Association between blood metabolites and basal cell carcinoma risk: a two-sample Mendelian randomization study.

Background: Circulating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC's progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression. Material and methods: We conducted a two-sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Results: In the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10-4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10-4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation. Conclusion: Our research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.

The roles and regulatory mechanisms of cigarette smoke constituents in vascular remodeling.

Vascular remodeling is a dynamic process involving cellular and molecular changes, including cell proliferation, migration, apoptosis and extracellular matrix (ECM) synthesis or degradation, which disrupt the homeostasis of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Cigarette smoke exposure (CSE) is thought to promote vascular remodeling, but the components are complex and the mechanisms are unclear. In this review, we overview the progression of major components of cigarette smoke (CS), such as nicotine and acrolein, involved in vascular remodeling in terms of ECs injury, VSMCs proliferation, migration, apoptosis, and ECM disruption. The aim was to elucidate the effects of different components of CS on different cells of the vascular system, to discover the relevance of their actions, and to provide new references for future studies.

Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance.

BACKGROUND: Zishenhuoxue decoction (ZSHX), a Chinese herbal medicine, exhibits myocardial and vascular endothelial protective properties. The intricate regulatory mechanisms underlying myocardial ischemic injury and its association with dysfunctional mitochondrial quality surveillance (MQS) remain elusive. HYPOTHESIS/PURPOSE: To study the protective effect of ZSHX on ischemic myocardial injury in mice using a TMBIM6 gene-modified animal model and mitochondrial quality control-related experiments. STUDY DESIGN: Using model animals and myocardial infarction surgery-induced ischemic myocardial injury TMBIM6 gene-modified mouse models, the pharmacological activity of ZSHX in inhibiting ischemic myocardial injury and mitochondrial homeostasis disorder in vivo was tested. METHODS: Our focal point entailed scrutinizing the impact of ZSHX on ischemic myocardial impairment through the prism of TMBIM6. This endeavor was undertaken utilizing mice characterized by heart-specific TMBIM6 knockout (TMBIM6CKO) and their counterparts, the TMBIM6 transgenic (TMBIM6TG) and VDAC1 transgenic (VDAC1TG) mice. RESULTS: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6CKO hindered ZSHX's cardio-therapeutic and mitochondrial protective effects, while ZSHX's benefits persisted in TMBIM6TG mice. TMBIM6CKO also blocked ZSHX's regulation of mitochondrial function in HR-treated cardiomyocytes. Hypoxia disrupted the MQS in cardiomyocytes, including calcium overload, excessive fission, mitophagy issues, and disrupted biosynthesis. ZSHX counteracted these effects, thereby normalizing MQS and inhibiting calcium overload and cardiomyocyte necroptosis. Our results also showed that hypoxia-induced TMBIM6 blockade resulted in the over-activation of VDAC1, a major mitochondrial calcium uptake pathway, while ZSHX could increase the expression of TMBIM6 and inhibit VDAC1-mediated calcium overload and MQS abnormalities. CONCLUSIONS: Our findings suggest that ZSHX regulates mitochondrial calcium homeostasis and MQS abnormalities through a TMBIM6-VDAC1 interaction mechanism, which helps to treat ischemic myocardial injury and provides myocardial protection. This study also offers insights for the clinical translation and application of mitochondrial-targeted drugs in cardiomyocytess.

Glioma-targeted oxaliplatin/ferritin clathrate reversing the immunosuppressive microenvironment through hijacking Fe2+ and boosting Fenton reaction.

