Inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by astragalus polysaccharide protects against transport stress-induced cardiac injury in chicks.

Transport stress (TS) not only weakens poultry performance but also affects animal welfare. Additionally, TS can evoke cardiac damage by triggering sterile inflammation in chicks, but the underlying mechanism is not fully understood. Here, we aimed to elucidate how TS induces sterile inflammation and heart injury and to clarify the antagonism effect of astragalus polysaccharides (APS). We randomly divided 60 chicks (one-day-old female) into 5 groups (n = 12): Control_0h (Con_0h) group (chicks were slaughtered at initiation), Control group (stress-free control), TS group (simulated TS exposure for 8 h), TS plus water (TS+W) group, and TS plus APS (TS+APS) group. Before simulation transport, the chicks of TS+W and TS+APS groups were, respectively, dietary with 100 µL of water or APS (250 µg/mL). H&E staining was employed for cardiac histopathological observation. ELISA assay was used to measure oxidative stress marker levels (GSH, GPX, GST, and MDA). A commercial kit was used to isolate the mitochondrial portion, and qRT-PCR was employed to measure the mitochondrial DNA (mtDNA) levels. Furthermore, we evaluated the activity of mtDNA-mediated NF-κB, NLRP3 inflammasome, and cGAS-STING inflammatory pathways and the expression of downstream inflammatory factors by Western Blotting or qRT-PCR. Our findings revealed that APS notably relieved TS-induced myocardial histopathological lesions and infiltrations. Likewise, the decrease in proinflammatory factors (TNF-α, IL-1ß, and IL-6) and IFN-ß by APS further supported this result. Meanwhile, TS caused severe oxidative stress in the chick heart, as evidenced by decreased antioxidant enzymes and increased MDA. Importantly, APS prevented mtDNA stress and leakage by reducing oxidative stress. Interestingly, TS-induced mtDNA leakage caused a series of inflammation events via mtDNA-PRRs pathways, including TLR21-NF-κB, NLRP3 inflammasome, and cGAS-STING signaling. Encouragingly, all these adverse changes related to inflammation events induced by mtDNA-PRRs activation were all relieved by APS treatment. In summary, our findings provide the first evidence that inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by APS could protect against TS-induced cardiac damage in chicks.

An updated advancement of bifunctional IL-27 in inflammatory autoimmune diseases.

Interleukin-27 (IL-27) is a member of the IL-12 family. The gene encoding IL-27 is located at chromosome 16p11. IL-27 is considered as a heterodimeric cytokine, which consists of Epstein-Barr virus (EBV)-induced gene 3 (Ebi3) and IL-27p28. Based on the function of IL-27, it binds to receptor IL-27rα or gp130 and then regulates downstream cascade. To date, findings show that the expression of IL-27 is abnormal in different inflammatory autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, Behcet's disease, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, type 1 diabetes, Vogt-Koyanagi-Harada, and ankylosing spondylitis). Moreover, in vivo and in vitro studies demonstrated that IL-27 is significantly in3volved in the development of these diseases by regulating innate and adaptive immune responses, playing either an anti-inflammatory or a pro-inflammatory role. In this review, we comprehensively summarized information about IL-27 and autoimmunity based on available evidence. It is hoped that targeting IL-27 will hold great promise in the treatment of inflammatory autoimmune disorders in the future.

Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study.

BACKGROUND: Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy. METHODS: This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes. RESULTS: The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies. CONCLUSIONS: This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.

Interaction of Nipah Virus F and G with the Cellular Protein Cortactin Discovered by a Proximity Interactome Assay.

