Construction and validation of m6A-related diagnostic model for psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory disease. N6-methyladenosine (m6A) is involved in numerous biological processes in both normal and diseased states. Herein, we aimed to explore the potential role of m6A regulators in the diagnosis of psoriasis and predict molecular mechanisms by which m6A regulators impact psoriasis. Methods: GSE30999 (170 human skin tissue samples) and GSE13355 (180 human skin tissue samples) were downloaded as the training analysis dataset and validation dataset respectively. M6A-related genes were obtained from the literature and their expression levels in GSE30999 samples were measured to identify M6A-related DEGs between psoriasis lesions (LS) and non-lesional lesions (NL). We identified m6A-related DEGs using differential expression analysis and assessed their interactions through correlation analysis and network construction. A logistic regression analysis followed by LASSO optimization was employed to select m6A-related DEGs for the construction of a diagnostic model. The performance of the model was validated using support vector machine (SVM) methodology with sigmoid kernel function and extensive cross-validation. Additionally, the correlation between m6A-related DEGs and immune cell infiltration was analyzed, as well as the association of these DEGs with psoriasis subtypes. Functional analysis of the m6A-related DEGs included the construction of regulatory networks involving miRNAs, transcription factors (TFs), and small-molecule drugs. The m6A modification patterns were also explored by examining the gene expression differences between psoriasis subtypes and their enriched biological pathways. Finally, the expression of significant m6A regulators involved in the diagnostic model was examined by RT-qPCR. Results: In this study, ten optimal m6A-related DEGs were identified, including FTO, IGF2BP2, METTL3, YTHDC1, ZC3H13, HNRNPC, IGF2BP3, LRPPRC, YTHDC2, and HNRNPA2B1. A diagnostic model based on these m6A-related DEGs was constructed, demonstrating high diagnostic accuracy with an area under the curve (AUC) in GSE30999 and GSE13355 of 0.974 and 0.730, respectively. Meanwhile, the expression level of m6A regulators verified by RT-qPCR was consistent with the results in GSE30999. The infiltration of activated mast cells and NK cells was significantly associated with all ten m6A-related DEGs in psoriasis. Among them, YTHDC1, HNRNPC, and FTO were targeted by most miRNAs and were regulated by nine related TFs. Therefore, patients may benefit from dorsomorphin and cyclosporine therapy. Between the two subgroups, 1,592 DEGs were identified, including LRPPRC and METTL3. These DEGs were predicted to be involved in neutrophil activation, cytokine-cytokine receptor interactions, and chemokine signaling pathways. Conclusions: A diagnostic model based on ten m6A-related DEGs in patients with psoriasis was constructed, which may provide early diagnostic biomarkers and therapeutic targets for psoriasis.

Leptin induces altered differentiation of keratinocytes by inducing insulin resistance: implications for metabolic syndrome-induced resistance of psoriatic therapy.

Background: Psoriatic patients tend to develop metabolic syndrome (MS). MS accelerates psoriasis, but the exact molecular mechanisms are poorly understood.Objectives: We aim to investigate the impact of leptin on keratinocyte insulin sensitivity and explore its underlying molecular mechanism, which might play a role in the pathogenesis of this disease.Methods: ELISA and immunohistochemistry were applied respectively to detect the level of leptin in serum and in lesion of psoriatic patients with and without MS. The HaCaT cell line was cultured and western-blot assay was performed to assess the change of insulin sensibility. q-PCR and western-blot assay were applied to detect the SOCS3 expressions. Knockdown of SOCS3 were generated in HaCaT cell line by siRNA. Leptin and insulin were treated for 6 days and K10 expression was evaluated by western-blot assay.Results: Patients with MS had higher level of leptin in serum and lesions than their counterparts without MS. Serum levels of leptin was negatively correlated to PASI decline index in psoriatic patients. Long-term treatment of leptin induced insulin resistance in HaCaT cell line, as indicated by elevated expression of p-IRS-1 (ser636) and lower p-PKB (ser473). Leptin treatment up-regulated the mRNA and protein expression of SOCS3. Knockdown of SOCS3 blocked the effect of leptin-induced insulin resistance. Leptin treatment attenuated insulin-elicited K10 expression.Conclusions: Leptin induces insulin resistance by upregulating SOCS3 and give rise to differentiation disorder of keratinocyte. Insulin resistance may serve as a target for anti-psoriatic therapies.

