P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) can be defined as a deadly illness with a dismal prognosis in advanced stages. Therefore, we seek to examine P4HA2 expression and effect in HNSCC, along with the underlying mechanisms. This study utilized integrated bioinformatics analyses to evaluate the P4HA2 expression pattern, prognostic implication, and probable function in HNSCC. The study conducted various in vitro experiments, including colony formation, CCK-8, flow cytometry, wound healing, and transwell assays, on the human HNSCC cell line CAL-27 to examine the involvement of P4HA2 in HNSCC progression. Moreover, western blotting was used to investigate epithelial-mesenchymal transition (EMT) markers and PI3K/AKT pathway markers to elucidate the underlying mechanisms. P4HA2 expression was significantly enhanced in HNSCC, and its overexpression was correlated to tumor aggressiveness and a poor prognosis in patients. Based on in vitro experiments, the overexpressed P4HA2 enhanced cell proliferation, migration, invasion, as well as EMT while reducing apoptosis, whereas P4HA2 silencing exhibited the reverse effect. P4HA2 overexpression enhanced PI3K/AKT phosphorylation in HNSCC cells. Moreover, LY294002 was observed to counteract the effects of upregulated P4HA2 on proliferation, migration, invasion, and EMT in HNSCC. Collectively, we indicated that P4HA2 promoted HNSCC progression and EMT via PI3K/AKT signaling pathway.

Machine Learning-assisted Rational Design of Si-rhodamine as Cathepsin-pH Activated Probe for Accurate Fluorescence Navigation.

High-performance fluorescent probes stand as indispensable tools in fluorescence-guided imaging, and are crucial for precise delineation of focal tissue while minimizing unnecessary removal of healthy tissue. Herein, we firstly proposed machine learning-assisted strategy to investigate the current available xanthene dyes, and constructed a quantitative prediction model to guide the rational synthesis of novel fluorescent molecules with desired pH responsivity. We successfully achieved two novel Si-rhodamine derivatives and constructed the Cathepsin/pH sequentially activated probe SiR-CTS-pH. The results reveal that SiR-CTS-pH exhibits higher signal-to-noise ratio of fluorescence imaging, compared to single pH or cathepsin-activate probe. Moreover, SiR-CTS-pH shows strong differentiation abilities for tumor cells and tissues and accurately discriminates the complex hepatocellular carcinoma tissues from normal ones, indicating its significant application potential in clinical practice. Therefore, the continuous development of xanthene dyes and the rational design of superior fluorescent molecules through Machine Learning-assisted model will broaden the path and provide more advanced methods to researchers. This article is protected by copyright. All rights reserved.

Half-life extension of single-domain antibody-drug conjugates by albumin binding moiety enhances antitumor efficacy.

Single-domain antibody-drug conjugates (sdADCs) have been proven to have deeper solid tumor penetration and intratumor accumulation capabilities due to their smaller size compared with traditional IgG format ADCs. However, one of the key challenges for improving clinical outcomes of sdADCs is their abbreviated in vivo half-life. In this study, we innovatively fused an antihuman serum albumin (αHSA) nanobody to a sdADCs targeting oncofetal antigen 5T4, conferring serum albumin binding to enhance the pharmacokinetic profiles of sdADCs. The fusion protein was conjugated with monomethyl auristatin E (MMAE) at s224c site mutation. The conjugate exhibited potent cytotoxicity against various tumor cells. Compared with the nonalbumin-binding counterparts, the conjugate exhibited a 10-fold extended half-life in wild-type mice and fivefold prolonged serum half-life in BxPC-3 xenograft tumor models as well as enhanced tumor accumulation and retention in mice. Consequently, n501-αHSA-MMAE showed potent antitumor effects, which were comparable to n501-MMAE in pancreatic cancer BxPC-3 xenograft tumor models; however, in human ovarian teratoma PA-1 xenograft tumor models, n501-αHSA-MMAE significantly improved antitumor efficacy. Moreover, the conjugate showed mitigated hepatotoxicity. In summary, our results suggested that fusion to albumin-binding moiety as a viable strategy can enhance the therapeutic potential of sdADCs through optimized pharmacokinetics.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc).

OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.

Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate.

In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from ~6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.

Synthesis of amide derivatives containing the imidazole moiety and evaluation of their anti-cardiac fibrosis activity.

Three series of N-{[4-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl}acetamides (14a-d, 15a-n, and 16a-f) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. The target compounds showed high ALK5 inhibitory activity and selectivity. The half maximal inhibitory concentration (IC50) for phosphorylation of ALK5 of 16f (9.1 nM), the most potent compound, was 2.7 times that of the clinical candidate EW-7197 (vactosertib) and 14 times that of the clinical candidate LY-2157299. The selectivity index of 16f against p38α mitogen-activated protein kinase was >109, which was much higher than that of positive controls (EW-7197: >41, and LY-2157299: 4). Furthermore, a molecular docking study provided the interaction modes between the target compounds and ALK5. Compounds 14c, 14d, and 16f effectively inhibited the protein expression of α-smooth muscle actin (α-SMA), collagen I, and tissue inhibitor of metalloproteinase 1 (TIMP-1)/matrix metalloproteinase 13 (MMP-13) in transforming growth factor-ß-induced human umbilical vein endothelial cells. Compounds 14c and 16f showed especially high activity at low concentrations, which suggests that these compounds could inhibit myocardial cell fibrosis. Compounds 14c, 14d, and 16f are potential preclinical candidates for the treatment of cardiac fibrosis.

Protective effect of crocin on peroxidation-induced oxidative stress and apoptosis in IPEC-J2 cells.

The antioxidant properties of crocin are attracting interest, yet the underlying mechanisms by which crocin mitigates oxidative stress-induced intestinal damage have not been determined. This study aimed to elucidate the effects of crocin on oxidative stress, apoptosis, and intestinal epithelial injury in intestinal epithelial cells (IPEC-J2). Using an H2O2-induced oxidative stress model in IPEC-J2 cells, crocin was added to assess its effects. Cell viability and apoptosis were evaluated using methyl thiazolyl tetrazolium assays and flow cytometry. Additionally, oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), reactive oxygen species (ROS), and malondialdehyde (MDA), were quantified. We investigated, in which cell oxidation and apoptosis were measured at the gene and protein levels and employed transcriptome analysis to probe the mechanism of action and validate relevant pathways. The results showed that crocin ameliorates H2O2-induced oxidative stress by reducing ROS and MDA levels and by countering the reductions in CAT, total antioxidant capacity, and SOD. Crocin also attenuates the upregulation of key targets in the Nrf2 pathway. Furthermore, it effectively mitigated IPEC-J2 cell apoptosis caused by oxidative stress, as evidenced by changes in cell cycle factor expression, apoptosis rate, mitochondrial membrane potential, and apoptosis pathway activity. In addition, crocin preserves the integrity of the intestinal barrier by protecting tight junction proteins against oxidative stress. Transcriptome sequencing analysis suggested that the mitochondrial pathway may be a crucial mechanism through which crocin exerts its protective effects. In summary, crocin decreases oxidative stress molecule formation, inhibits Nrf2 pathway activity, prevents apoptosis-induced damage, enhances oxidative stress resistance in IPEC-J2 cells, and maintains redox balance in the pig intestine.

Progress in novel delivery technologies to improve efficacy of therapeutic antibodies.

Monoclonal antibody-based therapeutics have achieved remarkable success in treating a wide range of human diseases. However, conventional systemic delivery methods have limitations in insufficient target tissue permeability, high costs, repeated administrations, etc. Novel technologies have been developed to address these limitations and further enhance antibody therapy. Local antibody delivery via respiratory tract, gastrointestinal tract, eye and blood-brain barrier have shown promising results in increasing local concentrations and overcoming barriers. Nucleic acid-encoded antibodies expressed from plasmid DNA, viral vectors or mRNA delivery platforms also offer advantages over recombinant proteins such as sustained expression, rapid onset, and lower costs. This review summarizes recent advances in antibody delivery methods and highlights innovative technologies that have potential to expand therapeutic applications of antibodies.

