Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model.

Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine "disease syndrome" and "macro micro" system modeling to facilitate translational research in CHM formulas.

Mediterranean diet for cardiovascular disease: an evidence mapping study.

OBJECTIVE: This study aimed to evaluate the methodological quality of existing meta-analyses (MA) and the quality of evidence for outcome indicators to provide an updated overview of the evidence concerning the therapeutic efficacy of the Mediterranean diet (MD) for various types of CVD. DESIGN: We conducted comprehensive searches of PubMed, Cochrane Library, and Embase databases. The quality of the MA was assessed using the A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) checklist, while the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence evaluation system was employed to evaluate the quality of evidence for significant outcomes. SETTING: The CVD remains a significant contributor to global mortality. Multiple MA have consistently demonstrated the efficacy of medical interventions in managing CVD. However, due to variations in the scope, quality and outcomes of these reviews, definitive conclusions are yet to be established. PARTICIPANTS: This study included five randomized trials and twelve non-randomized studies, with a combined participant population of 716 318. RESULTS: The AMSTAR 2 checklist revealed that 54·55 % of the studies demonstrated high quality, while 9·09 % exhibited low quality, and 36·36 % were deemed critically low quality. Additionally, there was moderate evidence supporting a positive correlation between MD and CHD/acute myocardial infarction, stroke, heart failure, cardiovascular events, coronary events and major adverse cardiovascular events. CONCLUSIONS: This study indicates that although recognizing the potential efficacy of MD in managing CVD, the quality of the methodology and the evidence for the outcome indicators remain unsatisfactory.

Assessment of Bidirectional Relationships between Mental Illness and Rheumatoid Arthritis: A Two-Sample Mendelian Randomization Study.

A correlation between mental illness and systemic rheumatoid arthritis (RA) has been observed in several prior investigations. However, little is known about the causative relationship between them. The present study aimed to systematically investigate the potential association between genetically determined mental illness and RA. Two-sample bidirectional Mendelian randomization (MR) analysis was performed using publicly released genome-wide association studies (GWAS). We selected independent genetic variants associated with four mental illnesses (bipolar disorder, broad depression, major depression, and anxiety) as instrumental variables. The inverse variance weighted (IVW) method was used as the primary analysis to assess the causal relationship between mental illness and RA. Results of the IVW analysis suggested that genetic predisposition to bipolar disorder was associated with a decreased risk of RA (odds ratio [OR] = 0.825, 95% CI = 0.716 to 0.95, p = 0.007). Furthermore, we did not find a significant causal effect of RA on bipolar disorder in the reverse MR analysis (p > 0.05). In addition, our study found no evidence of a bidirectional causal relationship between genetically predicted broad depression, major depression, anxiety, and RA (p > 0.05). The genetically proxied bipolar disorder population has a lower RA risk, which may indicate that there is a hidden mechanism for inhibiting the pathogenesis of RA in bipolar disorder. However, results do not support a causal connection between depression, anxiety, and RA.

Global research trends in atherosclerosis-related NF-κB: a bibliometric analysis from 2000 to 2021 and suggestions for future research.

Background: Atherosclerosis (AS) is closely related to stroke and cardiovascular diseases. Nuclear factor kappa-B (NF-κB) is the master regulator of inflammation, and thus, modulating the transcription of NF-κB can improve AS. Methods: In this study, we conducted a bibliometric analysis to identify the frontiers, hotspots, and features of global research output on NF-κB in AS from 2000 to 2021. Papers published from 2000 to 2021 and the recorded information were retrieved from the Science Citation Index-Expanded of the Web of Science Core Collection. Bibliometric analysis and visualization were performed using VOSviewer and CiteSpace, including an analysis of the general distribution of annual output, highly productive countries, active journals, active institutions and authors, keywords, and co-cited references. Results: A total of 5,439 original articles and reviews were retrieved and analyzed, and the results indicated that the annual number of publications on NF-κB in AS has been increasing in waves over the past 22 years. The majority of papers were published in China, while the USA had the highest number of citations and H-index. The most productive affiliation and journal were the University of California System and Arteriosclerosis Thrombosis and Vascular Biology, respectively. The papers of Chiu JJ. received the highest number of citations globally in 2011. The keywords, "nlrp3 inflammasome" and "microRNA", have recently attracted considerable attention, and very frequently occurring keywords included "NF kappa B", "atherosclerosis", "expression", "activation", "endogenous cell", and "oxidative stress". New keywords in 2021 included "muscle", "attenuates atherosclerosis", "mesenchymal transition", "metabolic disorder", and "palmitic acid". Conclusions: AS and inflammation have become research hotspots lately. Over the past decade, most studies have focused on basic research, and pathways associated with the regulatory role of NF-κB in AS have become a particular focus in recent studies. Moreover, our study revealed that NF-κB plays a remarkable role in AS and may be a therapeutic target.

