Magnetodielectric Effect in a Triangular Dysprosium Single-Molecule Toroics.

Single-molecule toroics are molecular magnets with vortex distribution of magnetic moments. The coupling between magnetic and electric properties such as the magnetodielectric effect will provide potential applications for them. Herein, the observation of significant magnetodielectric effect in a triangular Dy3 crystal with toroidal magnetic moment and multiple magnetic relaxations is reported. The analysis of magnetic and electric properties implies that the magnetodielectric effect is closely related to the strong spin-lattice coupling, magnetic interactions of Dy3+ ions, as well as molecular packing models.

Predictive values of novel high­density lipoprotein­related inflammatory indices in in­stent restenosis among patients undergoing elective percutaneous coronary intervention.

Inflammation and disorders in lipid metabolism play pivotal roles in the development and progression of in-stent restenosis (ISR). The present study aimed to investigate the association between the high-density lipoprotein (HDL)-related inflammatory indices and the risk of developing ISR among patients undergoing elective percutaneous coronary intervention (PCI). A sum of 1,471 patients undergoing elective PCI were retrospectively included and classified by tertiles of HDL-related inflammatory indices. The study endpoint was ISR. The multivariable Cox proportional hazards regression analysis with restricted cubic splines (RCS) was used to assess the associations. During a median follow-up of 62.27 months, 251 (17.06%) patients experienced ISR. The incidence of ISR increased with the increasing white blood cell-to-HDL ratio (WHR) tertiles (log-rank test, overall P=0.0082). After full adjustment, the highest tertile of WHR was significantly associated with a 1.603-fold risk of ISR (hazard ratio, 1.603; 95% confidence interval, 1.152-2.231; P=0.005) in contrast to the lowest tertile of the WHR. Results of RCS further indicated that the association between WHR and ISR was in a non-linear and dose-dependent manner (non-linear P=0.034; P overall=0.019). The lymphocyte-to-HDL ratio (LHR) and neutrophil-to-HDL ratio (NHR) were also significantly and positively associated with the risk of ISR, of which the third tertiles were at increased risk of 41.2 and 44.7% after full adjustment, respectively. Overall, lipid metabolism disorders and inflammation were interconnected in the development of ISR; therefore, HDL-related inflammatory indices, including WHR, LHR and NHR, might be potential predictors in the prognosis of elective PCI.

Strictosamide ameliorates LPS-induced acute lung injury by targeting ERK2 and mediating NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) ranks among the deadliest pulmonary diseases, significantly impacting mortality and morbidity. Presently, the primary treatment for ALI involves supportive therapy; however, its efficacy remains unsatisfactory. Strictosamide (STR), an indole alkaloid found in the Chinese herbal medicine Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Wutan), has been found to exhibit numerous pharmacological properties, particularly anti-inflammatory effects. AIM OF THE STUDY: This study aimes to systematically identify and validate the specific binding proteins targeted by STR and elucidate its anti-inflammatory mechanism in lipopolysaccharide (LPS)-induced ALI. MATERIALS AND METHODS: Biotin chemical modification, protein microarray analysis and network pharmacology were conducted to screen for potential STR-binding proteins. The binding affinity was assessed through surface plasmon resonance (SPR), cellular thermal shift assay (CETSA) and molecular docking, and the anti-inflammatory mechanism of STR in ALI treatment was assessed through in vivo and in vitro experiments. RESULTS: Biotin chemical modification, protein microarray and network pharmacology identified extracellular-signal-regulated kinase 2 (ERK2) as the most important binding proteins among 276 candidate STR-interacting proteins and nuclear factor-kappaB (NF-κB) pathway was one of the main inflammatory signal transduction pathways. Using SPR, CETSA, and molecular docking, we confirmed STR's affinity for ERK2. In vitro and in vivo experiments demonstrated that STR mitigated inflammation by targeting ERK2 to modulate the NF-κB signaling pathway in LPS-induced ALI. CONCLUSIONS: Our findings indicate that STR can inhibit the NF-κB signaling pathway to attenuate LPS-induced inflammation by targeting ERK2 and decreasing phosphorylation of ERK2, which could be a novel strategy for treating ALI.

Bioinformatics-led discovery of liver-specific genes and macrophage infiltration in acute liver injury.

