High-Entropy Alloy Array via Liquid Metal Nanoreactor.

High-entropy alloy (HEA) nanostructures arranged into well-defined configurations hold great potential for accelerating the development of electronics, photonics, catalysis, and device integration. However, the random nucleation induced by the disparity in physicochemical properties of multiple elements makes it challenging to achieve single-particle synthesis at the patterned preset sites in the high-entropy scenario. Herein, we proposed the liquid metal nanoreactor strategy to realize the construction of HEA arrays. The coalescence of the liquid metal driven by the tendency to decrease surface energy provides a restricted environment for the nucleation and growth to form single HEA particles at the preset locations, which could be regarded as a self-confinement reaction. Liquid metal endowing a low diffusion barrier on the substrate and a high diffusivity of the alloy system could dynamically promote the aggregation process. As a result, the HEA array was prepared with elements up to eleven and possessed uniform periodicity, which exhibited excellent holography response in a broad spectrum. Our work injects new vitality into the construction of HEA nanopatterns and provides an excellent platform for propelling their fundamental research and applications. This article is protected by copyright. All rights reserved.

Analysis of Risk Factors for Urinary Tract Infection after Lumbar Interbody Fusion.

OBJECTIVE: Urinary tract infection (UTI) is a common postoperative complication, so exploring its risk factors is helpful to provide a basis for clinical prevention. This study aims to analyse the risk factors for UTI after lumbar interbody fusion (LIF). METHODS: A single-centre retrospective study was conducted on the clinical data of 358 patients treated with LIF from April 2020 to April 2023. In accordance with the results of postoperative urine culture, the patients were divided into UTI group (n = 19, those with UTI after LIF) and control group (n = 332, those without UTI after LIF). Binary logistic regression analysis was carried out through collecting the medical records of the two groups to probe into the risk factors for UTI after LIF. RESULTS: After seven patients were excluded, the remaining 351 patients were included in the analysis. In this study, 19 patients (5.41%) developed postoperative UTI, whereas 332 patients (94.59%) had no UTI. Regression analysis results showed drinking (odds ratio (OR) = 16.193, 95% confidence interval (CI): 1.017-257.860) and high preoperative C-reactive protein (CRP) level (OR = 3.237, 95% CI: 1.213-8.636) as risk factors for UTI after LIF. A high professional title of main surgeon (OR = 0.095, 95% CI: 0.010-0.932) and preoperative red blood cell (RBC) count (OR = 0.001, 95% CI: 0.000-0.198) were protective factors for UTI after LIF (p < 0.05). CONCLUSIONS: This study advocated strengthening the prevention and treatment of UTI in patients who had drinking history, high preoperative CRP level and low preoperative RBC count, and received LIF based on the study results. Attention should be paid to the training of physicians with low professional title.

Knowledge, attitudes, and practices toward cardiovascular complications among end-stage renal disease patients undergoing maintenance hemodialysis.

BACKGROUND: This study aimed to investigate the knowledge, attitudes, and practices (KAP) toward cardiovascular complications among end-stage renal disease patients undergoing maintenance hemodialysis. METHODS: This web-based cross-sectional study was conducted at Guangdong Provincial People's Hospital between December 2022, and May 2023. RESULTS: A total of 545 valid questionnaires were collected, with an average age of 57.72 ± 13.47 years. The mean knowledge, attitudes and practices scores were 8.17 ± 2.9 (possible range: 0-24), 37.63 ± 3.80 (possible range: 10-50), 33.07 ± 6.10 (possible range: 10-50) respectively. Multivariate logistic regression analysis showed that patients from non-urban area had lower knowledge compared to those from urban area (odds ratio (OR) = 0.411, 95% CI: 0.262-0.644, P < 0.001). Furthermore, higher levels of education were associated with better knowledge, as indicated by OR for college and above (OR = 4.858, 95% CI: 2.483-9.504), high school/vocational school (OR = 3.457, 95% CI: 1.930-6.192), junior high school (OR = 3.300, 95% CI: 1.945-5.598), with primary school and below as reference group (all P < 0.001). Besides, better knowledge (OR = 1.220, 95% CI: 1.132-1.316, P < 0.001) and higher educational levels were independently associated with positive attitudes. Specifically, individuals with a college degree and above (OR = 2.986, 95% CI: 1.411-6.321, P = 0.004) and those with high school/vocational school education (OR = 2.418, 95% CI: 1.314-4.451, P = 0.005) have more positive attitude, with primary school and below as reference group. Next, better attitude (OR = 1.174, 95% CI: 1.107-1.246, P < 0.001) and higher education were independently associated with proactive practices. Those with college and above (OR = 2.870, 95% CI: 1.359-6.059, P = 0.006), and those with high school/vocational school education (OR = 1.886, 95% CI: 1.032-3.447, P = 0.039) had more proactive practices, with primary school and below as reference group. CONCLUSIONS: End-stage renal disease patients undergoing maintenance hemodialysis demonstrated insufficient knowledge, positive attitudes, and moderate practices regarding cardiovascular complications. Targeted interventions should prioritize improving knowledge and attitudes, particularly among patients with lower educational levels and income, to enhance the management of cardiovascular complications in end-stage renal disease.