Evaluation and prediction of water conservation of the Yellow river basin in Sichuan Province, China, based on Google Earth Engine and CA-Markov.

The Yellow River Basin in China has the world's most serious soil erosion problem. The Yellow River Basin in Sichuan Province (YRS), as the upper reaches of the Yellow River, and its water conservation (WC) capacity greatly affects the ecological environment of the downstream basin. In recent years, YRS has received more and more attention, and numerous policies have been developed to improve local WC. However, there is a vacancy in the long-term research of WC in the YRS due to the lack of in-situ data. This study quantitatively evaluated the WC of YRS from 2001 to 2020 through Google Earth Engine (GEE) and analyzed the spatio-temporal variations of WC and land cover (LC). CA-Markov predicted the LC and WC in 2025 under three scenarios to assess the contribution of different scenarios to WC. The WC in YRS fluctuated from 1.93 to 6.77 billion m3. The climate is the dominant factor of WC change, but the effect of LC on WC is also evident. The WC capacity increases with vegetation coverage and height. The WC capacity of forests per km2 exceeds 600 mm, while that of grasslands is about 250 mm, and barren can cause around 300 mm of WC loss. In 2025, the WC in YRS may exceed 7.5 billion m3, but the past ecological management mode should be transformed. Improving the quality of land use and converting grasslands to forests is better than reducing cropland to improve WC.

Role of TNF-α-induced m6A RNA methylation in diseases: a comprehensive review.

Tumor Necrosis Factor-alpha (TNF-α) is ubiquitous in the human body and plays a significant role in various physiological and pathological processes. However, TNF-α-induced diseases remain poorly understood with limited efficacy due to the intricate nature of their mechanisms. N6-methyladenosine (m6A) methylation, a prevalent type of epigenetic modification of mRNA, primarily occurs at the post-transcriptional level and is involved in intranuclear and extranuclear mRNA metabolism. Evidence suggests that m6A methylation participates in TNF-α-induced diseases and signaling pathways associated with TNF-α. This review summarizes the involvement of TNF-α and m6A methylation regulators in various diseases, investigates the impact of m6A methylation on TNF-α-induced diseases, and puts forth potential therapeutic targets for treating TNF-α-induced diseases.

Optimal figure of merit of low-dissipation quantum refrigerators.

The Drazin inverse of the Liouvillian superoperator provides a solution to determine the dynamics of a time-dependent system governed by the Markovian master equation. Under the condition of slow driving, the perturbation expansion of the density operator of the system in powers of time can be derived. As an application, a finite-time cycle model of the quantum refrigerator driven by a time-dependent external field is established. The method of the Lagrange multiplier is adopted as a strategy to find the optimal cooling performance. The figure of merit given by the product of the coefficient of performance and the cooling rate is taken as a new objective function, and, consequently, the optimally operating state of the refrigerator is revealed. The effects of the frequency exponent determining dissipation characteristics on the optimal performance of the refrigerator are discussed systemically. The results obtained show that the adjacent areas of the state of the maximum figure of merit are the best operation region of low-dissipative quantum refrigerators.

The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.