Glioma is easy to develop resistance to temozolomide (TMZ). TMZ-resistant glioma secretes interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), recruiting regulatory T cell (Treg) and inhibiting the activity of T cells and natural killer cell (NK cell), subsequently forming an immunosuppressive microenvironment. Oxaliplatin (OXA) greatly inhibits the proliferation of TMZ-resistant glioma cells, but the ability of OXA to cross blood-brain barrier (BBB) is weak. Thus, the therapeutic effect of OXA on glioma is not satisfactory. Transferrin receptor 1 (TfR1) is highly expressed in brain capillary endothelial cells and TMZ-resistant glioma cells. In this study, OXA was loaded into ferritin (Fn) to prepare glioma-targeted oxaliplatin/ferritin clathrate OXA@Fn. OXA@Fn efficiently crossed BBB and was actively taken up by TMZ-resistant glioma cells via TfR1. Then, OXA increased the intracellular H2O2 level and induced the apoptosis of TMZ-resistant glioma cells. Meanwhile, Fn increased Fe2+ level in TMZ-resistant glioma cells. In addition, the expression of ferroportin 1 was significantly reduced, resulting in Fe2+ to be locked up inside the TMZ-resistant glioma cells. This subsequently enhanced the Fenton reaction and boosted the ferroptosis of TMZ-resistant glioma cells. Consequently, T cell mediated anti-tumor immune response was strongly induced, and the immunosuppressive microenvironment was significantly reversed in TMZ-resistant glioma tissue. Ultimately, the growth and invasion of TMZ-resistant glioma was inhibited by OXA@Fn. OXA@Fn shows great potential in the treatment of TMZ-resistant glioma and prospect in clinical transformation.

Polymer-Initiating Caveolae-Mediated Endocytosis and GSH-Responsive MiR-34a Gene Delivery System for Enhanced Orthotopic Triple Negative Breast Cancer Therapy.

Gene therapy based on miRNAs has broad application prospects in the treatment of tumors. However, due to degradation and ineffective release during intracellular transport, current gene delivery vectors used for miRNAs limited their actual transfection efficiency. This study develops a novel nonviral vector PEI-SPDP-Man (PSM) that can simultaneously target cellular uptake pathways and intracellular responsive release for miR-34a. PSM is synthesized by connected mannitol (Man) to branched polyethylenimine (PEI) using a disulfide bond. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis to reduce the degradation of miR-34a in lysosomes. The disulfide bond is sensed at high concentration of glutathione (GSH) in the tumor cells and miR-34a is released, thereby reducing the expression of Bcl-2 and CD44 to suppress the proliferation and invasion of tumor cells. In vitro and in vivo experiments show that through the targeted cellular uptake and the efficient release of miR-34a, an effective antitumor and antimetastasis profiles for the treatment of orthotopic triple negative breast cancer (TNBC) are achieved. This strategy of controlling intracellular transport pathways by targeting cellular uptake pathways in the gene therapy is an approach that could be developed for highly effective cancer therapy.

Integrated analysis of high­throughput sequencing reveals the regulatory potential of hsa_circ_0035431 in HNSCC.

Circular RNAs (circRNAs) are molecular sponges that are involved in regulation of multiple types of cancer. The present study aimed to screen and explore the key circRNA/microRNA (miRNA or miR)/mRNA interactions in head and neck squamous cell carcinoma (HNSCC) using bioinformatics. A total of six pairs of cancerous and adjacent healthy tissue were obtained from patients with HNSCC and genome-wide transcriptional sequencing was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on differentially expressed genes (DEGs). Moreover, expression levels of DEGs were verified in HNSCC cells and tissues using reverse transcription-quantitative (RT-q)PCR. A molecular regulatory network consisting of three circRNAs, seven miRNAs and seven mRNAs was constructed, resulting in identification of two signaling axes, hsa_circ_0035431/hsa-miR-940/fucosyltransferase 6 (FUT6) and hsa_circ_0035431/hsa-miR-940/cingulin-like 1 (CGNL1). FUT6 and CGNL1 were downregulated in HNSCC compared with adjacent healthy tissue and the expression levels of these genes were associated with tumor stage. Low FUT6 and CGNL1 expression levels were associated with lower overall survival rate and progression-free intervals in HNSCC. RT-qPCR demonstrated that hsa_circ_0035431, FUT6 and CGNL1 were downregulated in HNSCC cells and tissue and hsa-miR-940 was upregulated. Notably, these results were consistent with those obtained using high-throughput sequencing. In conclusion, hsa_circ_0035431 may participate in regulation of FUT6 and CGNL1 expression by sponging hsa-miR-940, thus, impacting the occurrence, development and prognosis of HNSCC.