Nipah virus (NiV) is a highly lethal zoonotic virus with a potential large-scale outbreak, which poses a great threat to world health and security. In order to explore more potential factors associated with NiV, a proximity labeling method was applied to investigate the F, G, and host protein interactions systematically. We screened 1996 and 1524 high-confidence host proteins that interacted with the NiV fusion (F) glycoprotein and attachment (G) glycoprotein in HEK293T cells by proximity labeling technology, and 863 of them interacted with both F and G. The results of GO and KEGG enrichment analysis showed that most of these host proteins were involved in cellular processes, molecular binding, endocytosis, tight junction, and other functions. Cytoscape software (v3.9.1) was used for visual analysis, and the results showed that Cortactin (CTTN), Serpine mRNA binding protein 1 (SERBP1), and stathmin 1 (STMN1) were the top 20 proteins and interacted with F and G, and were selected for further validation. We observed colocalization of F-CTTN, F-SERBP1, F-STMN1, G-CTTN, G-SERBP1, and G-STMN1 using confocal fluorescence microscopy, and the results showed that CTTN, SERBP1, and STMN1 overlapped with NiV F and NiV G in HEK293T cells. Further studies found that CTTN can significantly inhibit the infection of the Nipah pseudovirus (NiVpv) into host cells, while SERBP1 and STMN1 had no significant effect on pseudovirus infection. In addition, CTTN can also inhibit the infection of the Hendra pseudovirus (HeVpv) in 293T cells. In summary, this study revealed that the potential host proteins interacted with NiV F and G and demonstrated that CTTN could inhibit NiVpv and HeVpv infection, providing new evidence and targets for the study of drugs against these diseases.

Genetic mutation profiling reveals biomarkers for targeted therapy efficacy and prognosis in non-small cell lung cancer.

Introduction: The genetic heterogeneity of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations may affect clinical responses and outcomes to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aims to investigate the genomic factors that influence the efficacy and clinical outcomes of first-line, second-line and third-line treatments in NSCLC and explore the heterogeneity of resistance mechanisms. Materials and methods: This real-world study comprised 65 patients with EGFR mutant NSCLC. Molecular alterations were detected using a customized DNA panel before and after administering targeted therapy. The efficacy and prognosis of each treatment line were evaluated. Results: In first-generation EGFR-TKIs treatment, gefitinib showed favorable efficacy compared to icotinib and erlotinib, particularly in patients with EGFR L858R mutations. The resistance mechanisms to first-generation EGFR-TKIs varied among different EGFR mutation cohorts and different first-generation EGFR-TKIs. In second-line EGFR-TKIs treatment, EPH receptor A3 (EPHA3), IKAROS family zinc finger 1 (IKZF1), p21 (RAC1) activated kinase 5 (PAK5), DNA polymerase epsilon, catalytic subunit (POLE), RAD21 cohesin complex component (RAD21) and RNA binding motif protein 10 (RBM10) mutations were markedly associated with poorer progression-free survival (PFS). Notably, EPHA3, IKZF1 and RBM10 were identified as independent predictors of PFS. The mechanisms of osimertinib resistance exhibited heterogeneity, with a higher proportion of non-EGFR-dependent resistant mutations. In third-line treatments, the combination of osimertinib and anlotinib demonstrated superior efficacy compared to other regimens. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) mutation was an independent risk indicator of shorter OS following third-line treatments. Conclusions: Comprehending the tumor evolution in NSCLC is advantageous for assessing the efficacy and prognosis at each stage of treatment, providing valuable insights to guide personalized treatment decisions for patients.

Differentiating Cell Entry Potentials of SARS-CoV-2 Omicron Subvariants on Human Lung Epithelium Cells.

The surface spike (S) glycoprotein mediates cell entry of SARS-CoV-2 into the host through fusion at the plasma membrane or endocytosis. Omicron lineages/sublineages have acquired extensive mutations in S to gain transmissibility advantages and altered antigenicity. The fusogenicity, antigenicity, and evasion of Omicron subvariants have been extensively investigated at unprecedented speed to align with the mutation rate of S. Cells that overexpress receptors/cofactors are mostly used as hosts to amplify infection sensitivity to tested variants. However, systematic cell entry comparisons of most prior dominant Omicron subvariants using human lung epithelium cells are yet to be well-studied. Here, with human bronchial epithelium BEAS-2B cells as the host, we compared single-round virus-to-cell entry and cell-to-cell fusion of Omicron BA.1, BA.5, BQ.1.1, CH.1.1, XBB.1.5, and XBB.1.16 based upon split NanoLuc fusion readout assays and the S-pseudotyped lentivirus system. Virus-to-cell entry of tested S variants exhibited cell-type dependence. The parental Omicron BA.1 required more time to develop full entry to HEK293T-ACE2-TMPRSS2 than BEAS-2B cells. Compared to unchanged P681, S-cleavage constructs of P681H/R did not have any noticeable advantages in cell entry. Omicron BA.1 and its descendants entered BEAS-2B cells more efficiently than D614G, and it was slightly less or comparable to that of Delta. Serine protease-pretreated Omicron subvariants enhanced virus-to-cell entry in a dose-dependent manner, suggesting fusion at the plasma membrane persists as a productive cell entry route. Spike-mediated cell-to-cell fusion and total S1/S2 processing of Omicron descendants were similar. Our results indicate no obvious entry or fusion advantages of recent Omicron descendants over preceding variants since Delta, thus supporting immune evasion conferred by antigenicity shifts due to altered S sequences as probably the primary viral fitness driver.