Acetyl-coenzyme A (Ac-CoA) is a core metabolite with essential roles throughout cell physiology. These functions can be classified into energetics, biosynthesis, regulation and acetylation of large and small molecules. Ac-CoA is essential for oxidative metabolism of glucose, fatty acids, most amino acids, ethanol, and of free acetate generated by endogenous metabolism or by gut bacteria. Ac-CoA cannot cross lipid bilayers, but acetyl groups from Ac-CoA can shuttle across membranes as part of carrier molecules like citrate or acetylcarnitine, or as free acetate or ketone bodies. Ac-CoA is the basic unit of lipid biosynthesis, providing essentially all of the carbon for the synthesis of fatty acids and of isoprenoid-derived compounds including cholesterol, coenzyme Q and dolichols. High levels of Ac-CoA in hepatocytes stimulate lipid biosynthesis, ketone body production and the diversion of pyruvate metabolism towards gluconeogenesis and away from oxidation; low levels exert opposite effects. Acetylation changes the properties of molecules. Acetylation is necessary for the synthesis of acetylcholine, acetylglutamate, acetylaspartate and N-acetyl amino sugars, and to metabolize/eliminate some xenobiotics. Acetylation is a major post-translational modification of proteins. Different types of protein acetylation occur. The most-studied form occurs at the epsilon nitrogen of lysine residues. In histones, lysine acetylation can alter gene transcription. Acetylation of other proteins has diverse, often incompletely-documented effects. Inborn errors related to Ac-CoA feature a broad spectrum of metabolic, neurological and other features. To date, a small number of studies of animals with inborn errors of CoA thioesters has included direct measurement of acyl-CoAs. These studies have shown that low levels of tissue Ac-CoA correlate with the development of clinical signs, hinting that shortage of Ac-CoA may be a recurrent theme in these conditions. Low levels of Ac-CoA could potentially disrupt any of its roles.

Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.

Deficiency of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase (HL) is an autosomal recessive inborn error of acyl-CoA metabolism affecting the last step of leucine degradation. Patients with HL deficiency (HLD) can develop a potentially fatal cardiomyopathy. We created mice with cardiomyocyte-specific HLD (HLHKO mice), inducing Cre recombinase-mediated deletion of exon 2 at two months of age. HLHKO mice survive, but develop left ventricular hypertrophy by 9 months. Also, within minutes after intraperitoneal injection of the leucine metabolite 2-ketoisocaproate (KIC), they show transient left ventricular hypocontractility and dilation. Leucine-related acyl-CoAs were elevated in HLHKO heart (e.g., HMG-CoA, 34.0 ± 4.4 nmol/g versus 0.211 ± 0.041 in controls, p < 0.001; 3-methylcrotonyl-CoA, 5.84 ± 0.69 nmol/g versus 0.282 ± 0.043, p < 0.001; isovaleryl-CoA, 1.86 ± 0.30 nmol/g versus 0.024 ± 0.014, p < 0.01), a similar pattern to that in liver of mice with hepatic HL deficiency. After KIC loading, HMG-CoA levels in HLHKO heart were higher than under basal conditions, as were the ratios of HMG-CoA/acetyl-CoA and of HMG-CoA/succinyl-CoA. In contrast to the high levels of multiple leucine-related acyl-CoAs, biomarkers in urine and plasma of HLHKO mice show isolated hyper-3-methylglutaconic aciduria (700.8 ± 48.4 mmol/mol creatinine versus 37.6 ± 2.4 in controls, p < 0.001), and elevated C5-hydroxyacylcarnitine in plasma (0.248 ± 0.014 µmol/L versus 0.048 ± 0.005 in controls, p < 0.001). Mice with liver-specific HLD were compared, and showed normal echocardiographic findings and normal acyl-CoA profiles in heart. This study of nonhepatic tissue-specific HLD outside of liver reveals organ-specific origins of diagnostic biomarkers for HLD in blood and urine and shows that mouse cardiac HL is essential for myocardial function in a cell-autonomous, organ-autonomous fashion.