Discovery, optimization and biological activity evaluation of genipin derivatives as potential KRAS G12D inhibitors.

A series of genipin derivatives were designed and synthesized as potential inhibitors targeted KRAS G12D mutation. The majority of these compounds demonstrated potential antiproliferative effects against KRAS G12D mutant tumor cells (CT26 and A427). Notably, seven compounds exhibited the anticancer effects with IC50 values ranging from 7.06 to 9.21 µM in CT26 (KRASG12D) and A427 (KRASG12D) cells and effectively suppressed the colony formation of CT26 cells. One representative compound SK12 was selected for further investigation into biological activity and action mechanisms. SK12 markedly induced apoptosis in CT26 cells in a concentration-dependent manner. Moreover, SK12 elevated the levels of reactive oxygen species (ROS) in tumor cells and exhibited a modulatory effect on the KRAS signaling pathway, thereby inhibiting the activation of downstream phosphorylated proteins. The binding affinity of SK12 to KRAS G12D protein was further confirmed by the surface plasmon resonance (SPR) assay with a binding KD of 157 µM. SK12 also exhibited notable anticancer efficacy in a nude mice tumor model. The relative tumor proliferation rate (T/C) of the experimental group (50 mg/kg) was 31.04 % (P < 0.05), while maintaining a commendable safety profile.

Controllable synthesis of high-entropy alloys.

High-entropy alloys (HEAs) involving more than four elements, as emerging alloys, have brought about a paradigm shift in material design. The unprecedented compositional diversities and structural complexities of HEAs endow multidimensional exploration space and great potential for practical benefits, as well as a formidable challenge for synthesis. To further optimize performance and promote advanced applications, it is essential to synthesize HEAs with desired characteristics to satisfy the requirements in the application scenarios. The properties of HEAs are highly related to their chemical compositions, microstructure, and morphology. In this review, a comprehensive overview of the controllable synthesis of HEAs is provided, ranging from composition design to morphology control, structure construction, and surface/interface engineering. The fundamental parameters and advanced characterization related to HEAs are introduced. We also propose several critical directions for future development. This review can provide insight and an in-depth understanding of HEAs, accelerating the synthesis of the desired HEAs.

Direct Photocatalytic Methane Oxidation to Formaldehyde by N Doping Co-Decorated Mixed Crystal TiO2.

In this paper, N-doped TiO2 mixed crystals are prepared via direct calcination of TiN for highly selective oxidation of CH4 to HCHO at room temperature. The structures of the prepared TiO2 samples are characterized to be N-doped TiO2 of anatase and rutile mixed crystals. The crystal structures of TiO2 samples are determined by XRD spectra and Raman spectra, while N doping is demonstrated by TEM mapping, ONH inorganic element analysis, and high-resolution XPS results. Significantly, the production rate of HCHO is as high as 23.5 mmol·g-1·h-1 with a selectivity over 90%. Mechanism studies reveal that H2O is the main oxygen source and acts through the formation of ·OH. DFT calculations indicate that the construction of a mixed crystal structure and N-doping modification mainly act by increasing the adsorption capacity of H2O. An efficient photocatalyst was prepared by us to convert CH4 to HCHO with high yield and selectivity, greatly promoting the development of the photocatalytic CH4 conversion study.

