The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the ...cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The isotopic composition of lithium (Li) in clinopyroxene (Cpx), determined via in situ micro‐analysis, has been employed as a potential geochemical tool for studying various geological processes ...such as crust‐mantle recycling, silicate weathering and fluid‐rock interaction. To obtain precise and accurate Li isotopic compositions in Cpx by LA‐MC‐ICP‐MS, synthetic Cpx matrix‐matched reference materials (RMs) were prepared in this study. Six Cpx‐matrix RMs were prepared by mixing metallic oxides with GSP‐2 (granodiorite) or pure L‐SVEC solution and melting them into glasses (GSP‐2 + oxide; L‐SVEC + oxide). Two representative synthetic glasses, CPXA01 and CPXB01, were subjected to a series of analyses to investigate the possible qualification of the RMs for in situ Li isotope measurement by LA‐MC‐ICP‐MS, including elemental homogeneity analysis (elemental mapping analysis and spot analysis), Li isotopic homogeneity analysis and accurate Li isotopic determination. The applicability of the synthetic Cpx‐matrix RMs was highlighted by comparing the δ7Li values of three natural Cpx calibrated against the synthetic Cpx‐matrix RMs and other commonly used RMs with different matrices (NIST SRM 612, BCR‐2G, GOR128‐G, StHs6/80‐G, KL2‐G and T1‐G), respectively. Additionally, CPXB01‐05 RMs with the same matrix but different Li contents were prepared to explore the Li content mismatch effect, which is significant for accurate determination of in situ Li isotopic composition by LA‐MC‐ICP‐MS. The results of the cross‐calibration of Li isotopes in CPXA01 and CPXB01 suggested no obvious Li isotopic fractionation between the two types of glasses (GSP‐2 + oxide; L‐SVEC + oxide). Thus, the two methods of producing Cpx‐matrix RMs are suitable for preparing the matrix‐matched RMs for in situ microanalysis for Li isotopes.
Key points
Synthetic clinopyroxene‐matrix glass.
Li isotopic homogeneity measured by LA‐MC‐ICP‐MS.
Application of synthetic reference material on natural samples, using existing reference materials for comparsion.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Murray (
.
) has been used both as traditional Chinese medicine and food. Recent studies indicated that anthocyanins are the most abundant bioactive compounds in the
.
fruits. The purpose of this ...study was to investigate the preventive effects and the mechanism of the anthocycanins from the fruit of
.
(ACN) in high-fat diet-induced obese mice. In total, 24 male C57BL/6J mice were divided into three groups: control group (fed a normal diet), high-fat diet group (fed a high-fat diet, HFD), and HFD +ACN group (fed a high-fat diet and drinking distilled water that contained 0.8% crude extract of ACN). The results showed that ACN could significantly reduce the body weight, inhibit lipid accumulation in liver and white adipose tissue, and lower the serum total cholesterol and low-density lipoprotein cholesterol levels compared to that of mice fed a high-fat diet. 16S rRNA gene sequencing of bacterial DNA demonstrated that ACN prevent obesity by enhancing the diversity of cecal bacterial communities, lowering the
-to-
ratio, increasing the genera
, and decreasing the genera
. We also studied the inhibitory effect of ACN on pancreatic lipase. The results showed that ACN has a high affinity for pancreatic lipase and inhibits the activity of pancreatic lipase, with IC50 values of 1.80 (main compound anthocyanin) and 3.03 mg/mL (crude extract), in a competitive way. Furthermore, fluorescence spectroscopy studies showed that ACN can quench the intrinsic fluorescence of pancreatic lipase via a static mechanism. Taken together, these findings suggest that the anthocyanins from
fruits could have preventive effects in high-fat-diet induced obese mice by regulating the intestinal microbiota and inhibiting the pancreatic lipase activity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP), and further explore the potential common ...mechanisms.
Methods
Totally 120 Spraque-Dawley rats were randomly divided into 5–8 groups including sham, vehicle, fluoxetine (20 mg/kg), mosapride (10 mg/kg), CSP (30 g/kg), MH (9.18 mg/kg), D-Lys3-GHRP-6 (Dlys, 0.5 mg/kg), and MH+Dlys groups by a random number table, 8 rats in each group. And 32 mice were randomly divided into wild-type, MH (18 mg/kg), growth hormone secretagogue receptor-knockout (GHSR-KO), and GHSR+MH groups, 8 mice in each group. The forced swimming test (FST), open field test (OFT), tail suspension test (TST), gastric emptying (GE) test, and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice, respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD).