Runx1 Deficiency Promotes M2 Macrophage Polarization Through Enhancing STAT6 Phosphorylation.

Our previous study had demonstrated that Runx1 promoted LPS-induced macrophage inflammatory response, however, the role of Runx1 in M2 macrophage polarization still remains largely unknown. This study was conducted to investigate the role of Runx1 in IL-4/IL-13-induced M2 macrophage polarization and its potential regulatory mechanism. We found that exposure of macrophages to IL-4/IL-13 induced a remarkable increasement in Runx1 expression level. Specifically, we established genetically modified mice lacking Runx1 in myeloid cells, including macrophages. RNA-Seq was performed to identify differentially expressed genes (DEGs) between Runx1 knockout and WT control bone marrow-derived macrophages (BMDMs). We identified 686 DEGs, including many genes which were highly expressed in M2 macrophage. In addition, bioinformatics analysis indicated that these DEGs were significantly enriched in extracellular matrix-related processes. Moreover, RT-qPCR analysis showed that there was an obvious upregulation in the relative expression levels of M2 marker genes, including Arg1, Ym1, Fizz1, CD71, Mmp9, and Tgm2, in Runx1 knockout macrophages, as compared to WT controls. Consistently, similar results were obtained in the protein and enzymatic activity levels of Arg1. Finally, we found that the STAT6 phosphorylation level was significantly enhanced in Runx1 knockout macrophages, and the STAT6 inhibitor AS1517499 partly reduced the upregulated effect of Runx1 deficiency on the M2 macrophage polarization. Taken together, Runx1 deficiency facilitates IL-4/IL-13-induced M2 macrophage polarization through enhancing STAT6 phosphorylation.

Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression.

Triple negative breast cancer (TNBC) is prone to develop drug resistance and metastasis. Bone is the most common distant metastasis site of breast cancer cell. Patients with bone metastasis from TNBC suffer from unbearable pain due to the growth of bone metastasis and bone destruction. Simultaneously blocking the growth of bone metastasis and reprogramming the microenvironment of bone resorption and immunosuppression is a promising strategy to treat bone metastasis from TNBC. Herein, we prepared a pH and redox responsive drug delivery system, named DZ@CPH, by encapsulating docetaxel (DTX) with hyaluronic acid-polylactic acid micelle then reinforcing with calcium phosphate and zoledronate for targeting to bone metastasis from TNBC. DZ@CPH reduced the activation of osteoclast and inhibited bone resorption by decreasing the expression of nuclear factor κB receptor ligand and increasing the expression of osteoprotegerin in drug-resistant bone metastasis tissue. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the apoptosis-related and invasion-related protein expression. It also increased the sensitivity of orthotopic drug-resistant bone metastasis to DTX by inhibiting the expression of P-glycoprotein, Bcl-2 and transforming growth factor-ß in tissue of drug-resistant bone metastasis. Moreover, the ratio between M1 type macrophage to M2 type macrophage in bone metastasis tissue was increased by DZ@CPH. In a word, DZ@CPH blocked the growth of bone metastasis from drug-resistant TNBC through inducing the apoptosis of drug-resistant TNBC cells and reprogramming the microenvironment of bone resorption and immunosuppression. DZ@CPH has a great potential in clinical application for the treatment of bone metastasis from drug-resistant TNBC. STATEMENT OF SIGNIFICANCE: Triple negative breast cancer (TNBC) is prone to develop bone metastasis. Now bone metastasis is still an intractable disease. In this study, docetaxel and zoledronate co-loaded calcium phosphate hybrid micelles (DZ@CPH) were prepared. DZ@CPH reduced the activation of osteoclasts and inhibited bone resorption. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the expression of apoptosis and invasion related protein in bone metastasis tissue. Moreover, the ratio between M1 type macrophages to M2 type macrophages in bone metastases tissue was increased by DZ@CPH. In a word, DZ@CPH blocked vicious cycle between the growth of bone metastasis and bone resorption, which greatly improved the therapeutic effect on bone metastasis from drug-resistant TNBC.