Huangqin decoction attenuates spared nerve injury (SNI)-induced neuropathic pain by modulating microglial M1/M2 polarization partially mediated by intestinal nicotinamide metabolism.

BACKGROUND: The incidence of neuropathic pain is progressively increasing over time. The activation of M1-type microglia plays a crucial role in the initiation and progression of neuropathic pain. Huangqin Decoction (HQD) is traditionally used to alleviate dysentery and abdominal pain. However, it remains unclear whether HQD can effectively mitigate neuropathic pain and the underlying mechanisms. PURPOSE: The present study aims to investigate the impact of HQD on neuropathic pain induced by spared nerve injury (SNI) in mice, and to elucidate whether the analgesic effect of HQD is associated with microglia polarization. METHODS: The analgesic effect of HQD on SNI mice was investigated through assessments of mechanical pain threshold, thermal pain threshold, cold pain threshold, and motor ability. We elucidated the molecular mechanisms of HQD in alleviating SNI-induced neuropathic pain by focusing on microglia polarization and intestinal metabolite abnormalities. The expression levels of markers associated with microglia polarization (Iba-1, CD68, CD206, iNOS) was detected by immunofluorescence and Western blot, and the levels of inflammatory factors (IL-4, IL-10, IL-6, TNF-α) were assessed by ELISA. UPLC-QTOF-MS metabolomics was utilized to identify differential metabolites in the intestines of SNI mice. We screened the differential metabolites related to microglial polarization by correlation analysis, subsequently nicotinamide was selected for validation in LPS-induced BV-2 cells. RESULTS: Our findings demonstrated that HQD (20 g/kg) significantly enhanced the mechanical pain threshold, thermal pain threshold, and cold pain threshold, and protected the injured DRG neurons of SNI mice. Moreover, HQD (20 g/kg) obviously suppressed the expression of microglia M1 polarization markers (Iba-1, CD68, iNOS, IL-6, TNF-α), and promoted the expression of microglia M2 polarization markers (CD206, IL-10, IL-4) in the spinal cord of SNI mice. Additionally, HQD (20 g/kg) prominently ameliorated intestinal barrier damage by upregulating Claudin 1 and Occludin expression in the colon of SNI mice. Furthermore, HQD (20 g/kg) rectified 19 metabolite abnormalities in the intestine. Notably, nicotinamide (100 µM), an amide derivative with anti-inflammatory property, effectively suppresses microglia activation and polarization in LPS-induced BV-2 cells by downregulating IL-6 level and CD68 expression while upregulating IL-4 level and CD206 expression. CONCLUSION: In summary, HQD alleviates neuropathic pain in SNI mice by regulating the activation and polarization of microglia, partially mediated through intestinal nicotinamide metabolism.

Extraction, purification, structural characteristics, biological activities, and applications of polysaccharides from the genus Lilium: A review.

The genus Lilium (Lilium) has been widely used in East Asia for over 2000 years due to its rich nutritional and medicinal value, serving as both food and medicinal ingredient. Polysaccharides, as one of the most important bioactive components in Lilium, offer various health benefits. Recently, polysaccharides from Lilium plants have garnered significant attention from researchers due to their diverse biological properties including immunomodulatory, anti-oxidant, anti-diabetic, anti-tumor, anti-bacterial, anti-aging and anti-radiation effects. However, the limited comprehensive understanding of polysaccharides from Lilium plants has hindered their development and utilization. This review focuses on the extraction, purification, structural characteristics, biological activities, structure-activity relationships, applications, and relevant bibliometrics of polysaccharides from Lilium plants. Additionally, it delves into the potential development and future research directions. The aim of this article is to provide a comprehensive understanding of polysaccharides from Lilium plants and to serve as a basis for further research and development as therapeutic agents and multifunctional biomaterials.

Enhancing Kinetics in Sodium Super Ion Conductor Na3MnTi(PO4)3 through Microbe-Assisted and Structural Optimization.

