.

Association of statin induced reduction in serum coenzyme Q10 level and conduction deficits in motor and sensory nerves: An observational cross-sectional study

Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner

Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.

CoQ10 protects against acetaminophen-induced liver injury by enhancing mitophagy

Obesity and overweight, frequently caused by a lack of exercise, are associated with many metabolic diseases, such as hypertension, diabetes, and dyslipidemia. Aerobic exercise effectively increases the high-density lipoproteins-cholesterol (HDL-C) levels and alleviates the triglyceride (TG) levels. The consumption of Cuban policosanol (Raydel®) is also effective in enhancing the HDL-C quantity and HDL functionality to treat dyslipidemia and hypertension. On the other hand, no study has examined the effects of a combination of high-intensity exercise and policosanol consumption in obese subjects to improve metabolic disorders. In the current study, 17 obese subjects (average BMI 30.1 ± 1.1 kg/m2, eight male and nine female) were recruited to participate in a program combining exercise and policosanol (20 mg) consumption for 12 weeks. After completion, their BMI, waist circumference, total fat mass, systolic blood pressure (SBP), and diastolic blood pressure (DBP) reduced significantly up to around -15%, -13%, -33%, -11%, and -13%, respectively. In the serum lipid profile, at Week 12, a significant reduction was observed in the total cholesterol (TC) and triglyceride (TG) levels, up to -17% and -54% from the baseline, respectively. The serum HDL-C was elevated by approximately +12% from the baseline, as well as the percentage of HDL-C in TC, and HDL-C/TC (%), was enhanced by up to +32% at Week 12. The serum coenzyme Q10 (CoQ10) level was increased 1.2-fold from the baseline in all participants at Week 12. In particular, the male participants exhibited a 1.4-fold increase from the baseline. The larger rise in serum CoQ10 was correlated with the larger increase in the serum HDL-C (r = 0.621, p = 0.018). The hepatic function parameters were improved; the serum γ-glutamyl transferase decreased at Week 12 by up to -55% (p < 0.007), while the aspartate aminotransferase and alanine transaminase levels diminished within the normal range. In the lipoprotein level, the extent of oxidation and glycation were reduced significantly with the reduction in TG content. The antioxidant abilities of HDL, such as paraoxonase (PON) and ferric ion reduction ability (FRA), were enhanced significantly by up to 1.8-fold and 1.6-fold at Week 12. The particle size and number of HDL were elevated up to +10% during the 12 weeks, with a remarkable decline in the TG content, glycation extent, and oxidation. The improvements in HDL quality and functionality were linked to the higher survivability of adult zebrafish and their embryos, under the co-presence of carboxymethyllysine (CML), a pro-inflammatory molecule known to cause acute death. In conclusion, 12 weeks of Cuban policosanol (Raydel®, 20 mg) consumption with high-intensity exercise displayed a significant improvement in blood pressure, body fat mass, blood lipid profile without liver damage, CoQ10 metabolism, and renal impairment.

This study investigates the morphological and physical/end-use properties of corn cob powder-filled recycled polypropylene composites. The composites were prepared by incorporating corn cob powder of particle sizes 150 µm, 300 µm and 425 µm respectively at filler loadings of 5 to 25 wt%. The properties were determined according to standard test procedures. Results showed that the incorporation of corn cob powder as filler resulted to enhancement of water absorption and solvent sorption, which were found to increase with both increase in filler loading and increase in filler particle size, probably due to the hydrophilic nature of corn cob powder. It was also discovered that solvent sorption was most pronounced with benzene, followed by toluene and lastly xylene, in accordance with the relative proximity of their solubility parameters to that of polypropylene. Flame propagation rate was also found to improve by the incorporation of corn cob powder due to its high content of cellulose, a combustible organic matter. However, specific gravities of the composites were found to be lower than for the unfilled polypropylene, an implication that the composites produced are lighter in weight than the unfilled. Specific gravity increased with increase in filler loading but decreased with increase in particle size. The Morphological studies showed increase in the number of spherulites with increase in filler loading and increase in the size of the spherulites with increase in particle size. Further observation showed that the particle sizes and pores sizes detected increased with increase in filler particle size probably due to poor interaction and distribution of coarse particles. It is hoped that this present study will to help place the usefulness of corn cob as filler in the development of thermoplastic composites in future and develop its niche in the scientific record.

