Small molecule deoxynyboquinone triggers alkylation and ubiquitination of Keap1 at Cys489 on Kelch domain for Nrf2 activation and inflammatory therapy.

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by Kelch-like ECH-associated protein 1 (Keap1) alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, ß-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, ß-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Profiling targets and potential target pairs of CAR-T cell therapy in clinical trials.

Since the approval of the first chimeric antigen receptor (CAR)-T product in 2017, the number of new CAR-T clinical trials worldwide exceeds 100 per year. 1649 clinical studies have been conducted to explore possible future clinical applications of targets or target pairs through different biotechnologies. In this study, we aim to take a data-driven analytical approach to explore potential dual-target pairs based on clinical trial information. We screened 1283 non-withdrawal interventional CAR-T clinical trials spanning 96 different targets and 74 target pairs from clinicaltrials.gov. Through the Circos plot and temporal network plots, the information between targets and indications was visualized. Based on the assumption that two targets of a target pair must target the same indication, five new target pairs were inferred, including CD19/CD7, CD19/CD5, CD19/CD37, and CD19/BAFFR and validated by expression pattern, literature and patent information. This study provides novel support for target profiling of CAR-T from the perspective of clinical trials and also provides a reference for researchers and developers to select new targets or target pairs of CAR-T cell therapy.

Characteristics of clinical trials of new oncology drugs approved in China.

BACKGROUND: Since reforms were introduced to incentivize drug innovation in 2015, the Chinese pharmaceutical market has experienced unprecedented prosperity, with more new drugs than ever before, especially anticancer treatments. In 2021, Chinese regulatory agencies issued the new guideline for clinical research and development of antitumor drugs, triggering a series of responses on the drug market. Limited research has outlined the nature of the original new drugs in China to understand the dynamic response of the market. METHODS: The objective of this article was to map the clinical development of approved new oncology drugs in China from 2015 to 2021 and differed from previous studies by focusing on original new drugs, using the United States as a benchmark, and elaborating the endogenous features of clinical trials. RESULTS: Clinical trials conducted in China have risen to a level similar to that of the United States in many aspects of trial design, but there is still distance between the implementation and operational details of clinical trials. In the meantime, China has made significant breakthroughs in drug approval. Greater than 60% of novel anticancer drugs in China received accelerated approved for their first listing. Approximately 90% of the pivotal clinical trials supporting initial drug approval used surrogate measures as end points, and one half were nonrandomized or did not have a control group. However, duplicate development without evidence of a clinical advantage compared with current therapies was widely observed. CONCLUSIONS: By presenting a multidimensional landscape of clinical trials and approvals in the real world, this review allows interested researchers, developers, and even regulators to understand what has been done and what should be done next in anticancer drug development in China.

A Novel Molecularly Imprinted Sensor Based on CuO Nanoparticles with Peroxidase-like Activity for the Selective Determination of Astragaloside-IV.

In this work, dopamine (DA) was polymerized on the surface of CuO nanoparticles (CuO NPs) to form a molecularly imprinted polymer (MIP@PDA/CuO NPs) for the colorimetric detection of astragaloside-IV (AS-IV). The synthesis process of MIP is simple and easy to operate, without adding other monomers or initiators. CuO NPs has high peroxidase (POD)-like activity that can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to generate oxidized TMB (OxTMB) in the presence of H2O2, having a maximum ultraviolet-visible (UV-Vis) absorption peak at 652 nm. The AS-IV can specifically bind to the surface imprinted cavities and prevent the entry of TMB and H2O2, which will lead to the inhibition of the catalytic reaction. Therefore, a new approach based on the POD-like activity of MIP@PDA/CuO NPs for AS-IV detection was developed with a linear range from 0.000341 to 1.024 mg/mL. The LOD and LOQ are 0.000991 and 0.000341 mg/mL, respectively. The developed method can accurately determine AS-IV in Huangqi Granules and different batches of Ganweikang Tablets, which are similar to the results measured by HPLC-ELSD and meet the requirements of Chinese Pharmacopoeia (2020 edition) for the amount of AS-IV in Huangqi Granules. The combination of MIP with CuO NPs not only endows the detection of AS-IV with high selectivity and reliability, but also expands the application of nanozymes in the detection of small-molecule compounds that have weak UV absorption, and do not have reducibility or oxidation properties.

Hereditary Hearing Loss: A Systematic Review of Potential Treatments and Interventions.