Sodium (Na) super ion conductor (NASICON) structure Na3MnTi(PO4)3 (NMTP) is considered a promising cathode for sodium-ion batteries due to its reversible three-electron reaction. However, the inferior electronic conductivity and sluggish reaction kinetics limit its practical applications. Herein, we successfully constructed a three-dimensional cross-linked porous architecture NMTP material (AsN@NMTP/C) by a natural microbe of Aspergillus niger (AsN), and the structure of different NMTP cathodes was optimized by adjusting different transition metal Mn/Ti ratios. Both approaches effectively altered the three-dimensional NMTP structure, not only improving electronic conductivity and controlling Na+ diffusion pathways but also enhancing the electrochemical kinetics of the material. The resultant AsN@NMTP/C-650, sintered at 650 °C, exhibits better electrochemical performance with higher reversible three-electron reactions corresponding to the voltage platforms of Ti4+/3+, Mn3+/2+, and Mn4+/3+ around 2.1, 3.6, and 4.1 V (vs Na+/Na), respectively. The capacity retention rate is up to 89.3% after 1000 cycles at a 2C rate. Moreover, a series of results confirms that the Na3.4Mn1.2Ti0.8(PO4)3 cathode has the most excellent electrochemical performance when the Mn/Ti ratio is 1.2/0.8, with a high capacity of 96.59 mAh g-1 and 97.1% capacity retention after 500 cycles.

Secondary cavitation bubble dynamics during laser-induced bubble formation in a small container.

We investigated secondary cavitation bubble dynamics during laser-induced bubble formation in a small container with a partially confined free surface and elastic thin walls. We employed high-speed photography to record the dynamics of sub-mm-sized laser-induced bubbles and small secondary bubble clouds. Simultaneous light scattering and acoustic measurements were used to detect the oscillation times of laser-induced bubbles. We observed that the appearance of secondary bubbles coincides with a prolonged collapse phase and with re-oscillations of the laser-induced bubble. We observed an asymmetric distribution of secondary bubbles with a preference for the upstream side of the focus, an absence of secondary bubbles in the immediate vicinity of the laser focus, and a migration of laser-induced bubble toward secondary bubbles at large pulse energies. We found that secondary bubbles are created through heating of impurities to form initial nanobubble nuclei, which are further expanded by rarefaction waves. The rarefaction waves originate from the vibration of the elastic thin walls, which are excited either directly by laser-induced bubble or by bubble-excited liquid-mass oscillations. The oscillation period of thin walls and liquid-mass were Twall = 116 µs and Tlm ≈ 160 µs, respectively. While the amplitude of the wall vibrations increases monotonically with the size of laser-induced bubbles, the amplitude of liquid-mass oscillation undulates with increasing bubble size. This can be attributed to a phase shift between the laser-induced bubble oscillation and the liquid-mass oscillator. Mutual interactions between the laser-induced bubble and secondary bubbles reveal a fast-changing pressure gradient in the liquid. Our study provides a better understanding of laser-induced bubble dynamics in a partially confined environment, which is of practical importance for microfluidics and intraluminal laser surgery.

A New Cloud-Native Tool for Pharmacogenetic Analysis.

BACKGROUND: The advancement of next-generation sequencing (NGS) technologies provides opportunities for large-scale Pharmacogenetic (PGx) studies and pre-emptive PGx testing to cover a wide range of genotypes present in diverse populations. However, NGS-based PGx testing is limited by the lack of comprehensive computational tools to support genetic data analysis and clinical decisions. METHODS: Bioinformatics utilities specialized for human genomics and the latest cloud-based technologies were used to develop a bioinformatics pipeline for analyzing the genomic sequence data and reporting PGx genotypes. A database was created and integrated in the pipeline for filtering the actionable PGx variants and clinical interpretations. Strict quality verification procedures were conducted on variant calls with the whole genome sequencing (WGS) dataset of the 1000 Genomes Project (G1K). The accuracy of PGx allele identification was validated using the WGS dataset of the Pharmacogenetics Reference Materials from the Centers for Disease Control and Prevention (CDC). RESULTS: The newly created bioinformatics pipeline, Pgxtools, can analyze genomic sequence data, identify actionable variants in 13 PGx relevant genes, and generate reports annotated with specific interpretations and recommendations based on clinical practice guidelines. Verified with two independent methods, we have found that Pgxtools consistently identifies variants more accurately than the results in the G1K dataset on GRCh37 and GRCh38. CONCLUSIONS: Pgxtools provides an integrated workflow for large-scale genomic data analysis and PGx clinical decision support. Implemented with cloud-native technologies, it is highly portable in a wide variety of environments from a single laptop to High-Performance Computing (HPC) clusters and cloud platforms for different production scales and requirements.