Identification of potential key molecules and signaling pathways for psoriasis based on weighted gene co-expression network analysis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, the pathogenesis of which is more complicated and often requires long-term treatment. In particular, moderate to severe psoriasis usually requires systemic treatment. Psoriasis is also associated with many diseases, such as cardiometabolic diseases, malignant tumors, infections, and mood disorders. Psoriasis can appear at any age, and lead to a substantial burden for individuals and society. At present, psoriasis is still a treatable, but incurable, disease. Previous studies have found that microRNAs (miRNAs) play an important regulatory role in the progression of various diseases. Currently, miRNAs studies in psoriasis and dermatology are relatively new. Therefore, the identification of key miRNAs in psoriasis is helpful to elucidate the molecular mechanism of psoriasis. AIM: To identify key molecular markers and signaling pathways to provide potential basis for the treatment and management of psoriasis. METHODS: The miRNA and mRNA data were obtained from the Gene Expression Omnibus database. Then, differentially expressed mRNAs (DEmRNAs) and differentially expressed miRNAs (DEmiRNAs) were screened out by limma R package. Subsequently, DEmRNAs were analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomics functional enrichment. The "WGCNA" R package was used to analyze the co-expression network of all miRNAs. In addition, we constructed miRNA-mRNA regulatory networks based on identified hub miRNAs. Finally, in vitro validation was performed. All experimental procedures were approved by the ethics committee of Chinese PLA General Hospital (S2021-012-01). RESULTS: A total of 639 DEmRNAs and 84 DEmiRNAs were identified. DEmRNAs screening criteria were adjusted P (adj. P) value < 0.01 and |logFoldChange| (|logFC|) > 1. DEmiRNAs screening criteria were adj. P value < 0.01 and |logFC| > 1.5. KEGG functional analysis demonstrated that DEmRNAs were significantly enriched in immune-related biological functions, for example, toll-like receptor signaling pathway, cytokine-cytokine receptor interaction, and chemokine signaling pathway. In weighted gene co-expression network analysis, turquoise module was the hub module. Moreover, 10 hub miRNAs were identified. Among these 10 hub miRNAs, only 8 hub miRNAs predicted the corresponding target mRNAs. 97 negatively regulated miRNA-mRNA pairs were involved in the miRNA-mRNA regulatory network, for example, hsa-miR-21-5p-claudin 8 (CLDN8), hsa-miR-30a-3p-interleukin-1B (IL-1B), and hsa-miR-181a-5p/hsa-miR-30c-2-3p-C-X-C motif chemokine ligand 9 (CXCL9). Real-time polymerase chain reaction results showed that IL-1B and CXCL9 were up-regulated and CLDN8 was down-regulated in psoriasis with statistically significant differences. CONCLUSION: The identification of potential key molecular markers and signaling pathways provides potential research directions for further understanding the molecular mechanisms of psoriasis. This may also provide new research ideas for the prevention and treatment of psoriasis in the future.

Vaccine-induced erythrodermic psoriasis in a child successfully treated with secukinumab: A case report and brief literature review.

We report a case of a 7-year-old male patient with vaccine-induced erythrodermic psoriasis (EP) complicated by pulmonary infection, hypoproteinemia, and liver dysfunction successfully treated with secukinumab in combination with symptomatic and supportive therapy. The patient presented with diffuse flushing on the head, face, trunk, and limbs, which were covered with chaff-like white scales in the rash-affected area, with no blisters, pustules, and no apparent abnormalities in the palms, soles, nails, and joints. Histopathology analysis revealed hyperkeratosis, focal parakeratosis, thinning or effacement of the granular layer, psoriasiform hyperplasia of the epidermis, neutrophilic microabscess formation in the upper part of the epidermis, edema of the dermal papilla, dilation of blood vessels, and lymphocyte infiltration. The patient was eventually diagnosed with EP. At weeks 0, 1, and 2, the patient received a subcutaneous injection of 150 mg secukinumab (three injections). Fluticasone propionate ointment, taccathitol ointment, yellow vaseline, and other drugs were also given topically. Following 2 weeks of treatment, the child's skin lesions resolved significantly with only slight pigmentation remaining and the Psoriasis Area and Severity Index (PASI) score decreased from 37.5 to 7.5 (PASI 75). Thereafter, 150 mg secukinumab was injected every 4 weeks until the last dose at 18 weeks (four more injections). After 18 weeks, the child's lesion resolved entirely (PASI 100), and no adverse effects were reported.