A therapeutic strategy of parthenolide in improving imiquimod-induced psoriasis-like skin inflammation targeting IL-36/NETs through skin transdermal therapeutic system.

BACKGROUND: Psoriasis is an inflammatory skin disease that occurs repeatedly over time. The natural product of sesquiterpene lactones, Parthenolide (Par), is isolated from Tanacetum parthenium L. (feverfew) which has significant effects on anti-inflammatory. The therapeutic effect of the medication itself is crucial, but different routes of administration of the same drug can also produce different effects. PURPOSE: The aim of our research sought to investigate the ameliorating effects of Par in psoriasis-like skin inflammation and its related mechanism of action. RESULTS: In the IMQ-induced model, intragastric administration of Par reduced the Psoriasis Area and Severity Index (PASI) score, improved skin erythema, scaling, and other symptoms. And Par decreased the expression of Ki67, keratin14, keratin16 and keratin17, and increased the expression of keratin1. Par could reduce IL-36 protein expressions, meanwhile the expression of Il1b, Cxcl1 and Cxcl2 mRNA were also decreased. Par regulated the expression levels of F4/80, MPO and NE. However, skin transdermal administration of Par was more effective. Similarly, Par attenuated IL-36γ, IL-1ß and caspase-1 activated by Poly(I:C) in in vitro and ex vivo. In addition, Par also reduced NE, PR3, and Cathepsin G levels in explant skin tissues. CONCLUSION: Par ameliorated psoriasis-like skin inflammation in both in vivo and in vitro, especially after treatment with transdermal drug delivery, possibly by inhibiting neutrophil extracellular traps and thus by interfering IL-36 signaling pathway. It indicated that Par provides a new research strategy for the treatment of psoriasis-like skin inflammation and is expected to be a promising drug.

Long-term variations in surface ozone at the Longfengshan Regional Atmosphere Background Station in Northeast China and related influencing factors.

Surface ozone (O3) is a crucial air pollutant that affects air quality, human health, agricultural production, and climate change. Studies on long-term O3 variations and their influencing factors are essential for understanding O3 pollution and its impact. Here, we conducted an analysis of long-term variations in O3 during 2006-2022 at the Longfengshan Regional Atmosphere Background Station (LFS; 44.44°N, 127.36°E, 330.5 m a.s.l.) situated on the northeastern edge of the Northeast China Plains. The maximum daily 8-h average (MDA8) O3 fluctuated substantially, with the annual MDA8 decreasing significantly during 2006-2015 (-0.62 ppb yr-1, p < 0.05), jumping during 2015-2016 and increasing clearly during 2020-2022. Step multiple linear regression models for MDA8 were obtained using meteorological variables, to decompose anthropogenic and meteorological contributions to O3 variations. Anthropogenic activities acted as the primary drivers of the long-term trends of MDA8 O3, contributing 73% of annual MDA8 O3 variability, whereas meteorology played less important roles (27%). Elevated O3 at LFS were primarily associated with airflows originating from the North China Plain, Northeast China Plain, and coastal areas of North China, primarily occurring during the warm months (May-October). Based on satellite products of NO2 and HCHO columns, the O3 photochemical regimes over LFS revealed NOx-limited throughout the period. NO2 increased first, reaching peak in 2011, followed by substantial decrease; while HCHO exhibited significant increase, contributing to decreasing trend in MDA8 O3 during 2006-2015. The plateauing NO2 and decreasing HCHO may contribute to the increase in MDA8 O3 in 2016. Subsequently, both NO2 and HCHO exhibited notable fluctuations, leading to significant changes in O3. The study results fill the gap in the understanding of long-term O3 trends in high-latitude areas in the Northeast China Plain and offer valuable insights for assessing the impact of O3 on crop yields, forest productivity, and climate change.