A review on extraction, purification, structural characteristics, biological activities, applications of polysaccharides from Hovenia dulcis Thunb. (Guai Zao).

Hovenia dulcis Thunb. (H. dulcis) is a widely distributed plant with a long history of cultivation and consumption. As a common plant, it has economic, edible and medicinal value. H. dulcis polysaccharides are one of their main bioactive ingredients and have many health benefits, such as anti-diabetes, antioxidation, anti-glycosylation, anti-fatigue, immune regulation activities and alcoholic liver disease protection activity. In this paper, the research progress of H. dulcis polysaccharides in extraction, purification, structural characteristics, biological activities, existing and potential applications were reviewed, which could provide new valuable insights for future studies.

Synthesis of Ultrathin High-Entropy Oxides with Phase Controllability.

High-entropy oxides (HEOs) with an ultrathin geometric structure are especially expected to exhibit extraordinary performance in different fields. The phase structure is deemed as a key factor in determining the properties of HEOs, rendering their phase control synthesis tempting. However, the disparity in intrinsic phase structures and physicochemical properties of multiple components makes it challenging to form single-phase HEOs with the target phase. Herein, we proposed a self-lattice framework-guided strategy to realize the synthesis of ultrathin HEOs with desired phase structures, including rock-salt, spinel, perovskite, and fluorite phases. The participation of the Ga assistor was conducive to the formation of the high-entropy mixing state by decreasing the formation energy. The as-prepared ultrathin spinel HEOs were demonstrated to be an excellent catalyst with high activity and stability for the oxygen evolution reaction in water electrolysis. Our work injects new vitality into the synthesis of HEOs for advanced applications and undoubtedly expedites their phase engineering.

STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway.

Ovarian cancer (OC) is a common malignant cancer in women with a low overall survival rate, and ferroptosis may be a potential new strategy for treatment. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a gene closely related to ferroptosis, yet the role of STEAP3 in OC has not yet been thoroughly investigated. Using biological information analysis, we first found that STEAP3 was highly expressed in OC, which was significantly associated with poor prognosis of patients and was an independent prognostic factor. Through cloning, scratch, and transwell experiments, we subsequently found that knockdown of STEAP3 significantly reduced the proliferation and migration ability of OC cells. Furthermore, we found that knockdown of STEAP3 induced ferroptosis in OC cells by detecting ferroptosis indicators. Mechanistically, we also found that knockdown of STEAP3 induced ferroptosis through the p53/SLC7A11 signaling pathway. Through tumorigenic experiments in nude mice, we finally verified that the knockdown of STEAP3 could inhibit tumor growth in vivo by promoting ferroptosis through the p53 pathway. Overall, our study identified a novel therapeutic target for ferroptosis in OC and explored its specific mechanism of action.

Serum/Plasma Proteome in Non-Malignant Liver Disease.

The liver is the central metabolic organ and produces 85-90% of the proteins found in plasma. Accordingly, the plasma proteome is an attractive source of liver disease biomarkers that reflects the different cell types present in this organ, as well as the processes such as responses to acute and chronic injury or the formation of an extracellular matrix. In the first part, we summarize the biomarkers routinely used in clinical evaluations and their biological relevance in the different stages of non-malignant liver disease. Later, we describe the current proteomic approaches, including mass spectrometry and affinity-based techniques, that allow a more comprehensive assessment of the liver function but also require complex data processing. The many approaches of analysis and interpretation and their potential caveats are delineated. While these advances hold the promise to transform our understanding of liver diseases and support the development and validation of new liver-related drugs, an interdisciplinary collaboration is needed.

Peptide-Driven Proton Sponge Nano-Assembly for Imaging and Triggering Lysosome-Regulated Immunogenic Cancer Cell Death.