Propionic acidemia in mice: Liver acyl-CoA levels and clinical course.

Propionic acidemia (PA) is a severe autosomal recessive metabolic disease caused by deficiency of propionyl-CoA carboxylase (PCC). We studied PA transgenic (Pat) mice that lack endogenous PCC but express a hypoactive human PCCA cDNA, permitting their survival. Pat cohorts followed from 3 to 20 weeks of age showed growth failure and lethal crises of lethargy and hyperammonemia, commoner in males (27/50, 54%) than in females (11/52, 21%) and occurring mainly in Pat mice with the most severe growth deficiency. Groups of Pat mice were studied under basal conditions (P-Ba mice) and during acute crises (P-Ac). Plasma acylcarnitines in P-Ba mice, compared to controls, showed markedly elevated C3- and low C2-carnitine, with a further decrease in C2-carnitine in P-Ac mice. These clinical and biochemical findings resemble those of human PA patients. Liver acyl-CoA measurements showed that propionyl-CoA was a minor species in controls (propionyl-CoA/acetyl-CoA ratio, 0.09). In contrast, in P-Ba liver the ratio was 1.4 and in P-Ac liver, 13, with concurrent reductions of the levels of acetyl-CoA and other acyl-CoAs. Plasma ammonia levels in control, P-Ba and P-Ac mice were 109 ± 10, 311 ± 48 and 551 ± 61 µmol/L respectively. Four-week administration to Pat mice, of carglumate (N-carbamyl-L-glutamic acid), an analogue of N-carbamylglutamate, the product of the only acyl-CoA-requiring reaction directly related to the urea cycle, was associated with increased food consumption, improved growth and absence of fatal crises. Pat mice showed many similarities to human PA patients and provide a useful model for studying tissue pathophysiology and treatment outcomes.

Michelson interferometer based phase demodulation for stable time transfer over 1556 km fiber links.

Time transfer based on phase modulation schemes has attracted extensive attention in recent years. We propose and experimentally demonstrate an adjustable and stable Michelson interferometer (MI) with a DC phase tracking algorithm for two-way time transfer. Time signal with one pulse per second (1 PPS) is loaded on an optical carrier modulated in phase and demodulated by a Michelson interferometer. The whole compact and cost-effective demodulator is symmetrical with a single coupler to split and recombine optical waves, flexible with one photodetector and a bias tee to separate the DC signal and recovery pulses and stable with a phase modulator to compensate for the drift-phase noise. We show the implementation of modulation and demodulation of the time signal and obtain the stability of 2.31 × 10-11 at 1000 s averaging time. We then demonstrate two-way time transfer over 1556 km lab fibers. The experimental result shows time interval stability of 1 PPS with 5.62 × 10-11 at 1000 s averaging time. It has the potential to transfer time signals in long-distance fiber optic links.

p53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and striatum. Aging is the most important risk factor of PD. Ferroptosis is an iron-dependent form of cell death associated with PD. However, it is not clear whether ferroptosis accelerates PD by promoting cellular senescence. This study investigated the mechanism of 1-methyl-4-phenylpyridinium (MPP+) -induced PC12 cells injury. We found that MPP+ induced cell senescence with increased ß-galactosidase activity and the expression of p53, p21 and p16 activation in cells. In addition, MPP+ treatment showed smaller mitochondria and increased membrane density, downregulation of ferritin heavy chain 1 expression and upregulation of acyl-CoA synthetase long chain family member 4 expression, and enhanced levels of oxidative stress, which were important characteristics of ferroptosis. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was tested to eliminate MPP+-induced cell senescence. Fer-1 downregulated the expression of p53 and upregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase-4 (GPX4) in MPP+-induced ferroptosis. Inhibition of p53 eliminated cell senescence by upregulation the expression of of SLC7A11 and GPX4. Thus, these results suggest that MPP+ induces senescence in PC12 cells via the p53/ SLC7A11/ GPX4 signaling pathway in the ferroptosis regulation mechanism.