PURPOSE: The purpose of this study was to systematically review the research literature with regards to treatments and intervention methods for hereditary hearing loss. Our goal was to provide reference guidelines for the rational use of medication and gene-targeted therapy for patients with hereditary hearing loss and discuss the future development of research in this area. METHOD: We searched two core databases, PubMed and Web of Science, for relevant literature relating to potential treatments and interventional methods for hereditary hearing loss. Then, we used Microsoft Excel to perform basic statistical analysis of the data, the R language to perform bibliometric analyses, and VOSviewer and CiteSpace to visualize data. In addition, we clustered and descriptively analyzed the data and identified the relative importance of each approach with regard to precise patient outcomes. RESULTS: In this study, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standardized screening process and identified a total of 103 research articles. The average annual growth rate of publications in this area was 12.73%. The country with the highest number of publications and citations was the United States; 80 of these publications (associated with 76.92% of funding) were supported by grants from 16 countries. Potential treatments and interventions were clustered according to the stage of research and showed that 8.74% remain in the research design stage, 59.22% are in the clinical validation stage, and 32.04% are being applied in the clinic. The main research focus in this field is cochlear implants and gene therapy. CONCLUSIONS: Hereditary hearing loss is in a critical period of transition from preventive to therapeutic research. Gene-targeted interventions represent one of the most promising and effective treatments. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24309193.

Association between the Composite Dietary Antioxidant Index and Atherosclerotic Cardiovascular Disease in Postmenopausal Women: A Cross-Sectional Study of NHANES Data, 2013-2018.

The relationship between composite dietary antioxidant index (CDAI) levels and the risk of atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women is unknown. In total, 3109 women from the National Health and Nutrition Examination Survey 2013-2018 were included in this cross-sectional study. We evaluated the association between CDAI levels and the risk of ASCVD by using three logistic regression models and restricted cubic splines. A stratified analysis and sensitivity analysis were also conducted. The restricted cubic splines exhibited an L-shaped dose-response association between CDAI levels and the ASCVD risk. Logistic regression analysis found that CDAI levels were negatively associated with the occurrence of ASCVD. The ORs associated with a per-SD increase in CDAI were 0.67 (95% CI: 0.51-0.88) for ASCVD risk. Similarly, women in the group with high CDAI levels were less likely to have ASCVD (OR = 0.71, 95% CI: 0.50-0.98) compared to those in the group with low CDAI levels. When the CDAI levels were divided into quartiles, it was found that the ORs for ASCVD with CDAI levels in Q2 (-1.04-1.11), Q3 (1.11-3.72), and Q4 (3.72-43.87) were 0.63 (0.44, 0.90), 0.64 (0.42, 0.94), and 0.51 (0.27, 0.97), respectively, compared to those with CDAI levels in Q1 (-6.83--1.04). In addition, age, high-density lipoprotein cholesterol levels, and smoking behaviors acted as potential modifiers, and ORs were more significant in women aged 40-69 years, in individuals with low high-density lipoprotein cholesterol levels, and in smokers (p for interaction <0.05). These findings may offer valuable insights into the role of CDAI levels in the development of ASCVD among postmenopausal women.

Methyl cinnamate protects against dextran sulfate sodium-induced colitis in mice by inhibiting the MAPK signaling pathway.

Effective and non-toxic therapeutic agents are lacking for the prevention and treatment of colitis. Previous studies found that methyl cinnamate (MC), extracted from galangal ( Alpinia officinarum Hance), has anti-inflammatory properties. However, whether MC is effective as anti-colitis therapy remains unknown. In this study, we investigate the therapeutic effects of MC on dextran sulfate sodium (DSS)-induced colitis in mice and further explore its potential mechanism of action. MC treatment relieves symptoms associated with DSS-induced colitis, including the recovery of DSS-induced weight loss, decreases the disease activity index score, and increases the colon length without toxic side effects. MC treatment protects the integrity of the intestinal barrier in mice with DSS-induced colitis and inhibits the overexpression of pro-inflammatory cytokines in vivo and in vitro. Moreover, the MAPK signaling pathway is found to be closely related to the treatment with MC of colitis. Western blot analysis show that phosphorylation of the p38 protein in colon tissues treated with MC is markedly reduced and phosphorylation levels of the p38, JNK and ERK proteins are significantly decreased in RAW 264.7 cells treated with MC, indicating that the mechanism of MC in treating DSS-induced colitis could be achieved by inhibiting the MAPK signaling pathway. Furthermore, 16S RNA sequencing analysis show that MC can improve intestinal microbial dysbiosis in mice with DSS-induced colitis. Altogether, these findings suggest that MC may be a novel therapeutic candidate with anti-colitis efficacy. Furthermore, MC treatment relieves the symptoms of colitis by inhibiting the MAPK signaling pathway and improving the intestinal microbiota.