Triggering lysosome-regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an "immune-cold" tumor "hot"-a key challenge faced by cancer immunotherapies. Proton sponge such as high-molecular-weight branched polyethylenimine (PEI) is excellent at rupturing lysosomes, but its therapeutic application is hindered by uncontrollable toxicity due to fixed charge density and poor understanding of resulted cell death mechanism. Here, a series of proton sponge nano-assemblies (PSNAs) with self-assembly controllable surface charge density and cell cytotoxicity are created. Such PSNAs are constructed via low-molecular-weight branched PEI covalently bound to self-assembling peptides carrying tetraphenylethene pyridinium (PyTPE, an aggregation-induced emission-based luminogen). Assembly of PEI assisted by the self-assembling peptide-PyTPE leads to enhanced surface positive charges and cell cytotoxicity of PSNA. The self-assembly tendency of PSNAs is further optimized by tuning hydrophilic and hydrophobic components within the peptide, thus resulting in the PSNA with the highest fluorescence, positive surface charge density, cell uptake, and cancer cell cytotoxicity. Systematic cell death mechanistic studies reveal that the lysosome rupturing-regulated pyroptosis and necroptosis are at least two causes of cell death. Tumor cells undergoing PSNA-triggered ICD activate immune cells, suggesting the great potential of PSNAs to trigger anticancer immunity.

Urinary Vitamin D Binding Protein: A Marker of Kidney Tubular Dysfunction in Patients at Risk for Type 2 Diabetes.

Context: Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective: Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods: Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results: Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 µg/mmol, 2.63 µg/mmol, and 2.48 µg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (ß = 30.67 and ß = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.

Tanshinone IIA, a component of the self-made Xiao-Yin decoction, ameliorates psoriasis by inhibiting IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways.

BACKGROUND: Psoriasis is a persistent inflammatory dermatological disorder. Tanshinone IIA (tan-IIA) is a biologically active compound in the self-made Xiao-Yin decoction (SMXYD) and exhibits diverse biological properties, such as anti-proliferative and anti-inflammatory effects. The objective of this investigation was to assess the potential of tan-IIA as a therapeutic agent against psoriasis. METHODS: Network pharmacology was employed to ascertain the active constituents and potential pathways associated with SMXYD and psoriasis. We conducted CCK-8, qRT-PCR, and western blotting to assess the proliferation of HaCaT keratinocytes and the expression of IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways. Additionally, we used H&E staining, western blotting, and ELISA to evaluate the therapeutic effects and signaling pathways of tan-IIA in psoriasis-like mice induced by imiquimod (IMQ). RESULTS: Network pharmacology analysis identified eight hub compounds. The Th17/IL-17 signaling was found to be a potential therapeutic pathway of SMXYD against psoriasis, with JUN (AP-1) as the core molecule. Next, PTGS2 was selected as the target of tan-IIA against psoriasis using network pharmacology analysis. Molecular docking showed a high affinity between PTGS2 and tan-IIA. Tan-IIA treatment attenuated M-5-induced hyperproliferation and inflammation in HaCaT keratinocytes. Additionally, Tan-IIA downregulated the PTGS2/NF-κB/AP-1 pathway in HaCaT keratinocytes. In the IMQ-induced psoriasis-like mouse, tan-IIA significantly reduced the severity of skin lesions and downregulated the PTGS2/NF-κB/AP-1 pathway. Moreover, the combination of methotrexate (MTX) and tan-IIA further inhibited the IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways. CONCLUSION: The administration of tan-IIA has shown a positive effect on psoriasis by inhibiting the IL-17/IL-23 and PTGS2/NF-κB/AP-1 pathways. The findings suggest that it has promising qualities that make it a potential candidate for the development of future anti-psoriatic agents.

Sudapyridine (WX-081) antibacterial activity against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo.

Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo. The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of M. avium and M. abscessus were 0.05-0.94 µg/mL, 0.88-7.22 µg/mL (M. abscessus subsp. abscessus), and 0.22-8.67 µg/mL (M. abscessus subsp. massiliense), respectively, which were slightly higher than those of BDQ. For M. avium, M. abscessus, and M. chelonae, WX-081 can reduce the intracellular bacterial load by 0.13-1.18, 0.18-1.50, and 0.17-1.03 log10 colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both in vivo and in vitro. WX-081 is a promising clinical candidate and should be studied further in clinical trials. IMPORTANCE: Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.