Interaction of Cyclodextrins with Amphiphilic Alternating Cooligomers Possessing the Dense Triazole Backbone.

The interaction of cyclodextrins (CDs) with structure-controlled polymers is expected to provide significant insights into macromolecular recognition. However, the interaction of CDs with structure-controlled polymers has been an underexamined issue of investigation. Herein, alternating amphiphilic cooligomers (oligoCnAH, where n denotes the carbon number of alkyl groups; n = 4, 8, and 12) were synthesized by copper(I)-catalyzed azide-alkyne cycloaddition polymerization of heterodimers of 4-azido-5-hexynoic acid (AH) derivatives carrying N-alkylamide and t-butyl (tBu) ester side chains, followed by hydrolysis of the tBu ester, to study the interaction of CDs with oligoCnAH by 1H NMR, nuclear Overhauser effect spectroscopy, and pulse-field-gradient spin-echo NMR. These NMR studies indicated that αCD interacted with oligoC4AH, αCD and ßCD interacted with oligoC8AH, and all CDs interacted with oligoC12AH. Based on the equilibrium models proposed, the binding constants were evaluated for the binary mixtures, which showed interaction. Comparing the interactions of the CDs/oligoC12AH binary mixtures with those of the binary mixtures of CDs and alternating copolymers of sodium maleate and dodecyl vinyl ether (polyC12M), it is concluded that oligoC12AH forms less stable micelles than does polyC12M presumably because of the lower molecular weight, the hydrophilic amide groups in the side chain, and the longer interval between neighboring C12 groups in oligoC12AH.

Mechanism exploration of Zoledronic acid combined with PD-1 in the treatment of hepatocellular carcinoma.

How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.

Targeted exome sequencing strategy (NeoEXOME) for Chinese newborns using a pilot study with 3423 neonates.

BACKGROUND: Newborn screening (NBS) aims to detect congenital anomalies, and next-generation sequencing (NGS) has shown promise in this aspect. However, the NBS strategy for monogenic inherited diseases in China remains insufficient. METHODS: We developed a NeoEXOME panel comprising 601 genes that are relevant to the Chinese population found through extensive research on available databases. An interpretation system to grade the results into positive (high-risk, moderate-risk, and low-risk genotypes), negative, and carrier according to the American College of Medical Genetics (ACMG) guidelines was also developed. We validated the panel to evaluate its efficacy by using data from the "1000 Genomes Project" and conducted a pilot multicenter study involving 3423 neonates. RESULTS: The NGS positive rate in the 1000 Genomes Project was 7.6% (23/301), whereas the rate was 12.0% in the multicenter study, including 3249 recruited neonates. Notably, in 200 neonates, positive per conventional NBS, 58.5% (69/118) showed results consistent with NGS. In the remaining 3049 neonates showing negative results in conventional NBS, 271 (8.9%) were positive per NGS, and nine of them were clinically diagnosed with diseases in the follow-up. CONCLUSION: We successfully designed a NeoEXOME panel for targeted sequencing of monogenic inherited diseases in NBS. The panel demonstrated high performance in the Chinese population, particularly for the early detection of diseases with no biochemical markers.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients with Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes (P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Computationally efficient composite triple beat cancellation for DML-based DA-RoF fronthaul.

The digital-analog radio-over-fiber (DA-RoF) scheme offers a high-fidelity and spectrally efficient solution for future mobile fronthaul. However, to be implemented in the low-cost directly modulated laser with direct detection (DML-DD) link, both the digital and analog parts in DA-RoF modulation would suffer from the composite second-order (CSO) and composite triple beat (CTB) caused by the chirp-dispersion interaction. In this Letter, we propose and experimentally demonstrate a computationally efficient composite triple beat cancellation (CTB-C) algorithm for DA-RoF fronthaul in the dispersion-uncompensated C-band DML-DD link. The CSO and CTB are suppressed at the receiver-side DSP based on the theoretical model of these nonlinear distortions. In the proof-of-concept experiment, a 1.2-dB improvement in the recovered signal-to-noise ratio (SNR) is obtained with 5.5-GHz 1024-QAM orthogonal frequency division multiplexing (OFDM) signal after 10-km standard single-mode fiber (SSMF) transmission. The proposed CTB-C technique does not require the training process and performs close to the Volterra-based feed-forward equalizer (VFE) under the complexity constraint.

Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.

mTOR, as a serine/threonine kinase, is a widely pursued anticancer target. Multiple clinical trials of mTOR kinase inhibitors are ongoing, but their specificity and safety features remain lacking. Here, we have employed an inducible kinase-inactive D2338A mTOR knock-in mouse model (mTOR-/KI) together with a mTOR conditional knockout model (mTOR-/-) to assess the kinase-dependent/-independent function of mTOR in hematopoiesis and the on-/off-target effects of mTOR kinase inhibitor AZD2014. Despite exhibiting many similar phenotypes to mTOR-/- mice in hematopoiesis, the mTOR-/KI mice survived longer and showed differences in hematopoietic progenitor cells compared to mTOR-/- mice, suggesting a kinase-independent function of mTOR in hematopoiesis. Gene expression signatures in hematopoietic stem cells (HSCs) further revealed both kinase-dependent and independent effects of mTOR. AZD2014, a lead mTOR kinase inhibitor, appeared to work mostly on-target in suppressing mTOR kinase activity, mimicking that of mTOR-/KI HSCs in transcriptome analysis, but it also induced a small set of off-target responses in mTOR-/KI HSCs. In murine and human myeloid leukemia, besides kinase-inhibitory on-target effects, AZD2014 displayed similar off-target and growth-inhibitory cytostatic effects. These studies provide new insights into kinase-dependent/-independent effects of mTOR in hematopoiesis and present a genetic means for precisely assessing the specificity of mTOR kinase inhibitors.

Exploring calcium channel blocker as a candidate drug for Pseudomonas aeruginosa through network pharmacology and experimental validation.

Calcium channel blocker (CCB) is known to possess antibacterial effects. We aimed to apply network pharmacology (docking and protein-protein interaction [PPI] analyses) to predict the potential targets and mechanisms of CCB against Pseudomonas aeruginosa (PA) as well as to verify the effect of these drugs. The chemical structures of three CCBs were obtained through the Drug Bank platform. The potential channel proteins, efflux pump proteins and ion channel proteins of CCB against bacteria were derived from the literature. These proteins were collected through the PDB and Uniprot platform. The binding mode of the docking complexes was simulated by the CB-Dock platform and Discovery Studio 2019 Client software. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. GO was explained by the PANTHER platform. The pathway diagram was drawn with the Pathway Builder Tool 2.0 software. The inhibitory effect of CCB on PA was verified through antibacterial experiments. Finally, 76 proteins were obtained: the iron channel protein of PA demonstrated a good docking relationship with all three CCBs, and the optimum binding energy was approximately -9.0 kcal/mol. GO analysis (biological process [BP], cellular component [CC], and molecular function [MF]) of protein genes showed a good docking relationship (optimum binding energy <-8.0 kcal/mol). The MF annotation results indicated that the target of CCB may be present on the PA membrane protein. The ion channel protein PPI enrichment p-value was 6.65e-08, and PfeA showed the strongest correlation. The experimental results suggested that CCB could inhibit the growth of PA. CCB might be an effective and interesting antimicrobial treatment strategy as CCB can potentially inhibit the growth of PA.

S1P-S1PR3-RAS promotes the progression of S1PR3hi TAL1+ T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist.

TAL1+ T-cell acute lymphoblastic leukemia (T-ALL) is a distinct subtype of leukemia with poor outcomes. Through the cooperation of co-activators, including RUNX1, GATA3, and MYB, the TAL1 oncoprotein extends the immature thymocytes with autonomy and plays an important role in the development of T-ALL. However, this process is not yet well understood. Here, by investigating the transcriptome and prognosis of T-ALL from multiple cohorts, we found that S1PR3 was highly expressed in a subset of TAL1+ T-ALL (S1PR3hi TAL1+ T-ALL), which showed poor outcomes. Through pharmacological and genetic methods, we identified a specific survival-supporting role of S1P-S1PR3 in TAL1+ T-ALL cells. In T-ALL cells, TAL1-RUNX1 up-regulated the expression of S1PR3 by binding to the enhancer region of S1PR3 gene. With hyperactivated S1P-S1PR3, T-ALL cells grew rapidly, partly by activating the KRAS signal. Finally, we assessed S1PR3 inhibitor TY-52156 in T-ALL patient-derived xenografts (PDXs) mouse model. We found that TY-52156 attenuated leukemia progression efficiently and extended the lifespan of S1PR3hi TAL1+ T-ALL xenografts. Our findings demonstrate that S1PR3 plays an important oncogenic role in S1PR3hi TAL1+ T-ALL and may serve as a promising therapeutic target.