A target map of clinical combination therapies in oncology: an analysis of clinicaltrials.gov.

Combination therapies have taken center stage for cancer treatment, however, there is a lack of a comprehensive portrait to quantitatively map the current clinical combination progress. This study aims to capture clinical combination therapies of the validated FDA-approved new oncology drugs by a macro data analysis and to summarize combination mechanisms and strategies in the context of the existing literature. A total of 72 new molecular entities or new therapeutic biological products for cancer treatment approved by the FDA from 2017 to 2021 were identified, and the data on their related 3334 trials were retrieved from the database of ClinicalTrials.gov. Moreover, these sampled clinical trials were refined by activity status and combination relevance and labeled with the relevant clinical arms and drug combinations, as well as drug targets and target pairs. Combination therapies are increasingly prevalent in clinical trials of new oncology drugs. From retrospective work, existing clinical combination therapies in oncology are driven by different patterns (i.e., rational design and industry trends). The former can be represented by mechanism-based or structure-based combinations, such as targeting different domains of HER2 protein or in-series co-targeting in RAF plus MEK inhibitors. The latter is an empirically driven strategy, including redundant combinations in hot targets, such as PD-1/PD-L1, PI3K, CDK4/6, and PARP. Because of an explosion in the number of clinical trials and the resultant shortage of available patients, it is essential to rationally design drug combinations.

Current Status and Trends in mHealth-Based Research for Treatment and Intervention in Tinnitus: Bibliometric and Comparative Product Analysis.

BACKGROUND: As a global medical problem, tinnitus can seriously harm human health and is difficult to alleviate, ranking among the top 3 complex diseases in the otolaryngology field. Traditional cognitive behavioral therapy and sound therapy require offline face-to-face treatment with medical staff and have limited effectiveness. Mobile health (mHealth), which, in recent decades, has been greatly applied in the field of rehabilitation health care, improving access to health care resources and the quality of services, has potential research value in the adjunctive treatment of tinnitus. OBJECTIVE: This study aimed to understand the research trends, product characteristics, problems, and research transformation of tinnitus treatment software by analyzing the research progress of mHealth for tinnitus treatment based on the literature and related marketed apps. METHODS: Bibliometric methods were used to describe the characteristics of the relevant literature in terms of the number and topics of publications, authors, and institutions. We further compared the features and limitations of the currently available tinnitus treatment software. RESULTS: Data published until February 28, 2022, were collected. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standardized screening process, 75 papers were included. The country with the highest number of publications was Germany, followed by the United Kingdom and the United States, whereas China had only a single relevant study. The most frequently found journals were the American Journal of Audiology and the Journal of the American Academy of Audiology (18/75, 24%). With regard to publication topics, cognitive behavioral therapy started to become a hot topic in 2017, and research on mHealth apps has increased. In this study, 28 tinnitus treatment apps were obtained (n=24, 86% from product data and n=4, 14% from literature data); these apps were developed mainly in the United States (10/28, 36%) or China (9/28, 32%). The main treatment methods were sound therapy (10/28, 36%) and cognitive behavioral therapy (2/28, 7%). Of the 75 publications, 7 (9%) described apps in the market stage. Of the 28 apps, 22 (79%) lacked literature studies or evidence from professional bodies. CONCLUSIONS: We found that, as a whole, the use of mHealth for treatment and intervention in tinnitus was showing a rapid development, in which good progress had been made in studies around sound therapy and cognitive behavioral therapy, although most of the studies (50/75, 67%) focused on treatment effects. However, the field is poorly accepted in top medical journals, and the majority are in the research design phase, with a lack of translation of the literature results and clinical validation of the marketed apps. Furthermore, in the future, novel artificial intelligence techniques should be used to address the issue of staged monitoring of tinnitus.

Expanding potential targets of herbal chemicals by node2vec based on herb-drug interactions.

