Metabolic self-feeding in HBV-associated hepatocarcinoma centered on feedback between circulation lipids and the cellular MAPK/mTOR axis.

INTRODUCTION: Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV- and HBV+ HCC have remained unchanged, limiting HCC treatment options. OBJECTIVES: In this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression. METHODS: We employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes. RESULTS: Our multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients' serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids. CONCLUSION: Our findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.

Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants.

Inherited retinal diseases (IRDs) are a group of common primary retinal degenerative disorders. Conventional genetic testing strategies, such as panel-based sequencing and whole exome sequencing (WES), can only elucidate the genetic etiology in approximately 60% of IRD patients. Studies have suggested that unsolved IRD cases could be attributed to previously undetected structural variants (SVs) and intronic variants in IRD-related genes. The aim of our study was to obtain a definitive genetic diagnosis by employing whole genome sequencing (WGS) in IRD cases where the causative genes were inconclusive following an initial screening by panel sequencing. A total of 271 unresolved IRD patients and their available family members (n = 646) were screened using WGS to identify pathogenic SVs and intronic variants in 792 known ocular disease genes. Overall, 13% (34/271) of IRD patients received a confirmed genetic diagnosis, among which 7% were exclusively attributed to SVs, 4% to a combination of single nucleotide variants (SNVs) and SVs while another 2% were linked to intronic variants. 22 SVs, 3 deep-intronic variants, and 2 non-canonical splice-site variants across 14 IRD genes were identified in the entire cohort. Notably, all of these detected SVs and intronic variants were novel pathogenic variants. Among those, 74% (20/27) of variants were found in genes causally linked to Retinitis Pigmentosa (RP), with the gene EYS being the most frequently affected by SVs. The identification of SVs and intronic variants through WGS enhances the genetic diagnostic yield of IRDs and broadens the mutational spectrum of known IRD-associated genes.

Design of Planar Differential Microphone Array Beampatterns with Controllable Mainlobe Beamwidth and Sidelobe Level.

The differential microphone array, or differential beamformer, has attracted much attention for its frequency-invariant beampattern, high directivity factor and compact size. In this work, the design of differential beamformers with small inter-element spacing planar microphone arrays is concerned. In order to exactly control the main lobe beamwidth and sidelobe level and obtain minimum main lobe beamwidth with a given sidelobe level, we design the desired beampattern by applying the Chebyshev polynomials at first, via exploiting the structure of the frequency-independent beampattern of a theoretical Nth-order differential beamformer. Next, the so-called null constrained and least square beamformers, which can obtain approximately frequency-invariant beampattern at relatively low frequencies and can be steered to any direction without beampattern distortion, are proposed based on planar microphone arrays to approximate the designed desired beampatterns. Then, for dealing with the white noise amplification at low-frequency bands and beampattern divergence problems at high-frequency bands of the null constrained and least square beamformers, the so-called minimum norm and combined solutions are deduced, which can compromise among the white noise gain, directivity factor and beampattern distortion flexibly. Preliminary simulation results illustrate the properties and advantages of the proposed differential beamformers.

Bufalin Inhibits Tumorigenesis and SREBP-1-Mediated Lipogenesis in Hepatocellular Carcinoma via Modulating the ATP1A1/CA2 Axis.

Altered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.

Flower-like Composite Material Delivery of Co-Packaged Lenvatinib and Bufalin Prevents the Migration and Invasion of Cholangiocarcinoma.