Prediction of acute kidney injury after cardiac surgery with fibrinogen-to-albumin ratio: a prospective observational study.

Background: The occurrence of acute kidney injury (AKI) following cardiac surgery is common and linked to unfavorable consequences while identifying it in its early stages remains a challenge. The aim of this research was to examine whether the fibrinogen-to-albumin ratio (FAR), an innovative inflammation-related risk indicator, has the ability to predict the development of AKI in individuals after cardiac surgery. Methods: Patients who underwent cardiac surgery from February 2023 to March 2023 and were admitted to the Cardiac Surgery Intensive Care Unit of a tertiary teaching hospital were included in this prospective observational study. AKI was defined according to the KDIGO criteria. To assess the diagnostic value of the FAR in predicting AKI, calculations were performed for the area under the receiver operating characteristic curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: Of the 260 enrolled patients, 85 developed AKI with an incidence of 32.7%. Based on the multivariate logistic analyses, FAR at admission [odds ratio (OR), 1.197; 95% confidence interval (CI), 1.064-1.347, p = 0.003] was an independent risk factor for AKI. The receiver operating characteristic (ROC) curve indicated that FAR on admission was a significant predictor of AKI [AUC, 0.685, 95% CI: 0.616-0.754]. Although the AUC-ROC of the prediction model was not substantially improved by adding FAR, continuous NRI and IDI were significantly improved. Conclusions: FAR is independently associated with the occurrence of AKI after cardiac surgery and can significantly improve AKI prediction over the clinical prediction model.

IFITM3 inhibits severe fever with thrombocytopenia syndrome virus entry and interacts with viral Gc protein.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.

Deciphering principles of nucleosome interactions and impact of cancer-associated mutations from comprehensive interaction network analysis.

Nucleosomes represent hubs in chromatin organization and gene regulation and interact with a plethora of chromatin factors through different modes. In addition, alterations in histone proteins such as cancer mutations and post-translational modifications have profound effects on histone/nucleosome interactions. To elucidate the principles of histone interactions and the effects of those alterations, we developed histone interactomes for comprehensive mapping of histone-histone interactions (HHIs), histone-DNA interactions (HDIs), histone-partner interactions (HPIs) and DNA-partner interactions (DPIs) of 37 organisms, which contains a total of 3808 HPIs from 2544 binding proteins and 339 HHIs, 100 HDIs and 142 DPIs across 110 histone variants. With the developed networks, we explored histone interactions at different levels of granularities (protein-, domain- and residue-level) and performed systematic analysis on histone interactions at a large scale. Our analyses have characterized the preferred binding hotspots on both nucleosomal/linker DNA and histone octamer and unraveled diverse binding modes between nucleosome and different classes of binding partners. Last, to understand the impact of histone cancer-associated mutations on histone/nucleosome interactions, we complied one comprehensive cancer mutation dataset including 7940 cancer-associated histone mutations and further mapped those mutations onto 419,125 histone interactions at the residue level. Our quantitative analyses point to histone cancer-associated mutations' strongly disruptive effects on HHIs, HDIs and HPIs. We have further predicted 57 recurrent histone cancer mutations that have large effects on histone/nucleosome interactions and may have driver status in oncogenesis.

Genetic alterations predict poor efficacy, outcomes and resistance to second-line osimertinib treatment in non-small cell lung cancer.