BACKGROUND: The identification of chemical-target interaction is key to pharmaceutical research and development, but the unclear materials basis and complex mechanisms of traditional medicine (TM) make it difficult, especially for low-content chemicals which are hard to test in experiments. In this research, we aim to apply the node2vec algorithm in the context of drug-herb interactions for expanding potential targets and taking advantage of molecular docking and experiments for verification. METHODS: Regarding the widely reported risks between cardiovascular drugs and herbs, Salvia miltiorrhiza (Danshen, DS) and Ligusticum chuanxiong (Chuanxiong, CX), which are widely used in the treatment of cardiovascular disease (CVD), and approved drugs for CVD form the new dataset as an example. Three data groups DS-drug, CX-drug, and DS-CX-drug were applied to serve as the context of drug-herb interactions for link prediction. Three types of datasets were set under three groups, containing information from chemical-target connection (CTC), chemical-chemical connection (CCC) and protein-protein interaction (PPI) in increasing steps. Five algorithms, including node2vec, were applied as comparisons. Molecular docking and pharmacological experiments were used for verification. RESULTS: Node2vec represented the best performance with average AUROC and AP values of 0.91 on the datasets "CTC, CCC, PPI". Targets of 32 herbal chemicals were identified within 43 predicted edges of herbal chemicals and drug targets. Among them, 11 potential chemical-drug target interactions showed better binding affinity by molecular docking. Further pharmacological experiments indicated caffeic acid increased the thermal stability of the protein GGT1 and ligustilide and low-content chemical neocryptotanshinone induced mRNA change of FGF2 and MTNR1A, respectively. CONCLUSIONS: The analytical framework and methods established in the study provide an important reference for researchers in discovering herb-drug interactions, alerting clinical risks, and understanding complex mechanisms of TM.

Global research trends in benign paroxysmal positional vertigo: a bibliometric analysis.

Background: Benign paroxysmal positional vertigo is the most common disease in which vertigo is the main clinical manifestation, and it has become a global medical problem, affecting a wide range of areas and seriously affecting the quality of human life. Objective: This article presents an analysis of the current characteristics of BPPV-related research and summarizes the current hot topics and trends, with the goal of inspiring future research into the prevention and treatment of BPPV, thereby improving the differential diagnosis and prevention of peripheral vertigo. Methods: A bibliometric approach was used to collect 1,219 eligible studies on BPPV from four databases-PubMed, Embase, Scopus, and Web of Science-published between 1974 and 2022. The characteristics and status of the accumulated scientific output were processed using R and VOSviewer so that we could visualize any trends or hotspots. Results: The results showed a significant increase in the annual number of publications, with an average annual growth rate of 21.58%. A possible reason for the especially pronounced peak in 2021 was an increase in the prevalence of BPPV as a result of COVID-19. The new coronavirus became a focus of research in 2021. A total of 3,876 authors (of whom 1,097 were first authors) published articles in 307 different journals; 15.7% of the articles were published in Acta Oto-Larygologica, Otology and Neurotology, and Frontiers in Neurology. Acta Oto-Laryngologica was well ahead of the other journals in terms of growth rate and number of articles published. American scholars generated the largest number of articles overall, and the USA was involved in the greatest number of international collaborations, followed by Italy and China. The themes of the research centered around three topics, namely the treatment of BPPV, its influencing factors, and diagnosis. Conclusions: There has been a major increase in BPPV-related research over the last 50 years, leading to an increase in related articles and rapid development of the field. Key directions for future research include the improvement of individualized treatment for residual symptoms after initial treatment of BPPV among the elderly; effective control of comorbidities such as osteoporosis; and secondary inner ear disease, such as Ménière's disease.

Leocarpinolide B Attenuates Collagen Type II-Induced Arthritis by Inhibiting DNA Binding Activity of NF-κB.

