Activity and mechanism of action of antimicrobial peptide ACPs against Candida albicans.

AIMS: Candida albicans is the most prevalent pathogenic fungus, exhibiting escalating multidrug resistance (MDR). Antimicrobial peptides (AMPs) represent promising candidates for addressing this issue. In this research, five antimicrobial peptides, ACP1 to ACP5 which named ACPs were studied as alternative fungicidal molecules. MAIN METHODS: CD assay was used to analyze the 2D structures, Absorbance method was used to test the antimicrobial activity, haemolytic activity, time-kill kinetics, biofilm inhibition and reduction activity, resistance induction activity and assessment against fluconazole-resistant C. albicans. SEM, TEM, CLSM, flow cytometer and FM were carried out to provide insight into the mechanisms of anti-Candida action. KEY FINDINGS: ACPs possessed an α-helical structure and strong anti-Candida activities, with minimum inhibitory concentrations (MICs) from 3.9 to 15.6 µg/mL. In addition, ACPs did not produce hemolysis at concentrations lower than 10 or 62 × MIC, indicating their low cytotoxicity. Fungicidal kinetics showed that they completely killed C. albicans within 8 h at 2 to 4 × MIC. Notably, ACPs were highly fungicidal against fluconazole-resistant C. albicans and showed low resistance. In addition, they were effective in inhibiting mycelium and biofilm formation. Fluorescence microscopy revealed that while fluconazole had minimal to no inhibitory effect on biofilm-forming cells, ACPs induced apoptosis in all of them. The research on mechanism of action revealed that ACPs disrupted the cell membranes, with ROS increasing and cellular mitochondrial membrane potential decreasing. SIGNIFICANCE: ACPs could be promising candidates for combating fluconazole-resistant C. albicans infections.

Human Biomonitoring of Environmental Chemicals among Elderly in Wuhan, China: Prioritizing Risks Using EPA's ToxCast Database.

In line with the "healthy aging" principle, we aim to assess the exposure map and health risks of environmental chemicals in the elderly. Blood samples from 918 elderly individuals in Wuhan, China, were analyzed using the combined gas/liquid-mass spectrometry technology to detect levels of 118 environmental chemicals. Cluster analysis identified exposure profiles, while risk indexes and bioanalytical equivalence percentages were calculated using EPA's ToxCast database. The detection rates for 87 compounds exceeded 70%. DEHP, DiBP, naphthalene, phenanthrene, DnBP, pyrene, anthracene, permethrin, fluoranthene, and PFOS showed the highest concentrations. Fat-soluble pollutants varied across lifestyles. In cluster 2, which was characterized by higher concentrations of fat-soluble substances, the proportion of smokers or drinkers was higher than that of nonsmokers or nondrinkers. Pesticides emerged as the most active environmental chemicals in peroxisome proliferator-activated receptor gamma antagonist, thyroid hormone receptor (TR) antagonist, TR agonist, and androgen receptor (AR) agonist activity assays. Additionally, PAEs and polycyclic aromatic hydrocarbons played significant roles as active contaminants for the corresponding targets of AR antagonists and estrogen receptor alpha. We proposed a list of priority pollutants linked to endocrine-disrupting toxic effects in the elderly, which may provide the groundwork for further research into environmental etiology.

Prevalence of synthetic phenolic antioxidants in food contact materials from China and their implications for human dietary exposure through take-away food.