Leptin is upregulated in epididymitis and promotes apoptosis and IL-1ß production in epididymal epithelial cells by activating the NLRP3 inflammasome.

Epididymitis, one of the most common urological disease, is a significant cause of male infertility. Leptin is capable of modulating both reproduction and immune response. We analyzed the serum and seminal plasma levels of leptin in infertile patients with or without chronic epididymitis. Experimental epididymitis models were generated by administrating 200 µg Lipopolysaccharide (LPS) to Sprague-Dawley rats. The expression of leptin in epididymis were detected using qPCR, Western blots 6-72 h after injection, and using immunohistochemistry 72 h after injection. Besides, rat epididymal epithelial cells were isolated as an in vitro model and were treated with leptin (5-40 ng/ml, 6-48 h), LPS (1ug/ml, 6 h), and NLRP3 inflammasome inhibitor MCC950 (10 µM, 2 h). Cell Counting Kits-8 assay and Annexin V/PE assay were used to evaluate cell viability and apoptosis. Quantitive PCR and ELISA assay were used to detected inflammatory cytokines interleukin-1beta (IL-1ß) production. Western Blots were used to detect molecular related to cell apoptosis, IL-1ß maturation, and NLRP3 inflammasome. We found that patients with chronic epididymitis presented a significantly higher level of seminal plasma leptin and correlated declined sperm progressive motility. Leptin and leptin receptor expression in epididymis was significantly upregulated 24 h after LPS administration both in mRNA and protein level, and highly expressed in the epididymis epithelium 72 h after LPS administration. In epididymal epithelial cells, leptin reduced cell viability and promoted apoptosis in a concentration-dependent manner via cleavage of caspase-9, caspase-3, and PARP. Leptin enhanced the LPS-induced production of IL-1ß, which was associated with increased IL-1ß maturation and caspase-1 activation. Furthermore, NLRP3 inhibitor MCC950 attenuated the effects of leptin or co-treatment with LPS on NLRP3, ASC expression, IL-1ß maturation, and caspase-1 activation, which indicated that leptin promotes IL-1ß production via activating the NLRP3 inflammasome. These data suggested that leptin may act as a potential evaluation and treatment target for epididymitis and male subfertility.

Nonstationary El Niño teleconnection on the post-summer upwelling off Vietnam.

Summer upwelling has often been observed off Vietnam in the South China Sea (SCS). Occasional disappearance of the upwelling has attracted much attention because it modulates the regional climate and harms surrounding fisheries. Fluctuations of the East Asian monsoon associated with El Niño are considered responsible for the weakened or abolished upwelling. However, analyses of observations performed in the present study were equivocal in terms of the dominant influence of El Niño. Based on long-term sea surface temperature data, we demonstrated that weak upwelling off Vietnam occurs more frequently during periods of accelerated global warming compared to warming hiatus periods. Warming signals in the Indian Ocean vanished relatively quickly during the hiatus period. The accompanying easterly anomalies south of the anomalous anticyclone (AAC) in the northwestern Pacific were also weakened, reducing the impact of the El Niño teleconnection on the SCS summer monsoon and thus preserving the regular post-summer upwelling off Vietnam during warming hiatus periods.

Gambogenic acid induces ferroptosis in melanoma cells undergoing epithelial-to-mesenchymal transition.