Rheumatoid arthritis (RA) is a chronic autoimmune disease triggered by a cascading inflammatory response. Sigesbeckia Herba (SH) has long been utilized as a traditional remedy to alleviate symptoms associated with rheumatism. Our previous study found that leocarpinolide B (LB), a sesquiterpene lactone isolated from the whole plant of SH, possesses potent a anti-inflammatory effect on macrophages. This study was designed to evaluate the therapeutic effects of LB on RA, and further investigate the underlying mechanisms. In collagen type II-induced arthritic mice, LB was demonstrated to decrease the production of autoimmune antibodies in serum and inflammatory cytokines in the joint muscles and recover the decreased regulatory T lymphocytes in spleen. Moreover, LB significantly suppressed the inflammatory infiltration, formation of pannus and bone erosion in the paw joints. In vitro testing showed that LB inhibited the proliferation, migration, invasion, and secretion of inflammatory cytokines in IL-1ß-induced human synovial SW982 cells. Network pharmacology and molecular docking suggested NF-κB p65 could be the potential target of LB on RA treatment, subsequent experimental investigation confirmed that LB directly interacted with NF-κB p65 and reduced the DNA binding activity of NF-κB in synovial cells. In conclusion, LB significantly attenuated the collagen type II-induced arthritis, which was at least involved in the inhibition of DNA binding activity of NF-κB through a direct binding to NF-κB p65. These findings suggest that LB could be a valuable lead compound for developing anti-RA drugs.

Mapping the regulatory effects of herbal organic compounds on gut bacteria.

Herbal organic compounds (HOCs) are bioactive natural products from medicinal plants and some traditional Chinese medicines (TCMs). Recently, ingestion of a few HOCs with low bioavailability has been associated with alterations in gut microbiota, but the extent of this phenomenon remains unclear. Here, we systematically screened 481 HOCs against 47 representative gut bacterial strains in vitro and found that almost one-third of the HOCs exhibited unique anticommensal activity. Quinones showed a potent anticommensal activity, while saturated fatty acids exhibited stronger inhibition of the Lactobacillus genus. Flavonoids, phenylpropanoids, terpenoids, triterpenoids, alkaloids and phenols displayed weaker anticommensal activity, but steroids, saccharides and glycosides had hardly any effect on strain growth. Notably, S-configuration HOCs demonstrated stronger anticommensal activity than R-configuration HOCs. The strict screening conditions ensured high accuracy (95%) through benchmarking validation. Additionally, the effects of HOCs on human fecal microbiota profiling were positively correlated with their anticommensal activity against bacterial strains. Molecular and chemical features such as AATS3i and XLogP3 were correlated with the anticommensal activity of the HOCs in the random forest classifier. Finally, we validated that curcumin, a polyhydric phenol with anticommensal activity, improved insulin resistance in HFD mice by modulating the composition and metabolic function of gut microbiota. Our results systematically mapped the profile of HOCs directly affecting human gut bacterial strains, offering a resource for future research on HOC-microbiota interaction, and broadening our understanding of natural product utilization through gut microbiota modulation.

Mechanisms of Ganweikang Tablets against Chronic Hepatitis B: A Comprehensive Study of Network Analysis, Molecular Docking, and Chemical Profiling.

The hepatitis B virus (HBV) is one of the major viral infection problems worldwide in public health. The exclusive proprietary Chinese medicine Ganweikang (GWK) tablet has been marketed for years in the treatment of chronic hepatitis B (CHB). However, the pharmacodynamic material basis and underlying mechanism of GWK are not completely clear. This study is aimed at investigating the pharmacological mechanism of the GWK tablet in the treatment of CHB. The chemical ingredient information was obtained from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID), and Shanghai Institute of Organic Chemistry of CAS. Ingredients and disease-related targets were defined by a combination of differentially expressed genes from CHB transcriptome data and open-source databases. Target-pathway-target (TPT) network analysis, molecular docking, and chemical composition analysis were adopted to further verify the key targets and corresponding active ingredients of GWK. Eight herbs of GWK were correlated to 330 compounds with positive oral bioavailability, and 199 correlated targets were identified. The TPT network was constructed based on the 146 enriched targets by KEGG pathway analysis, significantly associated with 95 pathways. Twenty-five nonvolatile components and 25 volatile components in GWK were identified in UPLC-QTOF/MS and GC-MS chromatograms. The key active ingredients of GWK include ferulic acid, oleanolic acid, ursolic acid, tormentic acid, 11-deoxyglycyrrhetic acid, dibenzoyl methane, anisaldehyde, wogonin, protocatechuic acid, psoralen, caffeate, dimethylcaffeic acid, vanillin, ß-amyrenyl acetate, formonentin, aristololactam IIIa, and 7-methoxy-2-methyl isoflavone, associated with targets CA2, NFKB1, RELA, AKT1, JUN, CA1, CA6, IKBKG, FOS, EP300, CREB1, STAT1, MMP9, CDK2, ABCB1, and ABCG2.

Virus diversity, wildlife-domestic animal circulation and potential zoonotic viruses of small mammals, pangolins and zoo animals.