The application of disposable tableware has increased substantially in recent times due to the rapidly growing food delivery business in China. Synthetic phenolic antioxidants (SPAs) are widely used in food contact materials (FCMs) to delay the process of oxidation; however, their compositions, concentrations, and potential health hazards remain unclear. Therefore, FCMs comprised of five materials obtained from 19 categories (n = 118) in China were analyzed for SPAs concentrations. FCMs have been found to contain a variety of SPAs, with ∑SPAs concentrations ranging from 44.18 to 69,485.12 µg/kg (median: 2615.63 µg/kg). The predominant congeners identified in the sample include 2,4-di-tert-butylphenol (2,4-DTBP), 2,6-di-tert-butylphenol (2,6-DTBP), and 2,6-di-tert-butyl-p-benzoquinone (BHT-Q) with a median concentration of 885.75, 555.45 and of 217.44 µg/kg, respectively. Milky tea paper cups, instant noodle buckets, milky teacups, and disposable cups showed high levels of SPAs. 2,2'-methylenebis(4-methyl-6-tert-butylphenol) (AO 2246) was predominantly detected in polyethylene and polyethylene terephthalate-based products. The migration test identified disposable plastic cups and bowls as the predominant FCMs and 2,4-DTBP as the dominant SPA. The exposure risk of SPAs decreased with age. In children, the estimated daily intake of ∑SPAs from FCMs was determined to be 17.56 ng/kg body weight/day, which was 8.3 times higher than that of phthalic acid esters. The current findings indicate the potential ingestion risk of SPAs during the daily life application of multiple FCM categories.

Density Functional Theory Study on the Mechanism of Nickel-Catalyzed 3,3-Dialkynylation of 2-Aryl Acrylamides Via Double Vinylic C-H Bond Activation.

The mechanisms of Ni-catalyzed 3,3-dialkynylation of 2-aryl acrylamide have been investigated by using density functional theory calculations. The result shows that this reaction includes double alkynylation, which involves sequential key steps of vinylic C-H bond activation, successive oxidative addition, and reductive elimination, with the second C-H bond activation being the rate-determining step. C-H and N-H bond activation occurs via the concerted metalation-deprotonation mechanism. The calculations show that no transition state exists in the first reductive elimination process, and a negative free energy barrier in the second reductive elimination process though a transition state is identified, indicating that the nickel-catalyzed vinylic C(sp2)-C(sp) bond formation does not require activation energy. Z-E isomerization is the prerequisite for the second alkynylation. In addition, our spin-flip TDDFT (SF-TDDFT) computational result discloses that the actual process of Z-E isomerization occurs on the potential energy surface of the first excited singlet state S1.

Density Functional Theory Study of the Mechanism of Ni-Catalyzed Carboxylation of Aryl C(sp2)-S Bonds with CO2: Computational Evidence for the Multifaceted Role of Additive Zn.

The mechanism of Ni-catalyzed carboxylation of aryl C(sp2)-S bonds with CO2 was studied for the first time by density functional theory calculations. We first proposed another possible reaction pathway in which CO2 insertion occurs prior to reduction. Then, we performed calculations on all proposed reaction pathways, and our calculation results show that the pathway in which reduction occurs prior to CO2 insertion is the favored pathway for this reaction. Additionally, our calculations disclose that additive Zn0 acts in multifaceted roles. (1) Zn0 acts as a reductant to reduce the NiI and NiII intermediates. (2) The simultaneously formed ZnIIBr2 can undergo transmetalation with NiI or NiII intermediates to produce an aryl reservoir by forming arylzinc species. (3) ZnIIBr2 can also coordinate to the CO2 to lower the energy barrier of the CO2 insertion step. Moreover, the calculation results suggest that CO2 insertion is the rate-determining step of the reaction, and CO2 is easier to insert into the NiI-Ph bond rather than into the NiII-Ph bond. These calculation results can improve our understanding of the mechanism of the carboxylation process and the multifaceted roles of metal additive Zn0 and provide theoretical guidance for improving the carboxylation reaction.

Exploring the potential prompting role of cervical human papilloma virus detection in vulvar lesions: a cross-sectional study in China.

