Utilizing nanotechnology and advanced machine learning for early detection of gastric cancer surgery.

Nanotechnology has emerged as a promising frontier in revolutionizing the early diagnosis and surgical management of gastric cancers. The primary factors influencing curative efficacy in GIC patients are drug inefficacy and high surgical and pharmacological therapy recurrence rates. Due to its unique optical features, good biocompatibility, surface effects, and small size effects, nanotechnology is a developing and advanced area of study for detecting and treating cancer. Considering the limitations of GIC MRI and endoscopy and the complexity of gastric surgery, the early diagnosis and prompt treatment of gastric illnesses by nanotechnology has been a promising development. Nanoparticles directly target tumor cells, allowing their detection and removal. It also can be engineered to carry specific payloads, such as drugs or contrast agents, and enhance the efficacy and precision of cancer treatment. In this research, the boosting technique of machine learning was utilized to capture nonlinear interactions between a large number of input variables and outputs by using XGBoost and RNN-CNN as a classification method. The research sample included 350 patients, comprising 200 males and 150 females. The patients' mean ± SD was 50.34 ± 13.04 with a mean age of 50.34 ± 13.04. High-risk behaviors (P = 0.070), age at diagnosis (P = 0.034), distant metastasis (P = 0.004), and tumor stage (P = 0.014) were shown to have a statistically significant link with GC patient survival. AUC was 93.54%, Accuracy 93.54%, F1-score 93.57%, Precision 93.65%, and Recall 93.87% when analyzing stomach pictures. Integrating nanotechnology with advanced machine learning techniques holds promise for improving the diagnosis and treatment of gastric cancer, providing new avenues for precision medicine and better patient outcomes.

Novel Withanolides from Tubocapsicum anomalum Suppress Triple-Negative Breast Cancer by Triggering Apoptosis and p53-ASCT2-SLC7A11-Mediated Ferroptosis.

Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe2+, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.

Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies.

Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer's disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit Aß1-42 peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC50 = 3.49 nM) and 43 (IC50 = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC50 = 63 nM). Besides, the selectivity indexes (SI = AChE IC50 / BChE IC50) of 39 (SI = 33) and 43 (SI = 20) were also higher than A3Q12 (SI = 14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective Ki values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Aß1-42 peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer's disease.

Effect of nanoparticle macroalgae in the treatment of fatty liver disease using logistic regression, and support vector machine.

One of the major health issues facing people worldwide is liver fibrosis. Liver fibrosis may be brought on by long-term exposure to harmful substances, medicines, and microorganisms. The development of liver fibrosis in children was particularly worrying due to their longer life-span, which was possibly related to a great risk of developing long-term complications. Marine algae species have provided a biological variety in the research phase of novel approaches to the treatment of numerous ailments. Marine macroalgae have recently been the subject of research due to their rich bioactive chemical composition and potential for the production of various nutraceuticals. Macroalgae are potentially excellent sources of bioactive substances with particular and distinct biological activity when compared to their terrestrial equivalents. Macroalgae in diverse marine cases offer a few biologically active metabolites, comprising sterols, polyunsaturated fatty acids, carotenoids, oligosaccharides, polysaccharides, proteins, polyphenols, vitamins, and minerals. Accordingly, there is great interest in their high potential for supporting immunomodulatory, antimicrobial, antidiabetic, antitumoral, anti-inflammatory, antiangiogenic, and neuroprotective properties. Using an experimental model, the current research intends to collect data on the therapeutic value of macroalgae nanoparticles for fatty liver disease. The researchers' goal of predicting illnesses from the extensive medical datasets is quite difficult. The purpose of this research is to assess the protective effects of a seaweed, Padina pavonia (PP), on liver fibrosis caused by carbon tetrachloride (CCl4). This research presents two models of logistic regression (LR) and support vector machines (SVM) for predicting the likelihood of liver disease incidence. The performance of the model was evaluated using a dataset. PP macro-algae considerably reduce the high blood concentrations of aminotransferases, alkaline phosphatases, and lactate dehydrogenases, as well as causing a considerable (p < 0.05) decrease in serum bilirubin levels. In addition to improving kidney function (urea and creatinine), algal extracts enhance fat metabolism (triglycerides and cholesterol). With an accuracy rate of 70.2%, a sensitivity of 92.3%, a specificity of 74.7%, a type I error of 9.1%, and a type II error of 21.0%, the predictive model has demonstrated excellent performance. The model validated laboratory tests' ability to predict illness (age; direct bilirubin (DB), total proteins (TP), and albumin (ALB). These classifier methods are compared on the basis of their execution time and classification accuracy.

A state-of-the-art analysis of pharmacological delivery and artificial intelligence techniques for inner ear disease treatment.

Over the last several decades, both the academic and therapeutic fields have seen significant progress in the delivery of drugs to the inner ear due to recent delivery methods established for the systemic administration of drugs in inner ear treatment. Novel technologies such as nanoparticles and hydrogels are being investigated, in addition to the traditional treatment methods. Intracochlear devices, which utilize current developments in microsystems technology, are on the horizon of inner ear drug delivery methods and are designed to provide medicine directly into the inner ear. These devices are used for stem cell treatment, RNA interference, and the delivery of neurotrophic factors and steroids during cochlear implantation. An in-depth analysis of artificial neural networks (ANNs) in pharmaceutical research may be found in ANNs for Drug Delivery, Design, and Disposition. This prediction tool has a great deal of promise to assist researchers in more successfully designing, developing, and delivering successful medications because of its capacity to learn and self-correct in a very complicated environment. ANN achieved a high level of accuracy exceeding 0.90, along with a sensitivity of 95% and a specificity of 100%, in accurately distinguishing illness. Additionally, the ANN model provided nearly perfect measures of 0.99%. Nanoparticles exhibit potential as a viable therapeutic approach for bacterial infections that are challenging to manage, such as otitis media. The utilization of ANNs has the potential to enhance the effectiveness of nanoparticle therapy, particularly in the realm of automated identification of otitis media. Polymeric nanoparticles have demonstrated effectiveness in the treatment of prevalent bacterial infections in pediatric patients, suggesting significant potential for forthcoming therapeutic interventions. Finally, this study is based on a research of how inner ear diseases have been treated in the last ten years (2012-2022) using machine learning.