Increased functional connectivity of amygdala subregions in patients with drug-naïve panic disorder and without comorbidities.

BACKGROUND: Amygdala plays an important role in the neurobiological basis of panic disorder (PD), and the amygdala contains different subregions, which may play different roles in PD. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the amygdala subregions in PD using resting-state functional magnetic resonance imaging and to explore the relationship between the abnormal spontaneous functional connectivity patterns of the regions of interest (ROIs) and the clinical symptoms of PD patients. METHODS: Fifty-three drug-naïve, non-comorbid PD patients and 70 healthy controls (HCs) were recruited. Seed-based resting-state functional connectivity (rsFC) analyses were conducted using the bilateral amygdalae and its subregions as the ROI seed. Two samples t test was performed for the seed-based Fisher's z -transformed correlation maps. The relationship between the abnormal spontaneous functional connectivity patterns of the ROIs and the clinical symptoms of PD patients was investigated by Pearson correlation analysis. RESULTS: PD patients showed increased rsFC of the bilateral amygdalae and almost all the amygdala subregions with the precuneus/posterior cingulate gyrus compared with the HC group (left amygdala [lAMY]: t  = 4.84, P  <0.001; right amygdala [rAMY]: t  = 4.55, P  <0.001; left centromedial amygdala [lCMA]: t  = 3.87, P  <0.001; right centromedial amygdala [rCMA]: t  = 3.82, P  = 0.002; left laterobasal amygdala [lBLA]: t  = 4.33, P  <0.001; right laterobasal amygdala [rBLA]: t  = 4.97, P  <0.001; left superficial amygdala [lSFA]: t  = 3.26, P  = 0.006). The rsFC of the lBLA with the left angular gyrus/inferior parietal lobule remarkably increased in the PD group ( t  = 3.70, P  = 0.003). And most of the altered rsFCs were located in the default mode network (DMN). A significant positive correlation was observed between the severity of anxiety and the rsFC between the lSFA and the left precuneus in PD patients ( r  = 0.285, P  = 0.039). CONCLUSIONS: Our research suggested that the increased rsFC of amygdala subregions with DMN plays an important role in the pathogenesis of PD. Future studies may further explore whether the rsFC of amygdala subregions, especially with the regions in DMN, can be used as a biological marker of PD.

Recent Advances in Graphitic Carbon Nitride Based Electro-Catalysts for CO2 Reduction Reactions.

The electrocatalytic carbon dioxide reduction reaction is an effective means of combating the greenhouse effect caused by massive carbon dioxide emissions. Carbon nitride in the graphitic phase (g-C3N4) has excellent chemical stability and unique structural properties that allow it to be widely used in energy and materials fields. However, due to its relatively low electrical conductivity, to date, little effort has been made to summarize the application of g-C3N4 in the electrocatalytic reduction of CO2. This review focuses on the synthesis and functionalization of g-C3N4 and the recent advances of its application as a catalyst and a catalyst support in the electrocatalytic reduction of CO2. The modification of g-C3N4-based catalysts for enhanced CO2 reduction is critically reviewed. In addition, opportunities for future research on g-C3N4-based catalysts for electrocatalytic CO2 reduction are discussed.

Development of a TMErisk model based on immune infiltration in tumour microenvironment to predict prognosis of immune checkpoint inhibitor treatment in hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) treatment has created the opportunity of improved outcome for patients with hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from ICI treatment owing to poor treatment efficacy and safety concerns. There are few predictive factors that precisely stratify HCC responders to immunotherapy. In this study, we developed a tumour microenvironment risk (TMErisk) model to divide HCC patients into different immune subtypes and evaluated their prognosis. Our results indicated that virally mediated HCC patients who had more common tumour protein P53 (TP53) alterations with lower TMErisk scores were appropriate for ICI treatment. HCC patients with alcoholic hepatitis who more commonly harboured catenin beta 1 (CTNNB1) alterations with higher TMErisk scores could benefit from treatment with multi-tyrosine kinase inhibitors. The developed TMErisk model represents the first attempt to anticipate tumour tolerance of ICIs in the TME through the degree of immune infiltration in HCCs.