Mineralocorticoid Receptors Mediate Diet-Induced Lipid Infiltration of Skeletal Muscle and Insulin Resistance.

Excess circulating lipids increase total intramyocellular (IMC) lipid content and ectopic fat storage, resulting in lipotoxicity and insulin resistance in skeletal muscle. Consumption of a diet high in fat and refined sugars-a Western diet (WD)-has been shown to activate mineralocorticoid receptors (MRs) and promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study, we investigated the mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic skeletal muscle lipid accumulation and related insulin resistance. Six-week-old C57BL/6J mice were fed either a mouse chow diet or a WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD-induced in vivo glucose intolerance and insulin resistance, and improved soleus insulin metabolic signaling. Improved insulin sensitivity was accompanied by increased glucose transporter 4 (Glut4) expression in conjunction with decreased soleus free fatty acid and IMC lipid content, as well as CD36 expression. Additionally, spironolactone prevented WD-induced soleus mitochondria dysfunction. Furthermore, MR signaling also mediated WD/aldosterone-induced reductions in soleus microRNA (miR)-99a, which was identified to negatively target CD36 and prevented palmitic acid-induced increases in CD36 expression, lipid droplet formation, mitochondria dysfunction, and insulin resistance in C2C12 cells. These data indicate that inhibition of MR activation with spironolactone prevented diet-induced abnormal expression of miR-99a, which had the capacity to reduce CD36, leading to reduced IMC lipid content and improved soleus mitochondria function and insulin sensitivity.

Identification and characterization of virus-encoded circular RNAs in host cells.

Emerging evidence has identified viral circular RNAs (circRNAs) in human cells infected by viruses, interfering with the immune system and inducing diseases including human cancer. However, the biogenesis and regulatory mechanisms of virus-encoded circRNAs in host cells remain unknown. In this study, we used the circRNA detection tool CIRI2 to systematically determine the virus-encoded circRNAs in virus-infected cancer cell lines and cancer patients, by analysing RNA-Seq datasets derived from RNase R-treated samples. Based on the thousands of viral circRNAs we identified, the biological characteristics and potential roles of viral circRNAs in regulating host cell function were determined. In addition, we developed a Viral-circRNA Database (http://www.hywanglab.cn/vcRNAdb/), which is open to all users to search, browse and download information on circRNAs encoded by viruses upon infection.

Vectorized rooftop area data for 90 cities in China.

Reliable information on building rooftops is crucial for utilizing limited urban space effectively. In recent decades, the demand for accurate and up-to-date data on the areas of rooftops on a large-scale is increasing. However, obtaining these data is challenging due to the limited capability of conventional computer vision methods and the high cost of 3D modeling involving aerial photogrammetry. In this study, a geospatial artificial intelligence framework is presented to obtain data for rooftops using high-resolution open-access remote sensing imagery. This framework is used to generate vectorized data for rooftops in 90 cities in China. The data was validated on test samples of 180 km2 across different regions with spatial resolution, overall accuracy, and F1 score of 1 m, 97.95%, and 83.11%, respectively. In addition, the generated rooftop area conforms to the urban morphological characteristics and reflects urbanization level. These results demonstrate that the generated dataset can be used for data support and decision-making that can facilitate sustainable urban development effectively.