Background: Acute liver injury (ALI) is an important global health concern, primarily caused by widespread hepatocyte cell death, coupled with a complex immune response and a lack of effective remedies. This study explores the underlying mechanisms, immune infiltration patterns, and potential targets for intervention and treatment ALI. Methods: The datasets of acetaminophen (APAP), carbon tetrachloride (CCl4), and lipopolysaccharide (LPS)-induced ALI were obtained from the GEO database. Differentially expressed genes (DEGs) were individually identified using the limma packages. Functional enrichment analysis was performed using KEGG, GO, and GSEA methods. The overlapping genes were extracted from the three datasets, and hub genes were identified using MCODE and CytoHubba algorithms. Additionally, PPI networks were constructed based on the String database. Immune cell infiltration analysis was conducted using ImmuCellAI, and the correlation between hub genes and immune cells was determined using the Spearman method. The relationship between hub genes, immune cells, and biochemical indicators of liver function (ALT, AST) was validated using APAP and triptolide (TP) -induced ALI mouse models. Results: Functional enrichment analysis indicated that all three ALI models were enriched in pathways linked to fatty acid metabolism, drug metabolism, inflammatory response, and immune regulation. Immune analysis revealed a significant rise in macrophage infiltration. A total of 79 overlapping genes were obtained, and 10 hub genes were identified that were consistent with the results of the biological information analysis after screening and validation. Among them, Clec4n, Ms4a6d, and Lilrb4 exhibited strong associations with macrophage infiltration and ALI.

Insights into DNMT1 and programmed cell death in diseases.

DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.

Inappropriate treatment response to DMARDs: A pathway to difficult-to-treat rheumatoid arthritis.

In recent years, difficult-to-treat rheumatoid arthritis (D2T RA) has attracted significant attention from rheumatologists due to its poor treatment response and the persistent symptoms or signs experienced by patients. The therapeutic demands of patients with D2T RA are not properly met due to unclear pathogenic causes and a lack of high-quality data for current treatment options, creating considerable management difficulties with this patient population. This review describes the clinical challenges associated with disease-modifying antirheumatic drugs (DMARDs) and explores contributing factors associated with inappropriate response to DMARDs that may lead to D2T RA and related immunological dysregulation. It is now understood that D2T RA is a highly heterogeneous pathological status that involves multiple factors. These factors include but are not limited to genetics, environment, immunogenicity, comorbidities, adverse drug reactions, inappropriate drug application, poor adherence, and socioeconomic status. Besides, these factors may manifest in the selection and utilization of specific DMARDs, either individually or in combination, thereby contributing to inadequate treatment response. Finding these variables may offer hints for enhancing DMARD therapy plans and bettering the condition of D2T RA patients.

Ethnobotany, phytochemistry and pharmacological properties of Fagopyri Dibotryis Rhizoma: A review.

Fagopyri Dibotryis Rhizoma (FDR) is an effective Chinese herbal medicine with a long history of use in China. FDR is effective in heat clearing and detoxifying, promotion of blood circulation, relieving carbuncles, dispelling wind, and removing dampness. Its seeds also have high nutritional value, are rich in protein, and contain a variety of mineral elements and vitamins. Therefore, FDR is considered a natural product with medical and economic benefits, and its chemical composition and pharmacological activity are of interest to scientists. The current review provides an overview of the available scientific information on FDR, particularly its botany, chemical constituents, and pharmacological activities. Various sources of valid and comprehensive relevant information were consulted, including the China National Knowledge Infrastructure, Web of Science, and PubMed. Among the keywords used were "Fagopyri Dibotryis Rhizoma", "botanical features", "chemical composition", and "pharmacological activity" in combination. Various ailments are treated with FDR, such as diabetes, tumor, sore throat, headache, indigestion, abdominal distension, dysentery, boils, carbuncles, and rheumatism. FDR is rich in organic acids, tannins, flavonoids, steroids, and triterpenoids. Experiments performed in vitro and in vivo showed that FDR extracts or fractions had a wide range of pharmacological activities, including antitumor, anti-inflammatory, immunomodulatory, antioxidant, antimicrobial, and antidiabetic. The current review provides an integrative perspective on the botany, phytochemistry and pharmacological activities of FDR. FDR may be used as a medicine and food. Based on its chemical composition and pharmacological effects, the main active ingredients of FDR are organic acids, tannins, and flavonoids, and it has obvious antitumor pharmacological activity against a variety of malignant tumors. Therefore, FDR is worthy of further study and application as a potential antitumor drug.

Progression of precancerous lesions of esophageal squamous cell carcinomas in a high-risk, rural Chinese population.