Preclinical animal study of electrospun poly (l-lactide-co-caprolactone) and formulated porcine fibrinogen for full-thickness diabetic wound regeneration.

Diabetic foot ulcer is one of the most serious chronic complications of diabetes mellitus. It may lead to amputation of the lower extremities for diabetics. Our study was to evaluate the effect of electrospun poly (L-lactide-co-caprolactone) and formulated porcine fibrinogen (PLCL/Fg) wound dressing on animal wound model. A blend ratio of PLCL/Fg scaffold was 4 (PLCL):1 (Fg). The scanning electron microscopy findings showed that the fibers' diameter was 122.5 ± 80.3 nm, and the tensile strength was 9.2 ± 0.2 MPa. In-vivo study of the hog normal model demonstrated that PLCL/Fg dressing had better biocompatibility, degradability, and ability to restore the skin's normal structure. We evaluated the wound healing processes in the rat diabetic model by macroscopic observation and histological observation at 1, 2, and 3 post-operation weeks. In our study, the PLCL/Fg group performed better 3 weeks after surgery, in terms of macroscopic healing and scarring. After surgery, the PLCL/Fg group showed better fibroblast accumulation, tissue granulation, and collagen expression than the control group. Topical treatment with PLCL/Fg dressing effectively enhanced wound healing in both normal and hyperglycemic conditions, suggesting that it may possess wound-healing potential.

Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling.

OBJECTIVE: To investigate autophagy-related mechanisms of electroacupuncture (EA) action in improving gastrointestinal motility in mice with functional constipation (FC). METHODS: According to a random number table, the Kunming mice were divided into the normal control, FC and EA groups in Experiment I. The autophagy inhibitor 3-methyladenine (3-MA) was used to observe whether it antagonized the effects of EA in Experiment II. An FC model was established by diphenoxylate gavage. Then the mice were treated with EA stimulation at Tianshu (ST 25) and Shangjuxu (ST 37) acupoints. The first black stool defecation time, the number, weight, and water content of 8-h feces, and intestinal transit rate were used to assess intestinal transit. Colonic tissues underwent histopathological assessment, and the expressions of autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunohistochemical staining. The expressions of phosphoinositide 3-kinases (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway members were investigated by Western blot and quantitative reverse transcription-polymerase chain reaction, respectively. The relationship between enteric glial cells (EGCs) and autophagy was observed by confocal immunofluorescence microscopy, localization analysis, and electron microscopy. RESULTS: EA treatment shortened the first black stool defecation time, increased the number, weight, and water content of 8-h feces, and improved the intestinal transit rate in FC mice (P<0.01). In terms of a putative autophagy mechanism, EA treatment promoted the expressions of LC3 and Beclin-1 proteins in the colonic tissue of FC mice (P<0.05), with glial fibrillary acidic protein (GFAP) and LC3 significantly colocalized. Furthermore, EA promoted colonic autophagy in FC mice by inhibiting PI3K/AKT/mTOR signaling (P<0.05 or P<0.01). The positive effect of EA on intestinal motility in FC mice was blocked by 3-MA. CONCLUSION: EA treatment can inhibit PI3K/AKT/mTOR signaling in the colonic tissues of FC mice, thereby promoting EGCs autophagy to improve intestinal motility.