Introduction: The etiology and clinical presentation of vulvar carcinomas, especially vulvar lesions, are not fully understood. Because the vulva and cervix are anatomically connected, human papillomavirus (HPV) is the main cause of cervical lesions. Thus, this study explored the potential characteristics and effects of specific HPV infection types across vulvar lesions and concurrent cervical lesions. Methods: This retrospective, cross-sectional study analyzed patients with cervical HPV or cytological results and concurrent vulvar biopsy who were seen in our hospital colposcopy clinic in Shanxi Province, China, between 2013 and 2023. Data on age, menopause status, vulvar manifestations, and cytology and HPV infection testing results were collected. Attributable fractions and multinominal logistic models were used to evaluate HPV genotyping and clinical characteristics across vulvar lesions. Results: Among the 1,027 participants, 83 (8.1%) had vulvar intraepithelial neoplasia (VIN) of high grade or worse (VIN2+), and 127 (12.4%) had non-neoplastic epithelial disorders of the vulva (NNEDV). A total of 175 patients had either VIN2+ or cervical intraepithelial neoplasia (CIN) lesions of grade 2 or worse (CIN2+). The most common HPV genotypes for VIN2+ or concurrent VIN2+/CIN2+ were HPV16, HPV52, and HPV58, although attributable fractions differed among lesions. Patients with normal cytological or histopathological result were more likely to have NNEDV detected, while abnormal cervical diagnosis was associated with higher detection of VIN2+. Multinominal logistic modeling showed that age and HPV16 infection were risk factors for VIN2+ or concurrent VIN2+/CIN2+; however, only vulvar presentation with depigmentation was a risk factor for NNEDV. Among patients with low-grade CIN1/VIN1, compared with those who were HPV16 negative, those who were HPV16 positive were at 6.63-fold higher risk of VIN2+/CIN2+ [95% confidence interval (CI): 3.32, 13.21]. Vulvar depigmentation was also associated with increased risk of NNEDV (odds ratio: 9.98; 95% CI: 3.02, 33.04). Conclusions: Chinese women may be at specific, high risk for HPV infection types associated with VIN or CIN. The use of cervical cell HPV detection along with vulvar presentation during cervical cancer screening may also contribute to vulvar lesion detection.

Differential Characteristics of the Metabolic Profiles and Microbial Community between Superior and Normal Grades of Nongxiangxing-daqu.

Nongxiangxing-daqu (NXDQ), as a saccharification and fermentation agent, directly affects the flavor and yield of fresh Nongxiangxing Baijiu (NXBJ). The difference in fermentation temperature owing to the artificial turning operation leads to the formation of superior (S) and normal (N) grades of NXDQ. Here, aiming to explore the discriminant characteristics of two grades of NXDQ, we studied the physicochemical properties, volatile compounds and microbial communities using HS-SPME-GC/MS and high-throughput sequencing technology. The NXDQ grades presented different physicochemical properties. Staphylococcus, Weissella, Lactobacillus and Thermoascus were dominant in the S grade (S-NXDQ), while Bacillus, Thermoactinomyces and Aspergillus were predominant in the N grade (N-NXDQ). Higher alcohols, aldehydes and ketones positively correlated with the bacterial biomarkers could be used as metabolic biomarkers for N-NXDQ; the S-NXDQ had a higher abundance of key enzymes involved in lactic acid and ethanol fermentation, while N-NXDQ had a higher abundance of key enzymes involved in amino acid synthesis and long-chain fatty acid and lipid metabolism. N-NXDQ and S-NXDQ had different microbial and metabolic biomarkers. These findings provide insight into the discriminant characteristics of different grades of NXDQ, a theoretical basis for rational evaluation of NXDQ, and effective information for quality improvement of daqu.

Efficacy and safety of endoscopic cardia peripheral tissue scar formation (ECSF) for the treatment of refractory gastroesophageal reflux disease: A systematic review with meta-analysis.