Antibody Nanotweezer Constructing Bivalent Transistor-Biomolecule Interface with Spatial Tolerance.

Establishing a multivalent interface between the biointerface of a living system and electronic device is vital to building intelligent bioelectronic systems. How to achieve multivalent binding with spatial tolerance at the nanoscale remains challenging. Here, we report an antibody nanotweezer that is a self-adaptive bivalent nanobody enabling strong and resilient binding between transistor and envelope proteins at biointerfaces. The antibody nanotweezer is constructed by a DNA framework, where the nanoscale patterning of nanobodies along with their local spatial adaptivity enables simultaneous recognition of target epitopes without binding stress. As such, effective binding affinity increases by 1 order of magnitude compared with monovalent antibody. The antibody nanotweezer operating on transistor offers enhanced signal transduction, which is implemented to detect clinical pathogens, showing ∼100% overall agreement with PCR results. This work provides a perspective of engineering multivalent interfaces between biosystems with solid-state devices, holding great potential for organoid intelligence on a chip.

Salinity-Driven Interface Self-Assembly of a Biological Amphiphilic Emulsifier to Form Stable Janus Core-Shell Emulsion for Enhancing Agrichemical Delivery.

Agrichemical losses are a severe threat to the ecological environment. Additionally, some agrichemical compounds contain abundant salt, which increases the instability of formulations, leading to a lower agrichemical utilization and soil hardening. Fortunately, the biological amphiphilic emulsifier sodium deoxycholate alleviates these problems by forming stable Janus core-shell emulsions through salinity-driven interfacial self-assembly. According to the interfacial behavior, dilational rheology, and molecular dynamics simulations, Janus-emulsion molecules are more closely arranged than traditional-emulsion molecules and generate an oil-water interfacial film that transforms into a gel film. In addition, at the same spray volume, the deposition area of the Janus emulsion increased by 37.70% compared with that of the traditional emulsion. Owing to the topology effect and deformation, the Janus emulsion adheres to rice micropapillae, achieving better flush resistance. Meanwhile, based on response of the Janus emulsion to stimulation by carbon dioxide (CO2), the emulsion lost to the soil can form a rigid shell for inhibiting the release of pesticides and metal ions from harming the soil. The pyraclostrobin release rate decreased by 50.89% at 4 h after the Janus emulsion was exposed to CO2. The Chao1 index of the Janus emulsion was increased by 12.49% as compared to coconut oil delivery in soil microbial community. The Janus emulsion ingested by harmful organisms can be effectively absorbed in the intestine to achieve better control effects. This study provides a simple and effective strategy, which turns waste into treasure, by combining metal ions in agrichemicals with natural amphiphilic molecules to prepare stable emulsions for enhancing agrichemical rainfastness and weakening environmental risk.

Small molecule and PROTAC molecule experiments in vitro and in vivo, focusing on mouse PD-L1 and human PD-L1 differences as targets.

In recent years, several monoclonal antibodies (mAbs) targeting PD-L1 have been licensed by the FDA for use in the treatment of cancer, demonstrating the effectiveness of blocking immune checkpoints, particularly the PD-1/PD-L1 pathway. Although mAb-based therapies have made great strides, they still have their limitations, and new small-molecule or PROTAC-molecule inhibitors that can block the PD-1/PD-L1 axis are desperately needed. Therefore, it is crucial to translate initial in vitro discoveries into appropriate in vivo animal models when creating PD-L1-blocking therapies. Due to their widespread availability and low experimental expenses, classical immunocompetent mice are appealing for research purposes. However, it is yet unclear whether the mouse (m) PD-L1 interaction with human (h) PD-1 in vivo would produce a functional immunological checkpoint. In this review, we summarize the in vitro and in vivo experimental studies of small molecules and PROTAC molecules, particularly the distinctions between mPD-L1 as a target and hPD-L1 as a target.

Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway.

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl4) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-ß (TGF-ß) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl4-induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1ß, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl4-induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1ß expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1ß expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.

The thermoelectric properties of CdBr, CdI, and Janus Cd2BrI monolayers with low lattice thermal conductivity.

The investigation and development of high thermoelectric value materials has become a research hotspot in recent years. In this work, based on the density functional theory on the Perdew-Burke-Ernzerhof (GGA-PBE) level, the thermoelectric properties of transition metal halides CdBr, Janus Cd2BrI, and CdI monolayers have been systematically investigated using Boltzmann transport theory. The calculation of the electronic band structure shows that these three materials have indirect band gap semiconductor properties. For carrier transport, the electron mobilities for CdBr, Janus Cd2BrI, and CdI monolayers are found to be 74, 16, 21 cm2 s-1 V-1 for p-type doping and 116, 102, 78 cm2 s-1 V-1 for n-type doping. Regarding their phonon transport, the CdBr, Cd2BrI, and CdI monolayers all have very low lattice thermal conductivity (4.78, 2.46, and 1.65 W m-1 K-1, respectively) that decreases with increasing temperature, which is favorable for obtaining large zT values. The electrical transport results show that the performance of p-type doping is better than that of n-type doping. At 300 K, the Seebeck coefficients of p-type doping for the CdBr, Cd2BrI, and CdI monolayers are 217.72, 246.43, and 226.24 µV K-1, respectively. In addition, we predict that the zT values of the CdBr, Cd2BrI, and CdI monolayers are 0.62, 1.64, and 0.87 for p-type doping at 300 K respectively. The zT values increase with the increase of temperature. In particular, the Janus Cd2BrI monolayer has a zT value of 3.03 at 600 K. These results suggest that all these materials can be good candidates for thermoelectric materials.

A meta-analysis for the diagnostic accuracy of SelectMDx in prostate cancer.

To overview the diagnostic accuracy of SelectMDx for the detection of clinically significant prostate cancer and to review sources of methodologic variability. Four electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library were searched for eligible studies investigating the diagnostic value of SelectMDx compared with the gold standard. The pooled sensitivity, specificity, and positive and negative predictive values were calculated. Included studies were assessed according to the Standards for Quality Assessment of Diagnostic Accuracy Studies 2 tool. The review identified 14 relevant publications with 2579 patients. All reports constituted phase 1 biomarker studies. Pooled analysis of findings found an area under the receiver operating characteristic analysis curve of 70% [95% CI, 66%-74%], a sensitivity of 81% [95% CI, 69%-89%], and a specificity of 52% [95% CI, 41%-63%]. The positive likelihood ratio was 1.68, and the negative predictive value is 0.37. Factors that may influence variability in test results included the breath collection method, the patient's physiologic condition, the test environment, and the method of analysis. Considerable heterogeneity was observed among the studies owing to the difference in the sample size. SelectMDx appears to have moderate to good diagnostic accuracy in differentiating patients with clinically significant prostate cancer from people at high risk of developing prostate cancer. Higher-quality clinical studies assessing the diagnostic accuracy of SelectMDx for clinically significant cancer are still needed.

Independent and interaction effects of prenatal exposure to high AQI and extreme Humidex on the risk of preterm birth: A large sample population study in northern China.