The genetic heterogeneity of non-small cell lung cancer (NSCLC) may impact clinical response and outcomes to targeted therapies. In second-line osimertinib treatment for NSCLC, real-world data on genetic biomarkers for treatment efficacy and prognosis remain incomplete. This real-world study involved 68 NSCLC patients receiving first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). All of these patients developed resistance, and 49 of them subsequently underwent second-line osimertinib treatment. A 639-gene DNA panel was employed to assess the impact of molecular alterations on treatment efficacy, clinical outcomes and resistance. The findings showed that the median progression-free survival (PFS) for second-line osimertinib therapy was 13.3 months. Genes alterations such as P21 (RAC1) activated kinase 5 (PAK5), RNA binding motif protein 10 (RBM10), and EPH receptor A3 (EPHA3) mutations were associated with significantly shorter PFS in osimertinib therapy. At multivariate analysis, they were all independent risk predictors of shorter PFS. Additionally, the median overall survival (OS) for osimertinib was 26.2 months. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), hepatocyte growth factor (HGF), and RBM10 mutations were significantly associated with poorer OS in osimertinib treatment. The multivariate analysis demonstrated that only RBM10 mutation emerged as an independent risk predictor of shorter OS. In vitro experiments showed that RBM10 mutations could promote the proliferation and migration ability of NSCLC cells and reduced cell apoptosis. The resistance mechanisms to osimertinib were heterogeneous. Histone cluster 1 H2B family member D (HIST1H2BD) acted as a novel resistance mechanism to osimertinib. Previously unreported HIST1H2BD mutations (p.K25Q and p.E36D) were detected in the NSCLC tissues. In vitro experiments confirmed that HIST1H2BD mutations led to resistance to osimertinib. In summary, we demonstrate that genetic biomarkers, such as PAK5, RBM10, and EPHA3, are independent predictors of PFS in second-line osimertinib treatment, with RBM10 emerging as an independent predictor of OS. Additionally, HIST1H2BD represents a novel resistance mutation to osimertinib. All of these findings offer valuable insights for making personalized treatment strategies for NSCLC patients.

Exposure to Chinese famine in early life and height across 2 generations: a longitudinal study based on the China Health and Nutrition Survey.

BACKGROUND: Poor nutrition early in life is associated with short stature, which is associated with increased risk of cardiovascular disease and mortality in later life. Less evidence is available about the impact of early-life nutrition on height growth in the subsequent generation. OBJECTIVES: This study investigated the associations of famine exposure in utero and early childhood with height across 2 generations. METHODS: We used longitudinal data from the China Health and Nutrition Survey. We included 5401 participants (F1) born in 1955-1966 (calendar year around the Chinese famine in 1959-1961) and their 3930 biological offspring (F2). We classified F1 participants into subgroups by famine exposure status (unexposed/exposed) and timing (fetal-/childhood-exposed) according to their birth year and grouped F2 by their parents' exposure. Linear regression models were applied to examine the associations of famine exposure with adult height of F1 and F2. Linear mixed effect models with fractional polynomial functions were performed to estimate the difference in height between exposure groups of F2 during childhood. RESULTS: Participants (F1) exposed to famine in utero or in childhood were shorter than those unexposed by 0.41 cm (95% CI: 0.03, 0.80) and 1.12 cm (95% CI: 0.75, 1.48), respectively. Offspring (F2) of exposed fathers were also shorter than those of unexposed parents by 1.07 cm (95% CI: 0.28, 1.86) during childhood (<18 y) and by 1.25 cm (95% CI: 0.07, 2.43) in adulthood (≥18 y), and those with exposed parents had a reduced height during childhood by 1.29 cm (95% CI: 0.68, 1.89) (all P values < 0.05). The associations were more pronounced among child offspring of highly-educated F1, particularly for paternal exposure and among female offspring (all P for interaction < 0.05). CONCLUSIONS: The findings support the intergenerational associations of famine exposure in early life with height in Chinese populations, indicating the public health significance of improving the nutritional status of mothers and children in the long run.

Anoikis-related signature identifies tumor microenvironment landscape and predicts prognosis and drug sensitivity in colorectal cancer.