To be or not to be: The double-edged sword roles of liver progenitor cells.

Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.

The efficacy of a transdiagnostic group cognitive behavioral intervention for Chinese elderly with emotional disorders: A one-year follow-up randomized clinical trial.

Background: With the global aging, geriatric emotional disorders have received more and more attention. Psychotherapy is an effective approach for alleviating the symptoms associated with emotional disorder, but the number of experienced therapists is low. Studies should be conducted to explore a low-cost and efficient treatment method. Previous findings indicate that transdiagnostic cognitive behavior therapy is an effective approach for treatment of emotional disorders. Group therapy is appropriate for the elderly as they are characterized by high levels of loneliness. In this study, we compared and explored the effects of a transdiagnostic group cognitive behavioral intervention (TD-GCBT), a transdiagnostic individual cognitive behavioral intervention (TD-CBT), and treatment as usual (TAU) on treatment of emotional disorders among the elderly. Method: A total of 120 elderly patients diagnosed with emotional disorders were randomly assigned to the TD-GCBT group (40), TD-CBT group (40), and TAU group (40). Changes in symptoms were assessed using HAMD, PHQ-9, HAMA, and GAD-7 scales at baseline, post-treatment (three months), six-month and twelve-months follow-up. The efficacies of the three intervention strategies were compared using linear mixed-effects models. Post-hoc and simple effect analyses were conducted to determine the differences among the three groups. Results: The HAMD, PHQ-9, HAMA, and GAD-7 scores revealed a significant effect from baseline to 12 months for time (p < 0.001), group (p < 0.001) and time × group interaction (p < 0.001) in TD-GCBT group compared with the TD-CBT group and TAU group. The effect of TD-GCBT (HAMD: Cohen's d (3th month, 6th month, 12th month) = 2.69, 3.98, 4.51; HAMA: Cohen's d = 2.84, 4.13, 5.20) and TD-CBT (HAMD: Cohen's d = 2.55, 2.87, 2.63; HAMA: Cohen's d = 2.43, 2.83, 2.78) group was better relative to that of the TAU group (HAMD: Cohen's d = 0.41, 1.13, 1.46; HAMA: Cohen's d = 0.64, 1.22, 1.57) (p < 0.001). The scores of the TD-GCBT group showed the most significant decrease compared with the other two groups. Conclusion: The findings indicate that TD-GCBT method is effective for treatment of emotional disorders among the elderly. TD-GCBT is effective for alleviating depression and anxiety symptoms up to at least nine months after treatment. The results indicate that TD-GCBT is a cost-effective and resource-effective strategy and can be used an alternative therapy for treatment of mental disorders. Clinical trial registration: [https://www.chictr.org.cn], identifier [ChiCTR1900021806].

Highly Selective Electrochemical CO2 Reduction to C2 Products on a g-C3N4-Supported Copper-Based Catalyst.

Herein, a novel approach used to enhance the conversion of electrochemical CO2 reduction (CO2R), as well as the capacity to produce C2 products, is reported. A copper oxide catalyst supported by graphite phase carbon nitride (CuO/g-C3N4) was prepared using a one-step hydrothermal method and exhibited a better performance than pure copper oxide nanosheets (CuO NSs) and spherical copper oxide particles (CuO SPs). The Faradaic efficiency reached 64.7% for all the C2 products, specifically 37.0% for C2H4, with a good durability at -1.0 V vs. RHE. The results suggest that the interaction between CuO and the two-dimensional g-C3N4 planes promoted CO2 adsorption, its activation and C-C coupling. This work offers a practical method that can be used to enhance the activity of electrochemical CO2R and the selectivity of C2 products through synergistic effects.

Multi-omics integration reveals a six-malignant cell maker gene signature for predicting prognosis in high-risk neuroblastoma.