The co-delivery of multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a monodisperse mesoporous silica nanoparticle (mSiO2) is prepared and functionalized into high-efficiency loaded Lenvatinib and Bufalin for targeted delivery to Cholangiocarcinoma (CCA). mSiO2 was synthesized on solid silica nanoparticles by oil-water interface method, and highly monodisperse mSiO2 with uniform morphology was obtained. mSiO2 was then sequentially modified by polyethylene glycol (PEG) and the targeting molecule folic acid (FA). mSiO2-FA was designed as co-delivery system for Lenvatinib (Le) and Bufalin (Bu) to increase drug availability and highly target tumor cells. Compared with unfunctionalized mSiO2, mSiO2-FA can more efficiently enter human CCA cell lines (9810 cells) and enhance intracellular drug delivery. Moreover, drug-loaded mSiO2-FA (Le/Bu@mSiO2-FA) significantly inhibited the viability, migration and invasion of 9810 cells. In vivo, the nanocomplex significantly reduced the tumor load in CCA tumor-bearing mouse models compared to Le or Bu alone. The current work provides a useful strategy for highly targeted and multidrug-resistance reversal therapy for CCA.

Identification and Validation of a Tumor Microenvironment-Related Gene Signature in Hepatocellular Carcinoma Prognosis.

Background: Hepatocellular carcinoma (HCC) is a typical inflammatory-related malignant tumor with complex immune tolerance microenvironment and poor prognosis. In this study, we aimed to construct a novel immune-related gene signature for the prognosis of HCC patients, exploring tumor microenvironment (TME) cell infiltration characterization and potential mechanisms. Methods: A total of 364 HCC samples with follow-up information in the TCGA-LIHC dataset were analyzed for the training of the prognostic signature. The Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the IRGs was conducted to identify the prognostic genes and establish an immune risk signature. The immune cell infiltration in TME was estimated via the CIBERSORT method. Gene Set Variation Analysis (GSVA) was conducted to compare the biological pathways involved in the low-risk and high-risk groups. Furthermore, paraffin sections of HCC tissue microarrays containing 77 patients from Fudan University Shanghai Cancer Center were used for IHC staining. The clinical characteristics of the 77 HCC patients were collected and summarized for survival analysis validation via the Kaplan-Meier (KM) method. Results: Three-gene signature with close immune correlation (Risk score = EPO * 0.02838 + BIRC5 * 0.02477 + SPP1 * 0.0002044) was constructed eventually and proven to be an effective prognostic factor for HCC patients. The patients were divided into a high-risk and a low-risk group according to the optimal cutoff, and the survival analysis revealed that HCC samples with high-risk immuno-score had significantly poorer outcomes than the low-risk group (p < 0.0001). The results of CIBERSORT suggested that the immune cell activation was relatively higher in the low-risk group with better prognosis. Besides, GSVA analysis showed multiple signaling differences between the high- and low-risk group, indicating that the three-gene prognostic model can affect the prognosis of patients by affecting immune-related mechanisms. Tissue microarray (TMA) results further confirmed that the expression of three genes in HCC tissues was closely related to the prognosis of patients, respectively. Conclusion: In this study, we constructed and validated a robust three-gene signature with close immune correlation in HCC, which presented a reliable performance in the prediction of HCC patients' survival.

Botanical Drug Puerarin Promotes Neuronal Survival and Neurite Outgrowth against MPTP/MPP+-Induced Toxicity via Progesterone Receptor Signaling.

BACKGROUND: Progesterone receptor (PR) modulates neuroprotective and regenerative responses in Parkinson's disease and related neurological diseases. OBJECTIVES: The present study was designed to determine whether botanical drug puerarin could exhibit neuroprotective and neurorestorative activities via PR signaling. METHODS: The neuroprotective and neurotrophic activities of puerarin were investigated in MPTP-lesioned mice and MPP+-challenged primary rat midbrain neurons. Rotarod performance test and tail suspension test were used to assess motor functions. Tyrosine hydroxylase (TH) and PR were determined by immunostaining, Western blotting, and luciferase reporter assays. Neurite outgrowth was assessed by fluorescence staining and immunostaining. RESULTS: Puerarin effectively ameliorated the MPTP-induced motor abnormalities in MPTP-lesioned mice and protected primary rat midbrain neurons against MPP+-induced toxicity via PR signaling although progesterone exhibited the neuroprotection. PR antagonist mifepristone (RU486) diminished the neuroprotection of puerarin in MPTP-lesioned mice and MPP+-induced primary rat midbrain neurons. Moreover, puerarin promoted the differentiation of primary rat midbrain neurons and potentiated NGF to induce neuritogenesis in PC12 cells. RU486 and PR-siRNA could inhibit the effect of puerarin. Puerarin and progesterone could enhance the PR promoter. CONCLUSION: Puerarin attenuated MPTP- and MPP+-induced toxicity and potentiated neurite outgrowth via PR. These results suggested that puerarin may become an alternative hormone for suppressing MPTP- and MPP+-induced toxicity in neurodegenerative diseases.