CXCL1 Clone Evolution Induced by the HDAC Inhibitor Belinostat Might Be a Favorable Prognostic Indicator in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its lack of treatment options. Patients with TNBC frequently develop resistance to chemotherapy. As epigenetic-based antineoplastic drugs, histone deacetylase inhibitors (HDACis) have achieved particular efficacy in lymphoma but are less efficacious in solid tumors, and the resistance mechanism remains poorly understood. In this study, the GSE129944 microarray dataset from the Gene Expression Omnibus database was downloaded, and fold changes at the transcriptome level of a TNBC line (MDA-MB-231) after treatment with belinostat were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the critical biological processes. Construction and analysis of the protein-protein interaction (PPI) network were performed to screen candidate genes related to cancer prognosis. A total of 465 DEGs were identified, including 240 downregulated and 225 upregulated genes. The cytokine-cytokine receptor pathway was identified as being significantly changed. Furthermore, the expression of CXCL1 was implicated as a favorable factor in the overall survival of breast cancer patients. With in vitro approaches, we also showed that belinostat could induce the expression of CXCL1 in another 2 TNBC cell lines (BT-549 and HCC-1937). We speculate that belinostat-induced CXCL1 expression could be one of the results of the stress clone evolution of cells after HDACi treatment. These findings provide new insights into clone evolution during HDACi treatment, which might guide us to a novel perspective that various mutation-targeted treatments should be implemented during the whole treatment cycle.

Aberrant resting-state cerebral blood flow and its connectivity in primary dysmenorrhea on arterial spin labeling MRI.

PURPOSE: This study aimed to clarify the resting-state cerebral blood flow alteration patterns induced by primary dysmenorrhea, investigate the relationships between cerebral blood flow alterations and clinical parameters of patients with primary dysmenorrhea, and explore whether brain regions with abnormal cerebral blood flow also feature functional connectivity changes. METHODS: Arterial spin labeling imaging and clinical parameters were acquired in 42 patients with primary dysmenorrhea and 41 healthy controls during their menstrual phases. Differences in cerebral blood flow were compared between the two groups, and the clusters with significant group differences were selected as the regions of interest for further statistical analyses. RESULTS: Compared to healthy controls, patients with primary dysmenorrhea exhibited increased cerebral blood flow in the bilateral precuneus, left posterior cingulate cortex, and right rolandic operculum. Among patients with primary dysmenorrhea, we identified a negative correlation between the cerebral blood flow in the right rolandic operculum and the visual analogue score for anxiety, and greater correlation between the functional connectivity in the precuneus/posterior cingulate cortex and the right middle cingulate cortex, and between the right rolandic operculum and the left inferior parietal lobule and the bilateral postcentral gyrus. DISCUSSION: Cerebral blood flow abnormalities associated with primary dysmenorrhea were mainly concentrated in the areas comprising the default mode network in primary dysmenorrhea patients, which could be involved in the central mechanism of primary dysmenorrhea. Cerebral blood flow alteration in the rolandic operculum may underlie an anxiety-induced compulsive tendency in patients with primary dysmenorrhea. Investigating the enhanced connectivity among various pain-related brain regions could improve understanding of the onset and development of primary dysmenorrhea.

[Comparison of therapeutic effect of soft-tissue relaxing needling and electroacupuncture for knee osteoarthritis].