BACKGROUND AND AIMS: This study investigated the natural history of esophageal squamous cell carcinoma (ESCC) in rural Chinese. We sought to help provide more data to support ESCC screenings. METHODS: This study was based on an existing Screening Program in Feicheng, China. Esophageal precancerous lesions were identified in 1753 cases, diagnosed from esophageal cancer screenings from 2006 to 2016. We followed up with them through endoscopic screening until October 1, 2017. Pathology results from various grades of precancerous lesions were recorded and the annual transition probabilities and incidence density of ESCC were calculated. RESULTS: As of October 1, 2017, a total of 4055.8 person-years has been observed. The ESCC incidence density of mild, moderate, and severe dysplasia (SD) was 0.17, 0.79, and 1.77 per 100 person-years, respectively. The median follow-up time of mild, moderate, and SD was 3.5, 2.3, and 2.2 years, respectively. The annual transition probability of mild, moderate, and SD to the next pathological level was 0.025, 0.038, and 0.016, respectively. The ESCC incidence density of males was 2.6 times higher than females (0.58 vs. 0.22), and the older age group (56-69 age group) had a ESCC incidence density 1.2 times higher than the younger group (40-55 age group) (0.45 vs. 0.39). CONCLUSIONS: The higher the grade of precancerous lesions, the higher the incidence density of ESCC. Screening of esophageal cancer in males and the elderly should be strengthened. It is recommended to reinforce follow-up management for untreated patients with SD/carcinoma in situ. For patients with mild and moderate dysplasia in high-risk rural Chinese populations, endoscopic follow-up intervals can be appropriately adjusted to once every 2 years.

Xinfuli granule alleviates metabolic remodeling through inhibition of endoplasmic reticulum stress and mitochondrial injury in heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: "Qi deficiency-blood stasis-water retention syndrome" was the most frequent syndrome among heart failure(HF) patients according to Traditional Chinese Medicine (TCM) theory. Xinfuli Granule (XG) was constructed on the basis of classical formula "Baoyuan decoction" to enhance the function of nourishing Qi, activating blood and removing water retention. XG treatment has obtained clinical effect on HF patients. AIM OF THE STUDY: The regulation of XG on energy metabolism of HF was investigated with special focus on endoplasmic reticulum stress (ERS) and mitochondrial function. MATERIALS AND METHODS: Components of XG was acquired by UPLC/Q-TOF-MS Analysis, left anterior descending ligation(LAD)-induced HF rats model and hypoxia-ischemia(H-I)-induced H9c2 cells model were constructed to evaluate the effect of XG treatment. Cardiac function was evaluated by echocardiographic parameters, energy metabolism was evaluated by metabolites and ATP/ADP/AMP levels in blood samples, cardiomyocyte morphology and myocardial fibrosis were assessed by HE staining and Masson staining, mitochondrial ultrastructure was observed under Transmission Electron Microscope, viability and apoptosis rate of H9c2 cells was detected by cell counting kit-8 reaction and flow cytometry analysis, respectively. Mitochondrial membrane potential (MMP) of H9c2 cells was observed by JC-1 kit under fluorescent microscope, expression of peroxisome-proliferator-activated receptor (PPAR)-coactivator (PGC1α), ERS-related genes and RHOA/ROCK pathway were analysed by Quantitative Real-time PCR (RT-qPCR) and Western Blot. RESULTS: Here, we showed that XG alleviated cardiac metabolic remodeling and stimulated ATP production through elevated expression of PGC1α in HF rats. XG also helped recover mitochondrial deformation and decrease apoptosis rate accompanied by an increase of the Bcl2/Bax ratio and the mitochondrial membrane potential in hypoxia-ischemia (H-I) H9c2 cells. In addition, we found that XG downregulated ERS-related proteins ATF4, CHOP, Phospho-eIF2α, and Phospho-PERK, and suppressed the RHOA/ROCK pathway, which served as a potential mediator of ERS. CONCLUSIONS: we found that XG improved energy production by alleviating mitochondrial injury and inhibiting ERS in heart failures mediated by the RHOA/ROCK pathway.

Ferroptosis and metabolic syndrome and complications: association, mechanism, and translational applications.