This study investigates the morphological and physical/end-use properties of corn cob powder-filled recycled polypropylene composites. The composites were prepared by incorporating corn cob powder of particle sizes 150 µm, 300 µm and 425 µm respectively at filler loadings of 5 to 25 wt%. The properties were determined according to standard test procedures. Results showed that the incorporation of corn cob powder as filler resulted to enhancement of water absorption and solvent sorption, which were found to increase with both increase in filler loading and increase in filler particle size, probably due to the hydrophilic nature of corn cob powder. It was also discovered that solvent sorption was most pronounced with benzene, followed by toluene and lastly xylene, in accordance with the relative proximity of their solubility parameters to that of polypropylene. Flame propagation rate was also found to improve by the incorporation of corn cob powder due to its high content of cellulose, a combustible organic matter. However, specific gravities of the composites were found to be lower than for the unfilled polypropylene, an implication that the composites produced are lighter in weight than the unfilled. Specific gravity increased with increase in filler loading but decreased with increase in particle size. The Morphological studies showed increase in the number of spherulites with increase in filler loading and increase in the size of the spherulites with increase in particle size. Further observation showed that the particle sizes and pores sizes detected increased with increase in filler particle size probably due to poor interaction and distribution of coarse particles. It is hoped that this present study will to help place the usefulness of corn cob as filler in the development of thermoplastic composites in future and develop its niche in the scientific record.

Coenzyme Q10 and cognition in atorvastatin treated dogs

Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid β-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.

Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.

Acute liver injury is a common consequence of taking overdose of acetaminophen (APAP). The aim of this study was to evaluate the antioxidant activity and hepatoprotective effect of a mangrove plant Sonneratia apetala fruit extract (SAFE) on APAP-induced liver injury in mice. Mice were orally pretreated with SAFE (100, 200, and 400 mg/kg) daily for one week. The control and APAP groups were intragastrically administered with distilled water, and NAC group was treated with N-Acetyl-L-cysteine (NAC) before APAP exposure. The results manifested that SAFE significantly improved survival rates, attenuated hepatic histological damage, and decreased the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum in APAP-exposed mice. SAFE treatment also increased glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity, enhanced catalase (CAT), and total antioxidant capacity (T-AOC), as well as reducing malondialdehyde (MDA) level in liver. In addition, the formation of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and elevation of myeloperoxidase (MPO) in APAP-exposed mice were inhibited after SAFE treatment. And SAFE also displayed high DPPH radical scavenging activity and reducing power in vitro. The main bioactive components of SAFE such as total phenol, flavonoid, condensed tannin, and carbohydrate were determined. The current study proved that SAFE exerted potential protective effect against APAP-induced acute liver injury, which might be associated with the antioxidant and anti-inflammatory activities of SAFE.

The diesel engine particulate which is one of the major sources of PM, affects the development of human health and production activities seriously. With the continuous strict of emission regulations, the diesel engine particles are subject to strict restriction in terms of quality and quantity. At present, the diesel particulate filter technology is an important technical measure to reduce the exhaust particulate matter of the diesel engine. And the efficient capture of particles is one of the key technologies for the diesel particulate filter. Diesel engine exhaust particles undergo nucleation, surface growth, agglomeration and other processes, in which the degree of agglomeration of exhaust particles will directly affect its number density, scale and the trapping efficiency of the filter and so on. The reason why particles can be agglomerated is mainly due to the interaction between the particles. Therefore, to explore the relationship between the force and the effect of particle agglomeration, it is necessary to carry out the study on the interaction between the exhaust particles of diesel engines. The interaction between particles will affect the process of particle agglomeration and related parameters significantly. The main forces include van der Waals force, electrostatic force and liquid bridge force. In this paper, theoretical models of Hamaker and some others are used to analyze the force between particles in the ideal state. The test methods of atomic force microscopy (AFM) and transmission electron microscopy (TEM) are used to investigate the total attraction force, adhesion force and adhesion energy between diesel exhaust particulates in dry environment (relative humidity RH≤20%), and measure the total attraction force, adhesion force and adhesion between particles, and explore the relationship between particle size and particle size. The results show that the particle size increases from 25 to 45 nm, the Van der Waals force increases about 4.6 times, the electrostatic force increases about 9.9 times, and the electrostatic force is smaller than the electrostatic force. The adhesion between particles and adhesion energy both increased about 1.8 times. The particles with the average particle size of 30, 37 and 46 nm are measured by AFM. With the increase of the particle size, the total attraction F at between the particle and the probe increases gradually, which is 1.04–1.38 nN. Van der Waals force F vdw is the main force of the F at, and Coulomb force is smaller. The attraction force F at and the adhesion energy W ad increase with the increase of particle size, F at increases from 3.21–3.75 nN, about 16.8%, while W ad increases from 2.03×10−16 J to 2.20×10−16 J, about 8.4%. The increase of F ad and W ad indicate that the adhesion as well as the energy barrier between the particles is increased, and the particle agglomeration is stable. With the increase of the average particle size, the particles agglomerate gradually and change from branch to cluster, showing a hill-like accumulation, and the particle density as well as the cluster size are increased, which indicates that there was a certain influence between the change of particle force and particle morphology.