OBJECTIVE: To compare the clinical efficacy of soft-tissue relaxing needling and electroacupuncture (EA) in the treatment of knee osteoarthritis (KOA), so as to explore a new and more effective therapy for KOA. METHODS: Forty patients with KOA who met our diagnostic criteria were randomly and equally divided into acupuncture group and soft-tissue relaxing needling (relaxing-needling) group. EA (20 Hz, a tolerable strength and duration of 20 min) was applied to the unilateral Neixiyan(EX-LE5) and Waixiyan(EX-LE5), and manual acupuncture stimulation was applied to Heding(EX-LE2), Xuehai (SP10), Xiyangguan (GB33), Liangqiu(ST34), Yanglingquan(GB34) and Yinlingquan(SP9) on the affected side by using uniform reinforcing-reducing technique. In the relaxing-needling group, after identifying the tender point and nodule-like or stiff-strip-muscle spot at the affected limb by palpation, we used filiform needles to insert into them, then, made a longitudinal separation or point-like pricking. The visual analog scale (VAS) pain score, knee flexion activity (range of motion, ROM), and the knee osteoarthritis severity (Lequesne index, composed of daily living, walking distance and pain) were measured before and after the treatment. The therapeutic effect was assessed by consulting the Guiding Principles for Researching New Drugs of Traditional Chinese Medicine (2002) and Criteria for Diagnosis and Assessment of Therapeutic Effect of Syndromes or Illnesses of Traditional Chinese Medicine (1994). RESULTS: After the treatment, the VAS score and Lequesne index were significantly decreased in both acupuncture and relaxing-needling groups (P<0.001), and the ROM score was considerably increased in both groups in comparison with their own pre-treatment (P<0.001). The difference values of VAS score and Lequesne index between pre- and post-treatment were significantly higher in the relaxing-needling group than in the acupuncture group (P<0.05). Of the two 20 cases in the relaxing-needling and acupuncture groups, 8 and 3 experienced a remarkable improvement in their symptoms, 10 and 13 were effective, 2 and 4 failed, with the effective rate being 90.0% and 80.0%, respectively. No significant difference was found between the two groups in the difference value of ROM score and the effective rate (P>0.05)．. CONCLUSION: Both relaxing-needling and EA therapies are comparable in the therapeutic effect for KOA, and the former is superior to the latter in reducing the joint pain and improving the knee joint locomotor function, thus being worthy of clinical application.

Effect of EZH2 knockdown on preimplantation development of porcine parthenogenetic embryos.

The EZH2 protein endows the polycomb repressive complex 2 (PRC2) with histone lysine methyltransferase activity that is associated with transcriptional repression. Recent investigations have documented crucial roles for EZH2 in mediating X-inactivation, stem cell pluripotency and cancer metastasis. However, there is little evidence demonstrating the maternal effect of EZH2 on porcine preimplantation development. Here, we took parthenogenetic activation embryos to eliminate the confounding paternal influence. We showed that the dynamic expression of EZH2 during early development was accompanied by changes in H3K27me3 levels. Depletion of EZH2 in MII oocytes by small interfering RNA not only impaired embryonic development at the blastocyst stage (P < 0.05), but also disrupted the equilibrium of H3K4me3 and H3K27me3 in the embryo. Interestingly, the expression of TET1, a member of Ten-Eleven Translocation gene family for converting 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5hmC), was decreased after EZH2 knockdown, in contrast to the increase of the other two members, TET2 and TET3 (P < 0.05). These results indicate a correlation between histone methylation and DNA methylation, and between EZH2 and TET1. Along with the downregulation of TET1, the expression of the pluripotency gene NANOG was decreased (P < 0.05), which is consistent with a previous finding in mouse ES cells. Meanwhile, the abundance of OCT4 and SOX2 were also down-regulated. Moreover, EZH2 knockdown reduced the capacity of cells in the blastocysts to resist apoptosis. Taken together, our data suggest that EZH2 is integral to the developmental program of porcine parthenogenetic embryos and exerts its function by regulating pluripotency, differentiation and apoptosis.

Roscovitine and Trichostatin A promote DNA damage repair during porcine oocyte maturation.

Faithful repair of DNA double-strand breaks in mammalian oocytes is essential for meiotic maturation and embryonic development. In the present study we investigated the roles of Roscovitine and Trichostatin A (TSA) in DNA damage recovery during invitro maturation of porcine oocytes. Etoposide was used to trigger DNA damage in oocytes. When these DNA-damaged oocytes were treated with 2µM Roscovitine, 50nM TSA or both for 22h, first polar body extrusion and blastocyst formation in all treated groups were significantly improved compared with the etoposide-only group. The most significant improvement was observed when Roscovitine was present. Further immunofluorescent analysis of γH2A.X, an indicator of DNA damage, indicated that DNA damage was significantly decreased in all treated groups. This observation was further supported by analysing the relative mRNA abundance of DNA repair-related genes, including meiotic recombination 11 homolog A (MRE11A), breast cancer type 1 susceptibility protein (BRCA1), Recombinant DNA Repair Protein 51 (RAD51), DNA-dependent protein kinase catalytic subunit (PRKDC) and X-ray cross complementing gene 4 (XRCC4). Compared with the etoposide-only group, the experimental group with combined treatment of Roscovitine and TSA showed a significant decrease of all genes at germinal vesicle and MII stages. The Roscovitine-only treatment group revealed a similar tendency. Together, these results suggest that Roscovitine and TSA treatments could increase the capacity of oocytes to recover from DNA damage by enlisting DNA repair processes.