Results
MH treatment improved depression-like behavior (FST, OFT) and hypomotility (GE, IT) in the acute forced swimming (FS) rats (all
P
<0.05), and the effects are similar to the parent formula CSP. The ghrelin antagonist D-Lys3-GHRP-6 inhibited the effect of MH on FST and GE (
P
<0.05). Similarly, MH treatment also alleviated depression-like behavior (FST, TST) in the wild-type mice, however, no effects were found in the GHSR KO mice. Additionally, administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both
P
<0.01), which were also prevented by D-Lys3-GHRP-6 (
P
<0.01). Besides, 3 main BOLD foci following acute FS rats implicated activity in hippocampus—thalamus—basal ganglia (HTB) circuits. The D-Lys3-GHRP-6 synchronously inhibited BOLD HTB foci. As expected, prokinetic mosapride only had effects on the thalamus and basal ganglia, but not on the hippocampus. Within the HTB, the hippocampus is implicated in depression and FD.
Conclusions
MH accounts for part of AP effects of parent formula CSP in acute FS rats, mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress, treatment, and regulation highlights anti-depression unified theory.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This ...emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Predicting imminent hepatocellular carcinoma (HCC) in liver cirrhotic patients is an unmet medical need. We aimed to investigate circulatory biomarkers and their optimum combinations in a prospective ...study.
We investigated plasma interleukin 17 (IL-17) concentrations, quantified using enzyme-linked immunosorbent assay (ELISA), for the prediction of HCC in a large cohort of 404 HCC-naïve liver cirrhotic patients regularly followed after recruitment. Additionally, IL-17 in surgically resected tumor tissues were evaluated using immunohistochemistry staining.
IL-17 was detected in HCC tissues. The IL-17 concentrations in the peripheral blood do not have correlation with an extensive list of 31 common demographic, metabolic and liver function variables in the cohort of liver cirrhotic patients. Furthermore, patients stratified by IL-17 and alpha-fetoprotein (AFP) showed distinctive cumulative incidence of HCC. Imminent HCC, defined here as HCC occurrence within 1 year, can be predicted by IL-17 alone with an area under the receiver operating characteristic curve AUC of 0.762 (P = 0.002). An multivariate analysis showed that age, hepatitis C viral infection, AFP and IL-17 were four independent factors associated with imminent HCC (adjusted P = 0.03, 0.041, 0.024 and 0.008 respectively). An explicit risk score (R) combining the concentrations of two plasma biomarkers, AFP and IL-17, achieved a high AUC of 0.933 (95% confidence interval 0.893-0.972, P < 0.001) in predicting imminent HCC, with 100% sensitivity and 79.9% specificity at the optimum cutoff. The score is defined as: Formula: see text CONCLUSIONS: The circulatory IL-17 concentration is a predictor of subsequent HCC occurrence in liver cirrhotic patients. The combination of AFP and IL-17 is highly effective in predicting imminent HCC within 1 year.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper ...gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury.
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•Oral fecal gavage (OFG) or pasteurized fecal gavage (OPG) mitigates AILI in mice•OFG and OPG enrich gut Lachnospiraceae and butyrate by UGI tract•Butyrate suppresses ferroptosis via activating AMPK-P62-Nrf2 signaling and mitophagy•Combined N-acetylcysteine and butyrate therapy significantly reduces AILI mortality
Yang et al. show that oral fecal gavage (OFG) reshapes gut microbiota, protecting mice from acetaminophen-induced liver injury (AILI). OFG enriches gut Lachnospiraceae and butyrate. Butyrate counteracts AILI-related ferroptosis through Nrf2 antioxidant signaling and mitophagy, highlighting upper gastrointestinal tract microbial selection and potential for microbial metabolites in AILI treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study investigated the antimicrobial resistance of isolates from patients with refractory Helicobacter pylori. The resistance rate was 34.1% for amoxicillin, 92.7% for clarithromycin, 65.9% for ...metronidazole, 85.4% for levofloxacin, and 29.3% for rifabutin. Dual resistance to both clarithromycin and levofloxacin was found in 73.2%. The antimicrobial resistance rate of refractory H. pylori was extremely high, which had become a major consideration in therapeutic challenge.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The selective reductive catalytic deconstruction (RCD) of lignin into phenolic monomers provides the possibility for making the full use of lignocellulose. However, the widespread use of precious ...metal catalysts and the harsh reaction conditions present the challenge of poor industrial utilization in the current research. Herein, we report a metal-organic framework (MOF)-derived copper oxide catalyst (CuO/c-UiO-66), which exhibits superior catalytic properties in the RCD of hardwood lignin and affords high yields (up to 42.8 wt%) of monomeric phenols
via
the C-O bond scission. The mechanistic reactions using lignin model compounds reveal that phenolic compounds with propyl or propanol end chains are selectively produced during the catalytic hydrogenolysis reaction. The enhanced catalytic reactivity is attributed to the synergy of acid and base sites of the catalyst, which facilitates the C-O bond cleavage process. The new insights of this study provide guidance toward the rational design of Cu-based catalysts for RCD of lignin.
The synergistic effects of the fabricated CuO/c-UiO-66 catalyst and hydrogen lead to the efficient scission of C-O bonds of the methoxylated β-
O
-4′ intermediates, transforming hardwood lignins into monophenols.
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