Model-based distributed node clustering and multi-speaker speech presence probability estimation in wireless acoustic sensor networks.

The knowledge of speech presence probability (SPP) plays an essential role in noise estimation and speech enhancement. Single channel SPP estimation and centralized multi-channel SPP estimation have been well studied. However, how to estimate SPP in wireless acoustic sensor networks (WASNs) remains a great challenge and few efforts can be found in this topic, particularly for WASN applications with multiple speakers. Accordingly, this paper is devoted to the problem of SPP estimation in WASNs and it presents a distributed model-based SPP estimation method for multi-speaker detection, which does not need any fusion center. A distributed k-means clustering method is first used to cluster the nodes into subnetworks, which detect different speakers. For each node in the subnetwork, the speech and noise power spectral densities are estimated locally by using a model-based method, then a distributed SPP estimator is developed and applied in every subnetwork. A distributed consensus method is used to obtain the distributed clustering and the distributed SPP estimation. Simulation results show that the proposed distributed clustering method can assign nodes into subnetworks based on their noisy observations. Moreover, the proposed distributed SPP estimator achieves robust speech detection performance under different noise conditions.

N-Propargyl caffeate amide (PACA) prevents cardiac fibrosis in experimental myocardial infarction by promoting pro-resolving macrophage polarization.

Macrophages control the initiation and resolution of cardiac fibrosis in post-infarction cardiac remodeling. The aim of the present study was to investigate whether N-propargyl caffeate amide (PACA) could suppress myocardial fibrosis via regulating macrophage polarization. By using rat model of isoproterenol-induced myocardial fibrosis, we discovered that PACA could reduce cardiac fibrosis in a dose-dependent manner. To elucidate the anti-fibrotic mechanisms, we examined whether PACA affected pro-inflammatory M1 and pro-resolving macrophage biomarkers in macrophage polarization. As result, PACA reduced the expression of pro-inflammatory M1 biomarkers (e.g., iNOS, TNF-α, CXCL10, IL-6, CCL2 and CD80) while increased the expression of pro-resolving M2a biomarkers (e.g., IL-10, arginase-1, FZZ1, YM-1 and CD163) in LPS-stimulated RAW264.7 macrophages. PACA also suppressed the elevation of M1 biomarker ED1 in the early phase but up-regulated the expression of pro-resolving biomarker ED2 in the later phase. Moreover, PACA reduced the expression of pro-fibrotic TGF-ß1 and PDGF-α while maintained or even increased the production of pro-apoptotic MMP-13, MMP-9 and TRAIL. Importantly, mechanistic studies revealed that PACA might promote the switch of macrophage polarization towards a pro-resolving macrophage phenotype via activating PPAR-γ pathway. Taken together, this study suggested that PACA might be a drug candidate for preventing cardiac fibrosis in myocardial infarction.

Interplay between Exosomes and Autophagy in Cardiovascular Diseases: Novel Promising Target for Diagnostic and Therapeutic Application.

Exosome, is identified as a nature nanocarrier and intercellular messenger that regulates cell to cell communication. Autophagy is critical in maintenance of protein homeostasis by degradation of damaged proteins and organelles. Autophagy and exosomes take pivotal roles in cellular homeostasis and cardiovascular disease. Currently, the coordinated mechanisms for exosomes and autophagy in the maintenance of cellular fitness are now garnering much attention. In the present review, we discussed the interplay of exosomes and autophagy in the context of physiology and pathology of the heart, which might provide novel insights for diagnostic and therapeutic application of cardiovascular diseases.