Melanoma is characterized by high malignancy and early onset of metastasis. Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Tumor cells that develop EMT can escape apoptosis, but they are vulnerable to ferroptosis inducers. Gambogenic acid (GNA), a xanthone found in Gamboge, has cytotoxic effects in highly invasive melanoma cells. This study investigated the anti-melanoma effect and mechanism of action of GNA in TGF-ß1-induced EMT melanoma cells. We found that GNA significantly inhibited the invasion, migration and EMT in melanoma cells, and these cells exhibited small mitochondrial wrinkling (an important feature of ferroptosis). An iron chelator, but not an apoptosis inhibitor or a necrosis inhibitor, abolished the inhibitory effects of GNA on proliferation, invasion and migration of TGF-ß1-stimulated melanoma cells. GNA upregulated the expression of p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the model cells, contributing to the mechanisms underlying GNA-induced ferroptosis. Collectively, our findings suggest that GNA induces ferroptosis in TGF-ß1-stimulated melanoma cells via the p53/SLC7A11/GPX4 signaling pathway.

Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice.

Humans and rodents with Comparative Gene Identification-58 (CGI-58) mutations manifest nonalcoholic fatty liver disease (NAFLD). Here we show that liver CGI-58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI-58 KO liver. CRISPR/Cas9-mediated knockout of CGI-58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet-fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression.

An Atlantic-driven rapid circulation change in the North Pacific Ocean during the late 1990s.

Interbasin interactions have been increasingly emphasized in recent years due to their roles in shaping climate trends and the global warming hiatus in the northern hemisphere. The profound influence from the North Atlantic on the Tropical Pacific has been a primary focus. In this study, we conducted observational analyses and numerical modeling experiments to show that the North Atlantic has also strongly influenced the Extratropical North Pacific. A rapid and synchronous change in the atmospheric and oceanic circulations was observed in the North Pacific during the late 1990s. The change was driven by the transbasin influence from the Atlantic Ocean. During the positive phase of the Atlantic Multidecadal Oscillation (AMO) since the 1990s, the anomalously warm North Atlantic triggers a series of zonally symmetric and asymmetric transbasin teleconnections involving the Inter-tropical Convergence Zone (ITCZ), Walker and Hadley circulations, and Rossby wave propagation that lead to a decrease in wind stress curls over the Pacific subtropics, resulting in an abrupt weakening in the North Pacific subtropical gyre (NPSG) and the Kuroshio Current.

Phospholipase C inhibits apoptosis of porcine primary granulosa cells cultured in vitro.

Phospholipase C (PLC) can participate in cell proliferation, differentiation and aging. However, whether it has a function in apoptosis in porcine primary granulosa cells is largely uncertain. The objective of this study was to examine the effects of PLC on apoptosis of porcine primary granulosa cells cultured in vitro. The mRNA expression of BAK, BAX and CASP3, were upregulated in the cells treated with U73122 (the PLC inhibitor). The abundance of BCL2 mRNA, was upregulated, while BAX and CASP3 mRNA expression was decreased after treatment with m-3M3FBS (the PLC activator). Both the early and late apoptosis rate were maximized with 0.5 µM U73122 for 4 h. The rate of early apoptosis was the highest at 4 h and the rate of late apoptosis was the highest at 12 h in the m-3M3FBS group. The protein abundance of PLCß1, protein kinase C ß (PKCß), calmodulin-dependent protein kinaseII α (CAMKIIα) and calcineurinA (CalnA) were decreased by U73122, and CAMKIIα protein abundance was increased by m-3M3FBS. The mRNA expression of several downstream genes (CDC42, NFATc1, and NFκB) was upregulated by PLC. Our results demonstrated that apoptosis can be inhibited by altering PLC signaling in porcine primary granulosa cells cultured in vitro, and several calcium-sensitive targets and several downstream genes might take part in the processes.

Hepatic NPC1L1 overexpression attenuates alcoholic autophagy in mice.