Background: Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survival rates despite the intensification of therapy. This study aimed to develop a malignant-cell marker gene signature (MMGS) that might serve as a prognostic indicator in HRNB patients. Methods: Multi-omics datasets, including mRNA expression (single-cell and bulk), DNA methylation, and clinical information of HRNB patients, were used to identify prognostic malignant cell marker genes. MMGS was established by univariate Cox analysis, LASSO, and stepwise multivariable Cox regression analysis. Kaplan-Meier (KM) curve and time-dependent receiver operating characteristic curve (tROC) were used to evaluate the prognostic value and performance of MMGS, respectively. MMGS further verified its reliability and accuracy in the independent validation set. Finally, the characteristics of functional enrichment, tumor immune features, and inflammatory activity between different MMGS risk groups were also investigated. Results: We constructed a prognostic model consisting of six malignant cell maker genes (MAPT, C1QTNF4, MEG3, NPW, RAMP1, and CDT1), which stratified patients into ultra-high-risk (UHR) and common-high-risk (CHR) group. Patients in the UHR group had significantly worse overall survival (OS) than those in the CHR group. MMGS was verified as an independent predictor for the OS of HRNB patients. The area under the curve (AUC) values of MMGS at 1-, 3-, and 5-year were 0.78, 0.693, and 0.618, respectively. Notably, functional enrichment, tumor immune features, and inflammatory activity analyses preliminarily indicated that the poor prognosis in the UHR group might result from the dysregulation of the metabolic process and immunosuppressive microenvironment. Conclusion: This study established a novel six-malignant cell maker gene prognostic model that can be used to predict the prognosis of HRNB patients, which may provide new insight for the treatment and personalized monitoring of HRNB patients.

Andrographolide exerted anti-inflammatory effects thereby reducing sex hormone synthesis in LPS-induced female rats, but had no effect on hormone production in healthy ones.

Females have higher inflammatory tolerance because they have some special sex-related anti-inflammatory pathways. Andrographolide, a diterpene lactone compound from Andrographis paniculata (Burm.f.) Nees, has a powerful anti-inflammatory effect. But whether andrographolide regulates sex-related anti-inflammatory pathways in females has yet to be reported. A non-targeted metabonomics method was employed to investigate the metabolic pathways of andrographolide in LPS-induced inflammatory female rats. Substances and genes were then selected out of gender-related pathways discovered by metabonomics experiments and their quantities or expressions were evaluated. Furthermore, the effects of andrographolide on these chemicals or genes in non-inflammatory female rats were also examined in order to investigate the cascade interaction between anti-inflammatory mechanisms and metabolites. The biomarkers of 24 metabolites in plasma were identified. Following pathway enrichment analysis, these metabolic markers were clustered into glycerophosphate, glycerolipids, inositol phosphate and steroid hormone synthesis pathways. Validation experiments confirmed that andrographolide lowered post-inflammatory female sex hormones such as progesterone, estradiol, corticosterone, and testosterone rather than increasing them. Andrographolide may have these effects via inhibiting the overexpression of CYP11a1 and StAR. However, andrographolide had no effect on the expression of these two genes or the four types of hormones in non-inflamed female rats. Similarly, andrographolide decreased TNF-α, IL-6 and IL-1ß production in inflammatory rats but showed no effect on these inflammatory markers in non-inflammatory rats. LPS and other inflammatory cytokines promote hormone production, which in turn will prevent increased inflammation. Therefore, it may be hypothesized that andrographolide's reduction of inflammatory cytokine is what generates its inhibitory action on sex hormones during inflammation. By blocking the activation of inflammatory pathways, andrographolide prevented the stimulation of inflammatory factors on the production of sex hormones. It does not, however, directly inhibit or enhance the synthesis of sex hormones.

The Pharmacological Mechanism of Xiyanping Injection for the Treatment of Novel Coronavirus Pneumonia (COVID-19): Based on Network Pharmacology Strategy.