BACKGROUND: Endoscopic treatment is increasingly used for refractory gastroesophageal reflux disease (rGERD). Unlike the mechanism of conventional surgical fundoplication, gastroesophageal junction ligation, anti-reflux mucosal intervention, and radiofrequency ablation have extremely similar anti-reflux mechanisms; hence, we collectively refer to them as endoscopic cardia peripheral tissue scar formation (ECSF). We conducted a systematic review and meta-analysis to assess the safety and efficacy of ECSF in treating rGERD. METHODS: We performed a comprehensive search of several databases, including PubMed, Embase, Medline, China Knowledge Network, and Wanfang, to ensure a systematic approach for data collection between January 2011 and July 2023. Forest plots were used to summarize and combine the GERD-health-related quality of life (HRQL), gastroesophageal reflux questionnaire score, and DeMeester scores, acid exposure time, lower esophageal sphincter pressure, esophagitis, proton pump inhibitors use, and patient satisfaction. RESULTS: This study comprised 37 studies, including 1732 patients. After ECSF, significant improvement in gastroesophageal reflux disease health-related quality of life score (mean difference [MD] = 18.27 95% CI: 14.81-21.74), gastroesophageal reflux questionnaire score (MD = 4.85 95% CI: 3.96-5.75), DeMeester score (MD = 42.34, 95% CI: 31.37-53.30), acid exposure time (MD = 7.98, 95% CI: 6.03-9.92), and lower esophageal sphincter pressure was observed (MD = -5.01, 95% CI: -8.39 to 1.62). The incidence of serious adverse effects after ECSF was 1.1% (95% CI: 0.9%-1.2%), and postoperatively, 67.4% (95% CI: 66.4%-68.2%) of patients could discontinue proton pump inhibitor-like drugs, and the treatment outcome was observed to be satisfactory in over 80% of the patients. Subgroup analyses of the various procedures showed that all 3 types improved several objective or subjective patient indicators. CONCLUSIONS: Based on the current meta-analysis, we conclude that rGERD can be safely and effectively treated with ECSF as an endoscopic procedure.

Biocompatible formulation of a hydrophobic antimicrobial peptide L30 through nanotechnology principles and its potential role in mouse pneumonia model infected with Staphylococcus aureus.

Hydrophobic antimicrobial peptide L30, a potential antibiotic candidate, has poor water solubility and hemolytic activity. Herein, a biocompatible nano-formulation composed of liposomes and dendritic mesoporous silica encapsulation (LDMSNs@L30) was constructed for L30 to solve the limits for its clinical development. The characterization, antimicrobial activity and therapeutic effect of LDMSNs@L30 on Staphylococcus aureus 9 (cfr+) infected mice models were investigated. LDMSNs@L30 displayed a smooth, spherical, and monodisperse nanoparticle with a hydrodynamic diameter of 177.40 nm, an encapsulation rate of 56.13%, a loading efficiency of 32.26%, a release rate of 66.5%, and effective slow-release of L30. Compared with free L30, the formulation could significantly increase the solubility of L30 in PBS with the maximum concentration from 8 µg/mL to 2.25 mg/mL and decrease the hemolytic activity of hydrophobic peptide L30 with the HC5 from 65.36 µg/mL to more than 500 µg/mL. The nano delivery system LDMSNs@L30 also exhibited higher therapeutic effects on mice models infected with S. aureus 9 (cfr+) than those of free L30 after 7 days of treatment by reducing the lung inflammation and the inflammatory cytokines levels in plasma, showing better health score and pulmonary pathological improvement. Our research suggests that nano-formulation can be expected to be a promising strategy for peptide drugs in therapeutic applications.

Studies on the in vitro mechanism and in vivo therapeutic effect of the antimicrobial peptide ACP5 against Trichophyton mentagrophytes.