Electro-Acupuncture Ameliorated MPTP-Induced Parkinsonism in Mice via TrkB Neurotrophic Signaling.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), have shown promise as neuroprotective agents, indicating their potential in therapeutic strategies for neurodegenerative disease. However, the inherent bioactivity and pharmaceutical limitations of BDNF compromise its clinical efficacy. Research has documented the beneficial effects of electroacupuncture (EA) against neurodegeneration, possibly by BDNF-mediated mechanisms. The present study was designed to clarify whether EA can mount a neuroprotective effect in mice lesioned with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) via stimulation of the BDNF-TrkB signaling pathway. We found that EA not only ameliorated the motor dysfunction but also restored the dopaminergic neuronal function and upregulated BDNF expression in MPTP-lesioned mice. Interestingly, the TrkB inhibitor K252a abolished the neuroprotective effects of EA. Western blot analyses further demonstrated that EA might recover the level of phospho-Akt, phospho-ERK1/2, and BDNF against MPTP neurotoxicity via reversing the imbalance between TrkB FL and TrkB T1. Taken together, the results of the present study show that EA stimulation can ameliorate MPTP-induced parkinsonism in mice. Such a neuroprotective effect may be partially mediated via restoring TrkB neurotrophic signaling.

Weight reduction and cardiovascular benefits: Protocol for a systematic review and meta-analysis.

BACKGROUND: There is widespread obesity paradox in cardiovascular diseases, the cardiovascular influence from weight management remains controversial. Moreover, previous publications indicating that different weight reduction extent might lead to various results. Thus, it is of importance to reassess the cardiovascular benefits of weight management strategies. OBJECTIVES: This review is designed to assess the association between weight loss and cardiovascular outcomes. METHODS: Clinical trials including randomized control trials, observational studies reported a weight change before and after weight interventions including lifestyle intervention, as well as pharmacotherapies were included. Three major databases will be searched to retrieve the appropriate studies. Dual selection and abstraction of data will be conducted by 2 authors independently. The population, intervention, comparator, outcomes, study characteristics framework will be used to extract all the necessary data from included studies. The risk of bias assessment will be conducted in duplicate based on the Cochrane risk of bias guideline for randomized controlled trials (RCTs) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for observational studies respectively. The primary outcomes will be the cardiovascular mortality, and the secondary outcomes are all-cause mortality and new cardiovascular events. A meta-analysis will be considered if there is sufficient homogeneity among selected studies. Follow the criteria of Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the quality of the cumulative evidence will be evaluated. RESULTS AND CONCLUSIONS: The results of this systematic review could provide reliable and concrete evidence for weight loss and its cardiovascular benefits.Prospero registration number: CRD42018108582.

A mechanistic overview of herbal medicine and botanical compounds to target transcriptional factors in Breast cancer.

The abnormalities of transcription factors, such as NF-κB, STAT, estrogen receptor, play a critical role in the initiation and progression of breast cancer. Due to the limitation of current treatment, transcription factors could be promising therapeutic targets, which have received close attention. In this review, we introduced herbal medicines, as well as botanical compounds that had been verified with anti-tumor properties via regulating transcription factors. Herbs, compounds, as well as formulae reported with various transcriptional targets, were summarized thoroughly, to provide implication for the future research on basic experiment and clinical application.

Roles and Mechanisms of Herbal Medicine for Diabetic Cardiomyopathy: Current Status and Perspective.

Diabetic cardiomyopathy is one of the major complications among patients with diabetes mellitus. Diabetic cardiomyopathy (DCM) is featured by left ventricular hypertrophy, myocardial fibrosis, and damaged left ventricular systolic and diastolic functions. The pathophysiological mechanisms include metabolic-altered substrate metabolism, dysfunction of microvascular, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, cardiomyocyte apoptosis, mitochondrial dysfunction, and impaired Ca2+ handling. An array of molecules and signaling pathways such as p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and extracellular-regulated protein kinases (ERK) take roles in the pathogenesis of DCM. Currently, there was no remarkable effect in the treatment of DCM with application of single Western medicine. The myocardial protection actions of herbs have been gearing much attention. We present a review of the progress research of herbal medicine as a potential therapy for diabetic cardiomyopathy and the underlying mechanisms.