[Study on the mechanism of electroacupuncture repairing intestinal barrier via regulating mast cell in rats with diarrhea-predominant irritable bowel syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on mast cell activation-related substances and intestinal barrier function in diarrhea-predominant irritable bowel syndrome (IBS-D) model rats, so as to explore its underlying mechanisms. METHODS: Thirty female SD rats were randomly divided into control group, model group and EA group, with 10 rats in each group. IBS-D model was established by chronic unpredictable mild stress combined with senna solution gavage. Rats in the EA group received EA treatment (2 Hz/15 Hz，0.1-1.0 mA) at "Zusanli" (ST36), "Taichong"(LR3) and "Tianshu"(ST25), 20 min per day, for a total of 14 days, with sides alternated daily. Visceral pain threshold was used to evaluate visceral hypersensitivity, diarrhea index was used to evaluate diarrhea degree. After all treatments, the pathological scores of colon were recorded after HE staining, the contents of cholecystokinin (CCK), substance P (SP), tryptase (TPS) and adenosine triphosphate (ATP) in colon were detected by ELISA, and the expressions of colonic tight junction protein ZO-1 and occludin were detected by Western blot. RESULTS: Compared with the control group, the visceral pain threshold, the expression levels of colonic ZO-1 and occludin proteins decreased (P<0.01), while the diarrhea index, the contents of colonic CCK, SP, TPS and ATP were significantly increased (P<0.01) in the model group. After intervention, in comparison with the model group, the visceral pain thre-shold, the protein expression levels of colonic ZO-1 and occludin protein increased (P<0.01), while the diarrhea index, the contents of colonic CCK, SP, TPS and ATP were significantly decreased (P<0.01) in the EA group. CONCLUSION: EA can significantly alleviate the symptoms of visceral hypersensitivity and diarrhea in IBS-D rats. Its mechanism may be related to down-regulating colonic CCK, SP, TPS and ATP, inhibiting mast cell activation and degranulation, and up-regulating colonic barrier tight junction proteins.

Tumor targeted combination therapeutic system for the effective treatment of drug resistant triple negative breast cancer.

Breast cancer has become the malignant tumor with the largest incidence, especially the drug resistant triple negative breast cancer (TNBC). The combination therapeutic system can play a better role in resisting drug resistant TNBC. In this study, dopamine and tumor targeted folic acid modified dopamine were synthesized as carrier materials to construct melanin-like tumor targeted combination therapeutic system. The optimized nanoparticles of CPT/Fe@PDA-FA10 with efficient loading of camptothecin and iron was achieved, which showed tumor targeted delivery ability, pH sensitive controlled release, effective photothermal conversion performance and excellent anti-tumor efficacy in vitro and in vivo. CPT/Fe@PDA-FA10 plus laser could significantly kill the drug resistant tumor cells, inhibit the growth of the orthotopic drug resistant triple negative breast cancer through apoptosis/ferroptosis/photothermal treatment, and had no significant side effects on the main tissues and organs. This strategy provided a new idea for the construction and clinical application of triple-combination therapeutic system as effective treatment for drug resistant triple negative breast cancer.

Bone targeted miRNA delivery system for miR-34a with enhanced anti-tumor efficacy to bone-associated metastatic breast cancer.

Bone metastatic cancer is the most common occurrence in breast cancer, and the treatment is also facing great challenges. MicroRNA-34a (miRNA-34a) is a promising anti-cancer miRNA for gene therapy to bone metastatic cancer patients. However, the lack of specificity to bone and low accumulation at the site of bone tumor remains the major challenge when used bone-associated tumor. To solve this problem, a bone-targeted vector for delivery of miR-34a to bone metastatic breast cancer was constructed by using the commonly used gene vector branched polyethylenimine 25 k (BPEI 25 k) as the skeleton and linking with alendronate (ALN) moieties for bone targeting group. The constructed gene delivery system PCA/miR-34a can efficiently prevent miR-34a from degradation during blood circulation and enhance the specific bone delivery and distribution. PCA/miR-34a nanoparticles can be uptake into tumor cells through clathrin and caveolae-mediated endocytosis, and directly regulate the expression of oncogenes, thus promoting tumor cell apoptosis and relieving bone tissue erosion. The results of experiments in vitro and in vivo confirmed that the constructed bone-targeted miRNA delivery system PCA/miR-34a can enhance the anti-tumor efficacy in bone metastatic cancer, and provide a potential strategy for gene therapy in bone metastatic cancer.