MiR-30a-5p confers cisplatin resistance by regulating IGF1R expression in melanoma cells.

BACKGROUND: Melanoma is notoriously resistant to all current modalities of cancer therapies including chemotherapy. In recent years, microRNAs (miRNAs) have emerged as molecular regulators in the development and progression of melanoma. However, the relationship between microRNA and chemo-resistance of melanoma is little known. In present study, we aimed to investigate the miRNAs related to cisplatin-resistance in melanoma cells. METHODS: After cisplatin (DDP) resistant melanoma cells (M8/DDP and SK-Mel-19/DDP) were established in-vitro, high-throughput screening of differentially expressed miRNAs between resistant cells and parental cells were performed. RESULTS: It was found that a cancer-related miRNA, miR-30a-5p, was highly over-expressed in resistant cells. Transfection of miR-30a-5p mimic or inhibitor could alter the sensitivity of melanoma cells to cisplatin. Next, we showed that Insulin Like Growth Factor 1 Receptor (IGF1R) gene turned out to be a direct target of miR-30a-5p. Knockdown of IGF1R in melanoma cells could not only reduce the sensitivity to cisplatin but also lead to cell cycle arrest by regulating phosphorylation of Serine-Threonine Protein Kinase (P-AKT (Ser473)) and Tumor Protein P53 (P53). CONCLUSION: Taken together, our study demonstrated that miR-30a-5p could influence chemo-resistance by targeting IGF1R gene in melanoma cells, which might provide a potential target for the therapy of chemo-resistant melanoma cells.

Long non-coding RNA MALAT-1 modulates metastatic potential of tongue squamous cell carcinomas partially through the regulation of small proline rich proteins.

BACKGROUND: We previously described several abnormally expressed long non-coding RNA (lncRNA) in tong squamous cell carcinomas (TSCCs) that might be associated with tumor progression. In the present study, we aimed to investigate the role of abnormally expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) lncRNA in the metastatic potential of TSCC cells and its molecular mechanisms. METHODS: Expression levels of MALAT-1 lncRNA were examined via quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in 127 TSCC samples as well as paired adjacent normal tissues and lymph node metastases (if exist). Lentiviral vectors expressing short hairpin RNA (shRNA) were used to knock down the expression of MALAT1 gene in two TSCC cell lines (CAL27 and SCC-25) with relatively higher MALAT-1 expression. Proliferational ability of the TSCC cells was analyzed using water soluble tetrazolium-1 (WST-1) assay. Metastatic abilities of TSCC cells were estimated in-vitro and in-vivo. We also performed a microarray-based screen to identify the genes influenced by MALAT-1 alteration, which were validated by real-time PCR analysis. RESULTS: Expression of MALAT-1 lncRNA was enhanced in TSCCs, especially in those with lymph node metastasis (LNM). Knockdown (KD) of MALAT-1 lncRNA in TSCC cells led to impaired migration and proliferation ability in-vitro and fewer metastases in-vivo. DNA microarray analysis showed that several members of small proline rich proteins (SPRR) were up-regulated by KD of MALAT-1 lncRNA in TSCC cells. SPRR2A over-expression could impair distant metastasis of TSCC cells in-vivo. CONCLUSION: Enhanced expression of MALAT-1 is associated with the growth and metastatic potential of TSCCs. Knock down of MALAT-1 in TSCCs leads to the up-regulation of certain SPRR proteins, which influenced the distant metastasis of TSCC cells.