Trichophyton mentagrophytes is a zoophilic dermatophyte that can cause dermatophytosis in humans and animals. Antimicrobial peptides (AMPs) are considered as a promising agent to overcome the drug-resistance of T. mentagrophytes. Our findings suggest that cationic antimicrobial peptide (ACP5) not only possesses stronger activity against T. mentagrophytes than fluconazole, but also shows lower toxicity to L929 mouse fibroblast cells than terbinafine. Notably, its resistance development rate after resistance induction was lower than terbinafine. The present study aimed to evaluate the fungicidal mechanism of ACP5 in vitro and its potential to treat dermatophyte infections in vivo. ACP5 at 1 ×MIC completely inhibited T. mentagrophytes spore germination in vitro. ACP5 severely disrupts the mycelial morphology, leading to mycelial rupture. Mechanistically, ACP5 induces excessive ROS production, damaging the integrity of the cell membrane and decreasing the mitochondrial membrane potential, causing irreversible damage in T. mentagrophytes. Furthermore, 1% ACP5 showed similar efficacy to the commercially available drug 1% terbinafine in a guinea pig dermatophytosis model, and the complete eradication of T. mentagrophytes from the skin by ACP5 was verified by tissue section observation. These results indicate that ACP5 is a promising candidate for the development of new agent to combat dermatophyte resistance.

Machine Learning Accelerates De Novo Design of Antimicrobial Peptides.

Efficient and precise design of antimicrobial peptides (AMPs) is of great importance in the field of AMP development. Computing provides opportunities for peptide de novo design. In the present investigation, a new machine learning-based AMP prediction model, AP_Sin, was trained using 1160 AMP sequences and 1160 non-AMP sequences. The results showed that AP_Sin correctly classified 94.61% of AMPs on a comprehensive dataset, outperforming the mainstream and open-source models (Antimicrobial Peptide Scanner vr.2, iAMPpred and AMPlify) and being effective in identifying AMPs. In addition, a peptide sequence generator, AP_Gen, was devised based on the concept of recombining dominant amino acids and dipeptide compositions. After inputting the parameters of the 71 tridecapeptides from antimicrobial peptides database (APD3) into AP_Gen, a tridecapeptide bank consisting of de novo designed 17,496 tridecapeptide sequences were randomly generated, from which 2675 candidate AMP sequences were identified by AP_Sin. Chemical synthesis was performed on 180 randomly selected candidate AMP sequences, of which 18 showed high antimicrobial activities against a wide range of the tested pathogenic microorganisms, and 16 of which had a minimal inhibitory concentration of less than 10 µg/mL against at least one of the tested pathogenic microorganisms. The method established in this research accelerates the discovery of valuable candidate AMPs and provides a novel approach for de novo design of antimicrobial peptides.

DFT Study on Mechanism of Ni-Al Bimetallic-Catalyzed C-H Cyclization to Construct Tricyclic Imidazoles: Roles of NHC Ligand and AlMe3.

The mechanism of the Ni-Al bimetallic-catalyzed C-H cyclization to construct tricyclic imidazoles is investigated using density functional theory calculations. The calculation result shows that the reaction mechanism involves sequential steps of substrate coordination, ligand-to-ligand hydrogen transfer (LLHT), and C-C reductive elimination to produce the final product tricyclic imidazole. The LLHT step is calculated to be the rate-determining step. The oxidative addition of the benzimidazole C-H bond to the Ni center and the insertion of the alkene into the Ni-H bond occur concertedly in the LLHT step. The effects of N-heterocyclic carbene (NHC) ligands and AlMe3 on the reactivity and regioselectivity were also analyzed. These calculation results shed light on some ambiguous suggestions from experiments.

Antibacterial micro/nanomotors: current research progress, challenges, and opportunities.