Background: Anoikis, a mechanism of programmed apoptosis, plays an important role in growth and metastasis of tumors. However, there are still few available comprehensive reports on the impact of anoikis on colorectal cancer. Method: A clustering analysis was done on 133 anoikis-related genes in GSE39582, and we compared clinical features between clusters, the tumor microenvironment was analyzed with algorithms such as "Cibersort" and "ssGSEA". We investigated risk scores of clinical feature groups and anoikis-associated gene mutations after creating a predictive model. We incorporated clinical traits to build a nomogram. Additionally, the quantitative real-time PCR was employed to investigate the mRNA expression of selected anoikis-associated genes. Result: We identified two anoikis-related clusters with distinct prognoses, clinical characteristics, and biological functions. One of the clusters was associated with anoikis resistance, which activated multiple pathways encouraging tumor metastasis. In our prognostic model, oxaliplatin may be a sensitive drug for low-risk patients. The nomogram showed good ability to predict survival time. And SIRT3, PIK3CA, ITGA3, DAPK1, and CASP3 increased in CRC group through the PCR assay. Conclusion: Our study identified two distinct modes of anoikis in colorectal cancer, with active metastasis-promoting pathways inducing an anti-anoikis subtype, which has a stronger propensity for metastasis and a worse prognosis than an anoikis-activated subtype. Massive immune cell infiltration may be an indicator of anoikis resistance. Anoikis' role in the colorectal cancer remains to be investigated.

Relationship between CD274 gene polymorphism and systemic lupus erythematosus risk in a Chinese Han population.

OBJECTIVE: Relationship between surface antigen differentiation cluster 274 (CD274) gene polymorphism and systemic lupus erythematosus (SLE) risk is limited. This study aims to discuss whether in a Chinese Han population, CD274 gene polymorphisms may relate to SLE susceptibility. METHODS: Three hundred and ten SLE patients and 390 healthy controls were included in this case-control study. Using the Kompetitive Allele-Specific PCR (KASP) approach, five single nucleotide polymorphisms (SNPs), including rs2890658, rs4143815, rs822339, rs2282055, and rs2297137, were genotyped for CD274 gene polymorphisms. Correlation between the polymorphisms and clinical, laboratory features in SLE patients were discussed. RESULTS: Frequency of C allele was substantially lower in SLE patients than in healthy controls (p = .015), and CC genotype was significantly negatively related to developing SLE at locus rs4143815 (p = .013). At locus rs822339, frequency of GA genotype was higher than that of the healthy controls (p = .006). At locus rs2282055, frequency of GG genotype was lower than that of healthy controls (p = .024). According to subgroup analysis, the CD274 gene polymorphisms rs2890658, rs4143815, rs822339, rs2282055, and rs2297137 were partly linked to some clinical symptoms of SLE patients, such as Complement 4 (C4), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). CONCLUSION: CD274 gene polymorphisms may be susceptible to SLE in the Chinese Han people.

One-Stop Integrated Nanoagent for Bacterial Biofilm Eradication and Wound Disinfection.

To meet the requirements of biomedical applications in the antibacterial realm, it is of great importance to explore nano-antibiotics for wound disinfection that can prevent the development of drug resistance and possess outstanding biocompatibility. Therefore, we attempted to synthesize an atomically dispersed ion (Fe) on phenolic carbon quantum dots (CQDs) combined with an organic photothermal agent (PTA) (Fe@SAC CQDs/PTA) via a hydrothermal/ultrasound method. Fe@SAC CQDs adequately exerted peroxidase-like activity while the PTA presented excellent photothermal conversion capability, which provided enormous potential in antibacterial applications. Based on our work, Fe@SAC CQDs/PTA exhibited excellent eradication of Escherichia coli (>99% inactivation efficiency) and Staphylococcus aureus (>99% inactivation efficiency) based on synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT). Moreover, in vitro experiments demonstrated that Fe@SAC CQDs/PTA could inhibit microbial growth and promote bacterial biofilm destruction. In vivo experiments suggested that Fe@SAC CQDs/PTA-mediated synergistic CDT and PTT exhibited great promotion to wound disinfection and recovery effects. This work indicated that Fe@SAC CQDs/PTA could serve as a broad-spectrum antimicrobial nano-antibiotic, which was simultaneously beneficial for bacterial biofilm eradication, wound disinfection, and wound healing.

Biological evaluation of 9-thioansamitocin P3.

Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key element necessary to retain the potency. However, in 1984 a patent was published by Takeda in which the synthesis of 9-thioansamitocyn (AP3SH) was described and its activity in xenograft models was shown. In this article we summarize the results of an extended study of the anti-tumor properties of AP3SH. Like other maytansinoids, it induces apoptosis and arrests the cell cycle in the G2/M phase. It is metabolized in liver microsomes predominately by C3A4 isoform and doesn't inhibit any CYP isoforms except CYP3A4 (midazolam, IC50 7.84 µM). No hERG inhibition, CYP induction or mutagenicity in Ames tests were observed. AP3SH demonstrates high antiproliferative activity against 25 tumor cell lines and tumor growth inhibition in U937 xenograft model. Application of AP3SH as a cytotoxic payload in drug delivery system was demonstrated by us earlier.

Neuropeptide Y, a potential marker for lupus, promotes lupus development.

OBJECTIVE: Relationship between neuropeptide Y (NPY) serum levels, NPY genetic mutation with systemic lupus erythematosus (SLE) pathogenesis is yet to be clarified, and role of NPY in development of SLE needs elucidation. METHOD: This study included 460 SLE patients, 472 non-SLE cases, 500 healthy volunteers. Serum NPY, matrix metalloproteinase-1 (MMP-1) and MMP-8 levels were tested by ELISA. Genotyping 7 NPY single nucleotides polymorphisms (SNPs) (rs5573, rs5574, rs16129, rs16138, rs16140, rs16147, rs16478) was obtained by Kompetitive Allele-Specific PCR (KASP) method. Pristane-induced lupus mice were treated with NPY-Y1 receptor antagonist, and histological analysis, serological changes of the mice were evaluated. RESULTS: NPY serum concentrations were significantly increased in SLE patients when compared to that in healthy volunteers, non-SLE cases. Rs5573 G allele, rs16129 T allele, rs16147 G allele frequencies were significantly different between SLE cases and healthy controls. Rs5574 TT + TC genotypes were related to levels of IgG, C3, C4 and erythrocyte sedimentation rate, and rs16138 GG + GC genotypes correlated with SLE cases with anti-double-stranded deoxyribonucleic acid antibody (anti-dsDNA) (+). Serum MMP-1, MMP-8 concentrations were higher in SLE patients, and NPY levels were significantly related to MMP-1, MMP-8 levels. After treatment of lupus mice with NPY-Y1 receptor antagonist, damage of liver, spleen and kidney was alleviated, production of autoantibodies (anti-nuclear antibody (ANA), total IgG, anti-dsDNA) and MMP-1, MMP-8 was down-regulated, and differentiation of CD3+, CD8+ T cells, B cells, monocytes, macrophages, T helper 1 (Th1), Th2, Th17 cells was reversed. CONCLUSION: NPY may be a biomarker for lupus, which may promote occurrence and development of lupus.

The One-Stop Integrated Nanoagent Based on Photothermal Therapy for Deep Infection Healing and Inflammation Inhibition.

Chronic wounds caused by bacterial infections are a major challenge in medical fields. The hypoxia condition extremely induces reactive oxygen species (ROS) generation and upregulates the expression of hypoxia-inducible factor, both of which can increase the pro-inflammatory M1 subtype macrophages production while reducing the anti-inflammatory M2 subtype macrophages. Besides, bacteria-formed biofilms can hinder the penetration of therapeutic agents. Encouraged by natural motors automatically executing tasks, hypothesized that supplying sufficient oxygen (O2 ) would simultaneously drive therapeutic agent movement, rescue the hypoxic microenvironment, and disrupt the vicious cycle of inflammation. Here, small organic molecule-based nanoparticles (2TT-mC6B@Cu5.4 O NPs) that possess high photothermal conversion efficiency and enzymatic activities are developed, including superoxide dismutase-, catalase-, and glutathione peroxidase-like activity. 2TT-mC6B@Cu5.4 O NPs exhibit superior ROS-scavenging and O2 production abilities that synergistically relieve inflammation, alleviate hypoxia conditions, and promote their deep penetration in chronic wound tissues. Transcriptome analysis further demonstrates that 2TT-mC6B@Cu5.4O NPs inhibit biological activities inside bacteria. Furthermore, in vivo experiments prove that 2TT-mC6B@Cu5.4 O NPs-based hyperthermia can effectively eliminate bacteria in biofilms to promote wound healing.