Alcohol consumption causes liver steatosis in humans. Metabolic disorders of lipids are one of the factors that cause liver steatosis in hepatocytes. Hepatic Niemann­Pick C1­like 1 (NPC1L1) regulates lipid homeostasis in mammals. The relationship between NPC1L1 and autophagy in those with a history of alcohol abuse is unclear. The present study aimed to investigate the function of NPC1L1 in the activation of hepatic autophagy in a mouse model with a human (h)NPC1L1 transgene under alcohol feeding conditions. The mice expressing hNPC1L1 (Ad­L1) or controls (Ad­null) were created by retro­orbital adenovirus injection. The Ad­L1 and Ad­null mice were fed with alcohol or a non­alcoholic diet to mimic chronic alcohol consumption in humans. Hepatic autophagy was demonstrated in isolated primary hepatocytes by monitoring autophagic vacuoles under fluorescence microscopy, and by western blotting for autophagic makers. Isolated hepatocytes from the livers of Ad­L1 mice were treated with different doses of ezetimibe to study the restoration of autophagy. Chronic alcohol feeding caused liver injury and steatosis, shown by significantly higher levels of plasma alanine transaminase and aspartate transaminase activity, and by hematoxylin and eosin staining in Ad­L1 and Ad­null mice. Compared to Ad­null control mice, the microtubule­associated proteins 1A/1B light chain 3 (LC3) particles in the isolated hepatocytes of Ad­L1 mice were decreased, both under alcohol and non­alcoholic feeding. The ratio of LC3II/LC3I was significantly decreased, and the level of p62/sequestosome­1 protein was significantly increased in Ad­L1 mice compared with Ad­null mice after alcohol feeding. Levels of LC3II protein were statistically increased in hepatocytes isolated from Ad­L1 mice with ezetimibe treatment. The increase in LC3II expression was dose dependent. Within the tested range, it reached its highest level at 40 µM. The livers of Ad­L1 mice represent a more human­like state for the study of hepatic autophagy. Hepatic expression of human NPC1L1 resulted in an inhibition of autophagy; it may contribute to alcoholic fatty liver disease in humans.

The effects of phospholipase C on oestradiol and progesterone secretion in porcine granulosa cells cultured in vitro.

Granulosa cells play important roles in the regulation of ovarian functions. Phospholipase C is crucial in several signalling pathways and could participate in the molecular mechanisms of cell proliferation, differentiation and ageing. The objective of this study was to identify the effects of phospholipase C on the steroidogenesis of oestradiol and progesterone in porcine granulosa cells cultured in vitro. Inhibitor U73122 or activator m-3M3FBS of phospholipase C was added to the in vitro medium of porcine granulosa cells, respectively. The secretion of oestradiol decreased after 2 hr, 8 hr, 12 hr, 24 hr and 48 hr of treatment with 500 nM U73122 (p < .05) and decreased after 2 hr of treatment in the 500 nM m-3M3FBS addition group (p < .05). The secretion of progesterone increased after 4 hr of treatment with 500 nM U73122 (p < .05) and increased after 2 hr and 8 hr of treatment in the 500 nM m-3M3FBS addition group (p < .05). The ratio of oestradiol to progesterone decreased at each time point, except 8 hr after the addition of 500 nM U73122 (p < .05). The ratio of oestradiol to progesterone decreased after 2 hr (p < .05) of treatment with 500 nM m-3M3FBS. In genes that regulate the synthesis of oestradiol or progesterone, the mRNA expression of CYP11A1 was markedly increased (p < .05), and the mRNA expression of other genes did not change significantly in the U73122 treatment group, while the addition of m-3M3FBS did not change those genes significantly despite the contrary trend. Our results demonstrated that phospholipase C can be a potential target to stimulate the secretion of oestradiol and suppress progesterone secretion in porcine granulosa cells cultured in vitro, which shed light on a novel biological function of phospholipase C in porcine granulosa cells.