Bacterial infections remain a formidable threat to human health, a situation exacerbated by the escalating problem of antibiotic resistance. While alternative antibacterial strategies such as oxidants, heat treatments, and metal nanoparticles (NPs) have shown potential, they come with significant drawbacks, ranging from non-specificity to potential environmental concerns. In the face of these challenges, the rapid evolution of micro/nanomotors (MNMs) stands out as a revolutionary development in the antimicrobial arena. MNMs harness various forms of energy and convert it into a substantial driving force, offering bright prospects for combating microbial threats. MNMs' mobility allows for swift and targeted interaction with bacteria, which not only improves the carrying potential of therapeutic agents but also narrows the required activation range for non-drug antimicrobial interventions like photothermal and photodynamic therapies, substantially improving their bacterial clearance rates. In this review, we summarized the diverse propulsion mechanisms of MNMs employed in antimicrobial applications and articulated their multiple functions, which include direct bactericidal action, capture and removal of microorganisms, detoxification processes, and the innovative detection of bacteria and associated toxins. Despite MNMs' potential to revolutionize antibacterial research, the translation from laboratory to clinical use remains challenging. Based on the current research status, we summarized the potential challenges and possible solutions and also prospected several key directions for future studies of MNMs for antimicrobial purposes. Collectively, by highlighting the important knowns and unknowns of antimicrobial MNMs, our present review would help to light the way forward for the field of antimicrobial MNMs and prevent unnecessary blindness and detours.

Mucoid Degeneration of the Anterior Cruciate Ligament: Characteristics and Conservative Management.

Clinical and radiographic characteristics of mucoid degeneration of the anterior cruciate ligament (MD-ACL) were poorly documented in previous literature. And the optimal management strategy for MD-ACL remains unclear. Here, we summarized the characteristics associated with MD-ACL, and evaluated the clinical outcome of conservative management to MD-ACL.A total of 18 knees in 18 patients diagnosed with MD-ACL were collected and reviewed retrospectively. Sixteen patients underwent conservative management and two patients underwent arthroscopic surgery. Baseline demographic, clinical data, and pathologic changes of knee in magnetic resonance imaging (MRI) were recorded. Clinical outcome was evaluated with Visual Analogue Scale (VAS) and Oxford Knee Score (OKS).The most common clinical characteristic in patients with MD-ACL was knee pain (18/18), and seconded by mobility limitation (38.9%, 7/18). All patients presented a typical celery stalk sign with increased signal and diffuse thickening volume in the ACL in MRI. Thirteen patients companied with meniscus tear (72.2%, 13/18), and nine complicated with cartilage injury (50.0%, 9/18). Sixteen patients who underwent conservative treatment were followed up for 21.8 months, and a positive clinical outcome was observed with VAS decreasing from 5.3 ± 2.3 to 1.5 ± 1.9 and OKS decreasing from 27.5 ± 12.7 to 17.9 ± 11.8 (p < 0.001). The post-OKS score was highly correlated with age, duration of disease, and meniscus tear (r = 0.844, 0.707, and 0.474, p < 0.05, respectively). And the post-VAS highly correlated with age (r = 0.693, p < 0.05). Two patients who underwent arthroscopic surgery were followed up for 24.5 months, and the pain and function of knee was improved.Knee pain and meniscus tear was the main characteristic of MD-ACL in clinical and radiographic exam. Conservative treatment could be an alternative management for treatment of MD-ACL with positive clinical outcome. Old age, long duration of disease and complications from meniscus tears were associated with inferior outcome of conservative treatment for MD-ACL. LEVEL OF EVIDENCE: IV.

DFT Study on the Mechanism of the Palladium-Catalyzed [3 + 2] Annulation of Aromatic Amides with Maleimides via Benzylic and meta-C-H Bond Activation: Role of the External Ligand Ac-Gly-OH.

The mechanism of the Ac-Gly-OH-assisted palladium-catalyzed [3 + 2] annulation of aromatic amides with maleimides is investigated using density functional theory calculations. The results show that the reaction undergoes the sequential steps of N-H bond deprotonation, first benzylic C-H bond activation, maleimide insertion, second meta-C-H bond activation, reductive elimination, and oxidation. The external ligand Ac-Gly-OH acts as the internal base for hydrogen abstraction in the first benzylic C-H bond activation. The maleimide insertion step is found to be the rate-determining step. Based on the nearly same energetic span of the two pathways to generate the enantio products, the computational results are consistent with the experimental observation that the terminal [3 + 2] annulation products are racemic when using an achiral ligand. These calculation results disclose the detailed reaction mechanism and shed light on some experimental ambiguities.