Metabolic syndrome is a medical condition characterized by several metabolic disorders in the body. Long-term metabolic disorders raise the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Therefore, it is essential to actively explore the aetiology of metabolic syndrome (MetS) and its comorbidities to provide effective treatment options. Ferroptosis is a new form of cell death that is characterized by iron overload, lipid peroxide accumulation, and decreased glutathione peroxidase 4(GPX4) activity, and it involves the pathological processes of a variety of diseases. Lipid deposition caused by lipid diseases and iron overload is significant in metabolic syndrome, providing the theoretical conditions for developing ferroptosis. Recent studies have found that the major molecules of ferroptosis are linked to common metabolic syndrome consequences, such as T2DM and atherosclerosis. In this review, we first discussed the mechanics of ferroptosis, the regulatory function of inducers and inhibitors of ferroptosis, and the significance of iron loading in MetS. Next, we summarized the role of ferroptosis in the pathogenesis of MetS, such as obesity, type 2 diabetes, and atherosclerosis. Finally, we discussed relevant ferroptosis-targeted therapies and raised some crucial issues of concern to provide directions for future Mets-related treatments and research.

Nauclea officinalis: A Chinese medicinal herb with phytochemical, biological, and pharmacological effects.

Nauclea officinalis (N. officinalis), a medicinal plant of the genus Nauclea in the family Rubiaceae, is used in the treatment of fever, pneumonia, pharyngolaryngitis, and enteritis in China. Extracts of N. officinalis include alkaloids, phenolic acids, pentacyclic triterpenoids, and flavonoids, which exert all kinds of pharmacological effects, for instance anti-inflammatory, anti-tumor, antibacterial, and antiviral and therefore show good effectiveness. To gain a comprehensive and deep understanding, the medicinal chemistry and chemical biology of N. officinalis are summarized in this review to provide a theoretical basis. The pharmacological effects were reviewed to provide evidence or insights into potential opportunities for further studies and medicinal exploitation of N. officinalis.

Complement use of Chinese herbal medicine after percutaneous coronary intervention: a prospective observational study.

BACKGROUND: Chinese herbal medicine is widely used as a complement or alternative treatment in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) in China. We compared the incidence of the major adverse cardiovascular event (MACE) of CAD patients with or without the complement use of Chinese herbal medicine after PCI. METHODS: In this prospective, observational study that was conducted from September 2016 to August 2019 in Fuwai Hospital (China), we followed up consecutive patients who received PCI treatment for two years. MACE was defined as the composite all-cause mortality, revascularization, and myocardial infarction (MI) and was compared between those using (integrative medicine group) or those not using Chinese herbal medicine as an additional treatment to standard Western medicine, with unadjusted (Kaplan-Meier curves) and risk-adjusted (multivariable Cox regression) analyses. RESULTS: A total of 5942 patients after PCI were enrolled in this study, and 5453 patients were included in the final analysis (4189 [76.8%] male; mean age: 61.9 ± 9.9% years). During the follow-ups, 2932 (53.8%) patients used only Western medicine while 2521(46.2%) patients had used Chinese herbal medicine as an additional treatment to standard Western medicine. Patients in the integrative medicine group (IM group) were older than the Western medicine group (WM group), had more females and less previous MI. The incidence of MACE was 15.3% (449/2932) in WM group and 11.54% (291/2521) in IM group. Cox regression analysis showed that cumulative incidence of MACE was 27% lower in patients of the IM group than those in WM group (hazard ratio = 0.73; 95% CI: 0.63-0.85; P < 0.0001). CONCLUSIONS: For CAD patients after PCI treatment, complement use of Chinese herbal medicine is associated with a lower 2-year MACE incidence. Randomized prospective studies are warranted to provide higher levels of benefit evidence in these patients.

Screening of co-pathogenic genes of non-alcoholic fatty liver disease and hepatocellular carcinoma.