Exploring the "gene-protein-metabolite" network of coronary heart disease with phlegm and blood stasis syndrome by integrated multi-omics strategy.

Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a "gene-protein-metabolite" network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Results: Our findings revealed that the "gene-protein-metabolite" network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 (Mirzaei et al., 2009, 95, 740-746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) (Katus et al., 2017; Knuuti, 2019). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina (Rousan et al., 2017). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy (Shaw et al., 2008; Antman and Braunwald, 2020). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations (Teng et al., 2016). TCM has become a principal complement in western countries (Wieland et al., 2013). Like "disease" is used in western medicine, "syndrome" is used in TCM to comprehend anomalous human conditions on the basis of patients' symptoms, tongue, and pulse (Li et al., 2012). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome (Ren et al., 2020; Liu et al., 2021; Zheng et al., 2022). The concept of "omics" originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources (Dai and Shen, 2022). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode (Pan et al., 2022). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals (Singh et al., 2016; Lal et al., 2018; Mohler et al., 2020). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine (Zhou et al., 2019). Li's metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome (Zheng et al., 2022). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other's research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the "gene-protein-metabolite" network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the "gene-protein-metabolite" network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules (Figure 1).

Correlation between Hashimoto's thyroiditis and polycystic ovary syndrome: A systematic review and meta-analysis.

Objective: A growing body of research suggests that patients with polycystic ovary syndrome (PCOS) may be at increased risk of developing Hashimoto's thyroiditis (HT), and having both conditions can make the condition worse. However, current research views are not uniform. Therefore, to explore the link between PCOS and HT, we conducted this study. Methods: From the establishment of the database to August 2022, we searched 2 databases to study the correlation between Hashimoto's and polycystic ovary syndrome. Two authors independently screened the articles for eligibility, and three authors extracted relevant data. Statistical analysis was performed using STATA16.0 software. Results: A total of 20 studies were included, including 7 case-control studies and 13 cross-sectional studies. A total of 13 countries and 7857 participants were embraced. Studies have demonstrated that both PCOS patients have an increased risk of HT, and meanwhile, HT patients also have an increased risk of PCOS compared with controls. The study also incorporated that the prevalence of HT in PCOS patients in India and Turkey was higher than in other countries, and the prevalence of HT in PCOS patients in South America was higher than in Asia and Europe. Conclusions: In conclusion, our study illustrates that there is a correlation between PCOS and HT, and it is necessary to further study the underlying mechanism between PCOS and HT. At the same time, it is of great significance to regularly screen PCOS patients for HT risk and HT patients for PCOS risk. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD 42022351168.

Tumor microenvironment and redox dual stimuli-responsive polymeric nanoparticles for the effective cisplatin-based cancer chemotherapy.

The serious side effects of cisplatin hindered its clinical application and the nanotechnology might be the potential strategy to address the limitation. However, rapid clearance in the blood circulation and ineffective controlled drug release from nanocarriers hamper the therapeutic efficacy of the nano-delivery system. We constructed a tumor microenvironment and redox dual stimuli-responsive nano-delivery system PEG-c-(BPEI-SS-Pt) by cross-linking the disulfide-containing polymeric conjugate BPEI-SS-Pt with the dialdehyde group-modified PEG2000via Schiff base. After optimized the cross-linking time, 72 h was selected to get the nano-delivery system.1H NMR and drug release assays showed that under the acidic tumor microenvironment (pH 6.5-6.8), the Schiff base can be broken and detached the PEG cross-linked outer shells, displaying the capability to release the drugs with a sequential pH- and redox-responsive manner. Moreover, PEG-c-(BPEI-SS-Pt) showed more effective anti-tumor therapeutic efficacyin vivowith no significant side effects when compared with the drug of cisplatin used in the clinic. This strategy highlights a promising platform with the dual stimuli-responsive profile to achieve better therapeutic efficacy and minor side effects for platinum-based chemotherapy.