Wildlife is reservoir of emerging viruses. Here we identified 27 families of mammalian viruses from 1981 wild animals and 194 zoo animals collected from south China between 2015 and 2022, isolated and characterized the pathogenicity of eight viruses. Bats harbor high diversity of coronaviruses, picornaviruses and astroviruses, and a potentially novel genus of Bornaviridae. In addition to the reported SARSr-CoV-2 and HKU4-CoV-like viruses, picornavirus and respiroviruses also likely circulate between bats and pangolins. Pikas harbor a new clade of Embecovirus and a new genus of arenaviruses. Further, the potential cross-species transmission of RNA viruses (paramyxovirus and astrovirus) and DNA viruses (pseudorabies virus, porcine circovirus 2, porcine circovirus 3 and parvovirus) between wildlife and domestic animals was identified, complicating wildlife protection and the prevention and control of these diseases in domestic animals. This study provides a nuanced view of the frequency of host-jumping events, as well as assessments of zoonotic risk.

Association between serum total testosterone levels and metabolic syndrome among adult women in the United States, NHANES 2011-2016.

Objective: To investigate the association between serum total testosterone (TT) levels and metabolic syndrome (MetS) or its components among adult women. Methods: 2,678 women from NHANES 2011-2016 were included in this cross-sectional study. MetS was determined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. The association between serum TT levels and MetS was evaluated by two logistics regression models and the adjusted restricted cubic spline (RCS). Stratified analysis and sensitive analysis were also conducted. Results: Continuous TT levels were negatively associated with the occurrence of MetS, and the ORs associated with per SD increase in ln TT were 0.70 (95%CI: 0.58-0.85) in 2011-2014 and 0.56 (95%CI: 0.39-0.79) in 2015-2016 in Model A. High TT group were less likely to have MetS (OR=0.60, 95%CI: 0.45-0.80 in 2011-2014 and OR=0.50, 95%CI: 0.32-0.78 in 2015-2016) when compared to the low TT group. When TT levels were divided into quartiles, TT levels were negatively correlated with the incidence of MetS (p for trend < 0.001). Similar trend was observed in Model B. Multivariate-adjusted logistic regression with RCS exhibited that TT had a L-shaped dose-response association with MetS or its components. Interaction analyses revealed that women who were less than 50 years old (OR=0.37, 95%CI: 0.22, 0.63), with depression (OR=0.50, 95%CI: 0.29, 0.87) or being smokers (OR=0.37, 95%CI: 0.23, 0.54) showed lower ORs than those who were over 50 years old (OR=0.66, 95%CI: 0.40, 1.09), without depression (OR=0.59, 95%CI: 0.41, 0.85) or non-smokers (OR=0.59, 95%CI: 0.39, 0.89) when measure the association between ln TT and the occurrence of MetS. Conclusions: Our study indicated that TT levels are negatively correlated with the occurrence of MetS, with interaction effects of age, smoke behaviors, and depressive status.

STING as an emerging therapeutic target for drug discovery: Perspectives from the global patent landscape.

BACKGROUND: The STimulator of INterferon Genes (STING) plays an essential role in the innate immune system by inducing the expression of type I interferons (IFNs) and inflammatory cytokines upon sensing cytosolic DNA. Although modulating STING has shown promise as a potential treatment for cancers and inflammatory and autoimmune diseases in substantial pre-clinical studies, current preliminary clinical results of STING agonists have demonstrated limited anti-tumor efficacy. Currently, there is ongoing R&D targeting STING and focusing on the delivery of next-generation therapeutics. Whereas no comprehensive analysis on the STING patent landscape has been conducted to fill the gap between basic research progress and drug development and commercialization. AIM OF REVIEW: This study summarized the current agents in the clinical stage and global patenting profiles to help identify the current status, development trends, and emerging technologies of the nascent field of STING modulation. KEY SCIENTIFIC CONCEPTS OF REVIEW: Rapidly increasing R&D efforts and outcomes targeting STING were indicated by the recently increasing number and pharmacologic classes of drug candidates in clinic as well as in emergent technological patenting activities. Despite the overall fragmental ownership of patents, several pioneers that have advanced the clinical evaluation of novel STING agonists have established the basis of STING-relevant inventions through their influential patents in the field. These patents also facilitated progress on novel STING modulators, relevant delivery systems, pharmaceutical compositions, and combination strategies with the potential for further enhancing therapeutic outcomes by targeting STING.