Metal-organic framework-modulated Fe3O4 composite au nanoparticles for antibacterial wound healing via synergistic peroxidase-like nanozymatic catalysis.

Bacterial wound infections are a serious threat due to the emergence of antibiotic resistance. Herein, we report an innovative hybrid nanozyme independent of antibiotics for antimicrobial wound healing. The hybrid nanozymes are fabricated from ultra-small Au NPs via in-situ growth on metal-organic framework (MOF)-stabilised Fe3O4 NPs (Fe3O4@MOF@Au NPs, FMA NPs). The fabricated hybrid nanozymes displayed synergistic peroxidase (POD)-like activities. It showed a remarkable level of hydroxyl radicals (·OH) in the presence of a low dose of H2O2 (0.97 mM). Further, the hybrid FMA nanozymes exhibited excellent biocompatibility and favourable antibacterial effects against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. The animal experiments indicated that the hybrid nanozymes promoted wound repair with adequate biosafety. Thus, the well-designed hybrid nanozymes represent a potential strategy for healing bacterial wound infections, without any toxic side effects, suggesting possible applications in antimicrobial therapy.

Saikosaponin-b2 Inhibits Primary Liver Cancer by Regulating the STK4/IRAK1/NF-κB Pathway.

The development of primary liver cancer (PLC) is associated with chronic liver inflammation and the loss of associated tumor suppressor genes, which characterizes inflammation-related tumors. In this study, we aimed to explore the effect of saikosaponin-b2 (SS-b2) on the development of PLC and its effect of the STK4 expression and IRAK1/NF-κB signaling axis. In vitro and in vivo experiments showed that SS-b2 exerted potent anti-inflammatory and antitumor effects. A PLC model was induced in vivo by treating male BALB/c mice with diethylnitrosamine, while an inflammatory model was induced in vitro by exposing RAW 264.7 macrophages to lipopolysaccharides (LPS). After treating cancer mice with SS-b2, the serum levels of alpha-fetoprotein, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly reduced. Ki67 expression also decreased. The carcinomatous lesions of the liver were attenuated. Similar results were observed in liver tissue and RAW 264.7 macrophages, where SS-b2 significantly elevated serine/threonine protein kinase 4 (STK4) expression and decreased the expression of interleukin-1 receptor-associated kinase 1 (IRAK1), nuclear factor-kappaB (NF-κB), and downstream inflammatory cytokines, thus exerting anti-cancer and anti-inflammatory effects. Moreover, we employed siRNA to silence the STK4 expression in HepG2 to investigate the anti-tumor effect of SS-b2 in vitro. The STK4 knockdown would upregulate IRAK1 and thus the activation of NF-κB activity revealed by the increase in the levels of proinflammatory cytokines, consequently impairing SS-b2-induced inhibition of liver cancer development. Consequently, SS-b2 effectively inhibited PLC by upregulating STK4 to suppress the IRAK1/NF-κB signaling axis and is a promising agent for treating this disease.

Design, synthesis and antitumour activity evaluation of novel dolutegravir derivatives.

Based on the modification of the structure of dolutegravir, we introduced 1,2,3-triazole moieties with different substituted groups and obtained a lot of novel dolutegravir derivatives. The activity of A549 cells treated with the derivatives was examined, and most compounds showed good inhibitory effects. Among them, compounds 4b and 4g were the most effective, and inhibited the growth of A549 cells with IC50 values of 8.72 ± 0.11 µM and 12.97 ± 0.32 µM, respectively. In addition, compound 4g induced apoptosis and clonal suppression in A549 tumor cells. Compound 4g also activated the LC3 signaling pathway to induce autophagy in tumor cells, and activated the γ-H2AX signaling pathway to induce DNA damage in tumor cells.