Background: Non-alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, its carcinogenic mechanism is still unclear, looking for both diseases' transcriptome levels, the same changes as we are looking for NAFLD may provide a potential mechanism of action of HCC. Thus, our study aimed to discover the coexisting pathogenic genes of NAFLD and HCC. Methods: We performed a variance analysis with public data for both diseases. At the same time, weighted gene correlation network analysis (WGCNA) was used to find highly correlated gene modules in both diseases. The darkturquoise gene module was found to be highly correlated with both diseases. Based on the diagnosis related module genes and the differential genes of the two diseases, we constructed diagnostic and prognostic models by logistic regression, univariate Cox regression, and LASSO regression. Public datasets verified the results. Meanwhile, we built a competing endogenous RNA (ceRNA) network based on the model genes and explored the related pathways and immune correlation involved in the two diseases by using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Immunohistochemistry was used to verify the different expression of ABCC5 and TUBG1 among the normal liver, NAFLD, and HCC tissues. Sodium palmitate/sodium oleate was used to establish high-fat cell models, and Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) was used to verify the messenger RNA (mRNA) expression of ABCC5 in lipidization cells. Results: A total of 26 upregulated genes and 87 downregulated genes were found using limma package identification analysis. According to WGCNA, the darkturquoise gene module was highly correlated with the prognosis of both diseases. The coexisting genes acquired by the two groups were only three central genes, that is, ABCC5, DHODH and TUBG1. The results indicated that the diagnostic and prognostic models constructed by ABCC5 and TUBG1 genes had high accuracy in both diseases. The results of immunohistochemistry showed that ABCC5 and TUBG1 were significantly overexpressed in NAFLD and HCC tissues compared with normal liver tissues. The Oil Red O staining and triglyceride identified the successful construction of HepG2 and LO2 high-fat models using PA/OA. The results of RT-qPCR showed that the lipidization of LO2 and HepG2 increased the mRNA expression of ABCC5. Conclusions: The gene model constructed by ABCC5 and TUBG1 has high sensibility and veracity in the diagnosis of NAFLD as well as the diagnosis and prognosis of HCC. ABCC5 and TUBG1 may play an important role in the development of NAFLD to HCC. In addition, lipidization could upregulate the mRNA expression of ABCC5 in HCC.

Plasma Exosomal hsa_circ_0015286 as a Potential Diagnostic and Prognostic Biomarker for Gastric Cancer.

Circular RNA (circRNA) is stable and abundant in exosomes as a potential biomarker for the diagnosis and prognosis of tumor. In this study, cancer specific exosomal circRNAs were identified through circRNA microarray, and 58 circRNAs were significantly upregulated in cancer cells derived exosomes. Then 60 patients with newly diagnosed gastric cancer (GC), 30 chronic gastritis patients and 30 healthy subjects were enrolled for further clinical validation. We detected that hsa_circ_0015286 was remarkably highly expressed in GC tissue, plasma and cancer cells compared with normal controls. Results of ROC curve analysis showed that the area under curve (AUC) of hsa_circ_0015286, CEA and CA 19-9 was 0.778, 0.673, and 0.665, respectively. The combined detection of three indicators had the highest AUC (0.843). Exosomal hsa_circ_0015286 expression was closely associated with tumor size, TNM stage and lymph node metastasis. The expression level of exosomal hsa_circ_0015286 in GC patients decreased significantly after surgery. Overall survival of patients with low hsa_circ_0015286 expression was longer than those with high expression. Our data demonstrated that exosomal hsa_circ_0015286 might be a promising noninvasive biomarker for the diagnosis and prognosis evaluation of GC.

Health-Related Quality of Life and Utility Scores of Posttreatment Patients with Gastric Cancer at Different Pathological Stages: A Cross-Sectional Study.

Background: Health-related quality of life (HRQoL) is a key variable in the evaluation of health economics. We aimed to evaluate the HRQoL and utility scores of patients with gastric cancer and related precancerous lesions by assessing their quality of life using a single standardized health measurement instrument. Methods: A cross-sectional study was conducted in six counties in Shangdong Province from November 2019 to March 2020. Subjects with precancerous lesions and gastric cancer (cardia and noncardia) were included and surveyed. Patients were divided into four groups: low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early gastric cancer (EGC), and advanced gastric cancer (AGC). All patients, except those with LGIN, received treatment. The five-level EQ-5D was used to assess HRQoL and generate utility scores using the Chinese-specific tariff published in 2017. Results: The study included 566 respondents. The average utility was 0.927 for precancerous lesions (LGIN: 0.930; HGIN: 0.926), 0.906 for early gastric cancer (EGC), and 0.756 for advanced gastric cancer (AGC). Visual analogue scale (VAS) means were 76.82 (LGIN: 78.08; HGIN: 74.81), 72.26, and 69.16 for precancerous lesions, EGC, and AGC, respectively. HRQoL was lower in women with AGC than in men (0.612 vs. 0.792, P = 0.035). AGC patients were more likely to report problems across all five dimensions than patients in other stages. The proportion of patients reporting pain/discomfort problems was highest across all gastric cancer stages (LGIN, 35.6%; HGIN, 34.4%; EGC, 35.6%; and AGC, 55.7%), followed by anxiety/depression (LGIN, 17.5%; HGIN, 18%; EGC, 22.8%; and AGC, 47.7%). Conclusions: HRQoL declined as cancer progressed, with the most dramatic decline observed in patients with AGC. A more advanced pathological stage was associated with a greater decrease in health utility. The obtained utilities for different pathological stages of gastric cancer were significant parameters for researchers to perform further cost-utility analysis. Pain/discomfort and anxiety/depression were problems that seriously affected the patients in all groups.

Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma.

BACKGROUND: Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need. OBJECTIVE: We sought to gain a better understanding of genetic contributions to T2-low asthma. METHODS: We utilized an unbiased genome-wide association study of patients with moderate to severe asthma stratified by T2 serum biomarker periostin. We also performed additional expression and biological analysis for the top genetic hits. RESULTS: We identified a novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated with T2-low asthma and establishes Kallikrein-related peptidase 5 (KLK5) as the causal gene mediating this association. Heterozygous carriers of the single nucleotide polymorphisms have reduced KLK5 expression. KLK5 is secreted by human bronchial epithelial cells and elevated in asthma bronchial alveolar lavage. T2 cytokines IL-4 and IL-13 downregulate KLK5 in human bronchial epithelial cells. KLK5, dependent on its catalytic function, induces epithelial chemokine/cytokine expression. Finally, overexpression of KLK5 in airway or lack of an endogenous KLK5 inhibitor, SPINK5, leads to spontaneous airway neutrophilic inflammation. CONCLUSION: Our data identify KLK5 to be the causal gene at a novel locus at chr19q13.41 associated with T2-low asthma.

Detoxification strategies of triptolide based on drug combinations and targeted delivery methods.

Tripterygium wilfordii Hook f. has a long history of use in Chinese medicine. Triptolide (TP), as its main pharmacological component, has been widely explored in various diseases, including systemic lupus erythematosus, rheumatoid arthritis and cancer. However, due to its poor water solubility, limited therapeutic range and multi-organ toxicity, TP's clinical application has been greatly hampered. To improve its clinical potential, many attenuated drug combinations have been developed based on its toxicity mechanism and targeted delivery systems aimed at its water-solubility and structure. This review, conducted a systematic review of TP detoxification strategies including drug combination detoxification strategies from metabolic and toxic mechanisms, as well as drug delivery detoxification strategies from the prodrug strategy and nanotechnology. Many detoxification strategies have demonstrated promising potential in vitro and in vivo due to previous extensive studies on TP. Therefore, summarizing and discussing TP detoxification strategies for clinical problems can serve as a reference for developing novel TP detoxification strategies, and provide opportunities for future clinical applications.

Chronic Activation of LXRα Sensitizes Mice to Hepatocellular Carcinoma.

The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and ß isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.

Atypical functions of xenobiotic receptors in lipid and glucose metabolism.

Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors, the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics. Emerging evidence suggests that "xenobiotic receptors" also have diverse endobiotic functions, including their effects on lipid metabolism and energy metabolism. Dyslipidemia is a major risk factor for cardiovascular disease, diabetes, obesity, metabolic syndrome, stroke, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Understanding the molecular mechanism by which transcriptional factors, including the xenobiotic receptors, regulate lipid homeostasis will help to develop preventive and therapeutic approaches. This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), in metabolic disorders, with a particular focus on their effects on lipid and glucose metabolism. Collectively, the literatures suggest the potential values of AhR, PXR and CAR as therapeutic targets for the treatment of NAFLD, NASH, obesity and diabetes, and cardiovascular diseases.

Magnetoelectric phase transition driven by interfacial-engineered Dzyaloshinskii-Moriya interaction.

Strongly correlated oxides with a broken symmetry could exhibit various phase transitions, such as superconductivity, magnetism and ferroelectricity. Construction of superlattices using these materials is effective to design crystal symmetries at atomic scale for emergent orderings and phases. Here, antiferromagnetic Ruddlesden-Popper Sr2IrO4 and perovskite paraelectric (ferroelectric) SrTiO3 (BaTiO3) are selected to epitaxially fabricate superlattices for symmetry engineering. An emergent magnetoelectric phase transition is achieved in Sr2IrO4/SrTiO3 superlattices with artificially designed ferroelectricity, where an observable interfacial Dzyaloshinskii-Moriya interaction driven by non-equivalent interface is considered as the microscopic origin. By further increasing the polarization namely interfacial Dzyaloshinskii-Moriya interaction via replacing SrTiO3 with BaTiO3, the transition temperature can be enhanced from 46 K to 203 K, accompanying a pronounced magnetoelectric coefficient of ~495 mV/cm·Oe. This interfacial engineering of Dzyaloshinskii-Moriya interaction provides a strategy to design quantum phases and orderings in correlated electron systems.