DGRUnit: Dual graph reasoning unit for brain tumor segmentation.

Many fully automatic segmentation models have been created to solve the difficulty of brain tumor segmentation, thanks to the rapid growth of deep learning. However, few approaches focus on the long-range relationships and contextual interdependence in multimodal Magnetic Resonance (MR) images. In this paper, we propose a novel approach for brain tumor segmentation called the dual graph reasoning unit (DGRUnit). Two parallel graph reasoning modules are included in our proposed method: a spatial reasoning module and a channel reasoning module. The spatial reasoning module models the long-range spatial dependencies between distinct regions in an image using a graph convolutional network (GCN). The channel reasoning module uses a graph attention network (GAT) to model the rich contextual interdependencies between different channels with similar semantic representations. Our experimental results clearly demonstrate the superior performance of the proposed DGRUnit. The ablation study shows the flexibility and generalizability of our model, which can be easily integrated into a wide range of neural networks and further improve them. When compared to several state-of-the-art methods, experimental results show that the proposed approach significantly improves both visual inspection and quantitative metrics for brain tumor segmentation tasks.

Cancer Risk in Hashimoto's Thyroiditis: a Systematic Review and Meta-Analysis.

Objective: Research data suggest that patients with Hashimoto's thyroiditis may increase the risk of cancer. However, existing research is inconsistent with this view. Therefore, to investigate the effect of Hashimoto's thyroiditis on the risk of developing cancer, we conducted this study. Methods: We searched the PubMed and Embase databases from database establishment until March 2022. After rigorous literature screening by two authors, 23 studies that met the inclusion criteria were identified, and the required data were independently extracted. Results: We retrieved 3591 records, and after the screening, 11 case-control studies and 12 cohort studies were included in the analysis. Data analysis suggested that patients with Hashimoto's thyroiditis had an increased risk of developing breast cancer, urogenital cancer, digestive organs cancer, hematologic cancer, and a low risk of respiratory cancers. Conclusions: This systematic review and meta-analysis showed that patients with HT may have a significantly increased risk of thyroid cancer, breast cancers, lung cancer, digestive system cancer, urogenital cancers, blood cancers, and prolactinoma people without HT. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD 42022320741.

Discovery of once-weekly, peptide-based selective GLP-1 and cholecystokinin 2 receptors co-agonizts.

A group of long-acting, peptide-based, and selective GLP-1R/CCK-2R dual agonizts were identified by rational design. Guided by sequence analysis, structural elements of the CCK-2R agonist moiety were engineered into the GLP-1R agonist Xenopus GLP-1, resulting in hybrid peptides with potent GLP-1R/CCK-2R dual activity. Further modifications with fatty acids resulted in novel metabolically stable peptides, among which 3d and 3 h showed potent GLP-1R and CCK-2R activation potencies and comparable stability to semaglutide. In food intake tests, 3d and 3 h also showed a potent reduction in food intake, superior to that of semaglutide. Moreover, the acute hypoglycemic and insulinotropic activities of 3d and 3 h were better than that of semaglutide and ZP3022. Importantly, the limited pica response following 3d and 3 h administration in SD rats preliminarily indicated that the food intake reduction effects of 3d and 3 h are independent of nausea/vomiting. In a 35-day study in db/db mice, every two days administration of 3d and 3 h increased islet areas and numbers, insulin contents, ß-cell area, ß-cell proliferation, as well as improved glucose tolerance, and decreased HbA1c, to a greater extent than ZP3022 and semaglutide. In a 21-day study in DIO mice, once-weekly administration of 3d and 3 h significantly induced body weight loss, improved glucose tolerance, and normalized lipid metabolism, to a greater extent than semaglutide. The current study showed the antidiabetic and antiobesity potentials of GLP-1R/CCK-2R dual agonizts that warrant further investigation.