Purpose: The possible mechanism of Xiyanping injection treatment COVID-19 is discussed through the network pharmacology. Methods: Obtaining the chemical structure of Xiyanping injection through the patent application and obtaining control compounds I, II, III, IV, V, Yanhuning injection (VI, VII), Chuanhuning injection (VIII, IX), 10 compounds were analyzed by D3Targets-2019-nCoV. The human anti-COVID-19 gene in COVID-19 DisGeNET was intersected with the CTD Andrographolide target gene and then combined with D3Targets-2019-nCoV, resulting in 93 genes, using the Venny 2.1 platform. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. The GO, KEGG, and tissue of the target were analyzed using the Metascape platform and DAVID platform. The gene expression in the respiratory system was analyzed using the ePlant platform. The CB-Dock is used for the docking verification and degree values of the first 20 genes. Results: Finally, 1599 GO and 291 KEGG results were obtained. GO is mostly associated with the cell stress response to chemicals, the cell response to oxidative stress, and the cell response to reactive oxygen species. In total, 218 KEGG pathway concentrations were related to infection and other diseases and 73 signaling pathways mostly related to inflammation and immune pathways, such as TNF signaling pathway and MAPK signaling pathway. The molecular docking results show that Xiyanping injection, compound III, has a good docking relationship with 20 target proteins such as HSP90AA1. Tissue has 22 genes that are pooled in the lungs. Conclusion: Xiyanping injection may inhibit the release of various inflammatory factors by inhibiting intracellular pathways such as MAPK and TNF. It acts on protein targets such as HSP90AA1 and plays a potential therapeutic role in COVID-19. Thus, compound III may be treated as a potential new drug for the treatment of COVID-19 and the Xiyanping injection may treat patients with COVID-19 infection.

Androgens drive sexual dimorphism in liver metastasis by promoting hepatic accumulation of neutrophils.

The liver is one of the most-favored distant metastatic sites for solid tumors, and interactions between cancer cells and components of the hepatic microenvironment are essential for liver metastasis (LM). Although sex is one of the determinants for primary liver cancer, sexual dimorphism in LM (SDLM) and the underlying mechanisms remain unclear. We herein demonstrate a significant male-biased SDLM, which is attributed to host androgen/androgen receptor (Ar) signaling that promotes hepatic seeding of tumor cells and subsequent outgrowth in a neutrophil-dependent manner. Mechanistically, androgen/Ar signaling promotes hepatic accumulation of neutrophils by promoting proliferation and development of neutrophil precursors in the bone marrow, as well as modulating hepatic recruitment of neutrophils and their functions. Antagonizing the androgen/Ar/neutrophil axis significantly mitigates LM in males. Our data thus reveal an important role of androgen in LM and suggest that androgen/Ar modulation represents a promising target for LM therapy in men.

Norcantharidin Nanostructured Lipid Carrier (NCTD-NLC) Suppresses the Viability of Human Hepatocellular Carcinoma HepG2 Cells and Accelerates the Apoptosis.

Malignant tumors have become the main cause of harm to human life and health. Development for new antitumor drugs and the exploration to drug carriers are becoming the concerned focus. In this study, we exploited our experiments to explore the effect of NCTD-NLC on liver cancer cells: the HepG2 cells cultured in vitro were given with NCTD-NLC administration; then, the estimation on cellular proliferation and apoptosis was accomplished through MTT and flow cytometry. Six hours after the administration, we performed the High Performance Liquid Chromatography (HPLC) detection to estimate the NCTD content in the heart, liver, spleen, lung, kidney and plasma of rats. Then, our outcomes showed that NCTD-NLC had a notable inhibitory effect on HepG2 cells, leading to a gradually decreased cellular viability. Cell viability was negatively correlated with NCTD-NLC concentration. Along with the concentration increasing, significantly increasing cellular apoptosis and gradually decreasing cellular viability were observed. The apoptosis rate was positively correlated with the concentration of NCTD-NLC. On the basis of the data we obtained, we found that the group with NCTD-NLC tail vein injection had an obvious advantage in drug delivery when compared with other groups. Through the tumorigenesis test to nude mice, we found that the tumor inhibition rate of the NCTD-NLC tail vein injection group had a 27.48% elevation in contrast to the NCTD gavage group, and it was also the group with the best tumor inhibition efficiency. In conclusion, the NCTD-NLC prepared in this study had a mighty inhibitory effect towards HepG2 cellular viability and an accelerating work on apoptosis. Tail vein injection of NCTD-NLC has the best drug delivery effect.