The combined effects of air pollution and extreme temperature on PTB remain unclear. To evaluate the independent effect and interaction effect of prenatal extreme exposure to air quality index (AQI) and Humidex, on PTB. Based on the National Health Care Data Platform of Shandong University, women who gave birth in 2019-2020 were selected for the study. First, the independent effects of AQI and Humidex on PTB were assessed by logistic regression model. Subsequently, the interaction effects of AQI and Humidex on PTB were estimated separately by calculation of the relative excess risk of interaction (RERI). A total of 34365 pregnant women were included and 1975 subjects were diagnosed with PTB. We observed a significant increase in the odds of PTB associated with maternal high AQI exposure, with an OR of 1.70 (95% CI: 1.59, 1.81). Similarly, extreme exposure to Humidex also demonstrated an elevated PTB odds, with a low Humidex OR of 2.48 (95% CI: 2.23, 2.76) and a high Humidex OR of 1.48 (95% CI: 1.31, 1.67). Finally, we observed an interaction between high AQI and extreme Humidex during the 1st trimester. Interaction effects were noted between high AQI and low Humidex throughout the entire trimester and the 2nd trimester. This study suggests that prenatal exposure to high AQI and extreme Humidex could increase the odds of PTB, with effects exhibiting the sensitivity window and a cumulative trend. Additionally, there is an interaction between AQI and Humidex.

A Rapid and Sensitive Gold Nanoparticle-Based Lateral Flow Immunoassay for Chlorantraniliprole in Agricultural and Environmental Samples.

Chlorantraniliprole (CAP) is a new type of diamide insecticide that is mainly used to control lepidopteran pests. However, it has been proven to be hazardous to nontarget organisms, and the effects of its residues need to be monitored. In this study, five hybridoma cell lines were developed that produced anti-CAP monoclonal antibodies (mAbs), of which the mAb originating from the cell line 5C5B9 showed the highest sensitivity and was used to develop a gold nanoparticle-based lateral flow immunoassay (AuNP-LFIA) for CAP. The visible limit of detection of the AuNP-LFIA was 1.25 ng/mL, and the detection results were obtained in less than 10 min. The AuNP-LFIA showed no cross-reactivity for CAP analogs, except for tetraniliprole (50%) and cyclaniliprole (5%). In the detection of spiked and blind samples, the accuracy and reliability of the AuNP-LFIA were confirmed by a comparison with spiked concentrations and verified by ultra-performance liquid chromatography-tandem mass spectrometry. Thus, this study provides the core reagents for establishing CAP immunoassays and a AuNP-LFIA for the detection of residual CAP.

Regulation of Hippo-YAP/CTGF signaling by combining an HDAC inhibitor and 5-fluorouracil in gastric cancer cells.

Histone deacetylase (HDAC) inhibitors diminish carcinogenesis, metastasis, and cancer cell proliferation by inducing death in cancer cells. Tissue regeneration and organ development are highly dependent on the Hippo signaling pathway. Targeting the dysregulated hippo pathway is an excellent approach for cancer treatment. According to the results of this study, the combination of panobinostat, a histone deacetylase inhibitor, and 5-fluorouracil (5-FU), a chemotherapy drug, can act synergistically to induce apoptosis in gastric cancer cells. The combination of panobinostat and 5-FU was more effective in inhibiting cell viability than either treatment alone by elevating the protein levels of cleaved PARP and cleaved caspase-9. By specifically targeting E-cadherin, vimentin, and MMP-9, the combination of panobinostat and 5-FU significantly inhibited cell migration. Additionally, panobinostat significantly increased the anticancer effects of 5-FU by activating Hippo signaling (Mst 1 and 2, Sav1, and Mob1) and inhibiting the Akt signaling pathway. As a consequence, there was a decrease in the amount of Yap protein. The combination therapy of panobinostat with 5-FU dramatically slowed the spread of gastric cancer in a xenograft animal model by deactivating the Akt pathway and supporting the Hippo pathway. Since combination treatment exhibits much higher anti-tumor potential than 5-FU alone, panobinostat effectively potentiates the anti-tumor efficacy of 5-FU. As a result, it is believed that panobinostat and 5-FU combination therapy will be useful as supplemental chemotherapy in the future.

Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage.

BACKGROUND: Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated. HYPOTHESIS/PURPOSE: This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms. METHOD: C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-ß or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy. RESULTS: In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/ß expressions and decreased MAPLC3α/ß and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/ß expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62 and IL-1ß in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62, caspase-1 and IL-1ß. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy. CONCLUSION: SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.