Meta-Analysis of the Effect of Obstructive Sleep Apnea on Cardiovascular Events After Percutaneous Coronary Intervention.

Increasing evidence proved that obstructive sleep apnea (OSA) is associated with a variety of diseases, especially cardiovascular diseases. This study systematically reviewed the existing publications to assess the influence of OSA on cardiovascular survival among patients who underwent percutaneous coronary intervention. Eleven eligible publications, including 3,008 participants, were finally evaluated. Eight studies conducted adjustment of risk ratio for potential cardiovascular risk factors, 5 studies defined OSA groups as AHI (apnea hypopnea index) ≥15/hour, whereas the remaining eligible studies used AHI ≥5/hour, AHI ≥10/hour, or AHI ≥30/hour as the criteria. According to the result from 5 studies that use AHI ≥15/hour as OSA group, the existence of OSA could, to some extent, increase the risk of cardiovascular events (risk ratio 1.59, 95% confidence interval 1.22 to 2.06). Meanwhile, hazard ratio was also observed in separate co-morbidities, such as cardiac death, all-cause mortality, stroke, target lesion revascularization, non-fatal myocardial infarction, hospitalization for heart failure, and recurrence of acute coronary syndrome, regardless if the estimates are varied among studies. In conclusion, OSA can independently increase the risk of cardiovascular events, even after adjustment for confounders. Sleep health should be given utmost importance due to its extensive influence on cardiovascular disorders.

Mechanisms and Clinical Application of Tetramethylpyrazine (an Interesting Natural Compound Isolated from Ligusticum Wallichii): Current Status and Perspective.

Tetramethylpyrazine, a natural compound from Ligusticum wallichii (Chuan Xiong), has been extensively used in China for cardiovascular and cerebrovascular diseases for about 40 years. Because of its effectiveness in multisystems, especially in cardiovascular, its pharmacological action, clinical application, and the structural modification have attracted broad attention. In this paper its mechanisms of action, the clinical status, and synthetic derivatives will be reviewed briefly.

Chinese herbal medicine bushen qinggan formula for blood pressure variability and endothelial injury in hypertensive patients: a randomized controlled pilot clinical trial.

Background. Blood pressure variability (BPV) independent of average blood pressure is related to cardiovascular damage. Meanwhile, BPV is also associated with measures of endothelial injury. Decoction, a traditional used form of Traditional Chinese Medicine (TCM), is inconvenient to prepare, carry, and store. Dispensing granules is now developing as an alternative to decoction, but the evidence supporting its clinical efficacy the same as decoction remains unclear. Objective. To examine the therapeutic effects on mean blood pressure (MBP), blood pressure variability, and endothelial function by giving Bushen Qinggan Formula, a compound Chinese Herbal Medicine and also to evaluate the difference in efficacy between decoction and granule. Methods. A total of 150 patients with hypertension were enrolled and randomly assigned to receive the placebo, Bushen Qinggan decoction, or Bushen Qinggan granule in addition to the standard medications (amlodipine-5 mg/d) for the treatment of essential hypertension (EH). The outcome was the reduction in the MBP and BPV and also included changes in the endothelial markers including endothelin-1 (ET-1) and nitric oxide (NO) after 8 weeks of treatment. Results. Compared with the control group, the Bushen Qinggan decoction and granule groups had significant improvement (P < 0.01) in BPV and endothelial founction. The level of BPV and endothelial function between decoction and granule group had no significant difference (P > 0.05). Conclusion. Based on the standard treatment, Bushen Qinggan Formula further improved BPV and endothelial function. The efficacy of Bushen Qinggan decoction and granule is similar in improving BPV and endothelial function. However, no significant antihypertensive effects could be demonstrated.