Application of nanotechnology in breast cancer screening under obstetrics and gynecology through the use of CNN and ANFIS.

Breast cancer is the leading reason of death among women aged 35 to 54. Breast cancer diagnosis still presents significant challenges, and preventing the disease's most severe symptoms requires early detection. The role of nanotechnology in the tumor-treatment has recently attracted a lot of interest. In cancer therapies, nanotechnology plays a major role in the medication distribution process. Nanoparticles have the ability to target tumors. Nanoparticles are favorable and maybe preferable for usage in tumor detection and imaging due to their incredibly small size. Quantum dots, semiconductor crystals with increased labeling and imaging capabilities for cancer cells, are one of the particles that have received the most research attention. The design of the research is cross-sectional and descriptive. From April through September of 2020, data were gathered at the State Hospital. All pregnant women who came to the hospital throughout the first and second trimesters of the research's data collection were included in the study population. 100 pregnant women between the ages of 20 and 40 who had not yet had a mammogram comprised the research sample. 1100 digitized mammography images are included in the dataset, which was obtained from a hospital. Convolutional neural networks (CNN) were used to scan all images, and breast masses and mass comparisons were made using the malignant-benign categorization. The adaptive neuro-fuzzy inference system (ANFIS) then examined all of the data obtained by CNN in order to identify breast cancer early using inputs based on the nine different inputs. The precision of the mechanism used in this technique to determine the ideal radius value is significantly impacted by the radius value. Nine variables that define breast cancer indicators were utilized as inputs to the ANFIS classifier, which was then used to identify breast cancer. The parameters were given the necessary fuzzy functions, and the combined dataset was applied to train the method. Testing was initially performed by 30% of dataset that was later done with the real data obtained from the hospital. The accuracy of the results for 30% data was 84% (specificity =72.7%, sensitivity =86.7%) and the results for the real data was 89.8% (sensitivity =82.3%, specificity =75.9%), respectively.

Eupalinolide J Inhibits Cancer Metastasis by Promoting STAT3 Ubiquitin-Dependent Degradation.

Eupalinolide J (EJ) is an active component from Eupatorium lindleyanum DC. (EL), which was reported to have good antitumor activity via STAT3 and Akt signaling pathways. In this study, we identified Eupalinolide J (EJ) as a potential anti-cancer metastatic agent by target prediction and molecular docking technique screening. Follow-up experiments demonstrated that EJ exhibited a good inhibitory effect on cancer cell metastasis both in vitro and in vivo, and could effectively reduce the expression of STAT3, MMP-2, and MMP-9 proteins in cells, while the knockdown of STAT3 could weaken the inhibitory effect of EJ on cancer cell metastasis. Further molecular biology experiments revealed that EJ promoted STAT3 ubiquitin-dependent degradation, and thus, downregulated the expression of the metastasis-related genes MMP-2 and MMP-9. In conclusion, our study revealed that EJ, a sesquiterpene lactone from EL, could act as a STAT3 degradation agent to inhibit cancer cell metastasis and is expected to be applied in cancer therapy.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

Structural Characterization and Tumor Microvascular Inhibition Activity of Total Polysaccharide from Trametes sanguinea Lloyd.

Trametes sanguinea Lloyd total polysaccharide (TsLTP), was obtained by water extraction and ethanol precipitation from T. sanguinea. The structural characterization of TsLTP was elucidated mutually by TsL1 and TsL2, whose mass ratio is 1: 4. TsL1 is mainly composed of mannose, glucose, galactose, and fucose, and consist of T-Linked-Fucp, T-Linked-Manp, T-Linked-Galp, 1,4-Linked-Manp, 1,4-Linked-Glcp, 1,6-Linked-Manp, 1,6-Linked-Galp, 1,3,4-Linked-Glcp, 1,4,6-Linked-Glcp and 1,3,6-Linked-Glcp, with a molar ratio of 2.1: 1.7: 1.4: 1.0: 3.6: 2.0: 8.6: 1.3: 2.2: 1.2, while TsL2 mainly comprise of glucose and consist of T-Linked-Glcp, 1,3-Linked-Glcp, 1,4-Linked-Glcp and 1,4,6-Linked-Glcp, with a molar ratio of 1.0: 2.1: 7.6: 1.4. TsLTP exhibited strong inhibitory effects on the migration, invasion, and tube formation of human umbilical vein endothelial cells (iHUVECs) and chick embryo chorioallantoic membrane (CAM) angiogenesis, whereas no inhibitory activity on human TNBC cell lines. Taken together, our study suggests that TsLTP possesses a significant inhibition of tumor microvascular activity both in vitro and in vivo. The study of TsLTP with novel monosaccharide composition and tumor microvascular inhibitory activity might be a beneficial attempt for application of polysaccharide from the genus Trametes in tumor therapy.

Design, synthesis, and biological evaluation of C-8 modified curcumol derivatives against colorectal cancer cell lines.

A series of structurally modified curcumol derivatives at C-8 position were designed and synthesized, whose structures were confirmed by 1H NMR,13C NMR, and HRMS analysis. The tested compounds were evaluated for in vitro antitumor activity against colorectal cancer cell lines SW620, HCT116, and CaCo2. Many of the tested candidates exhibited higher inhibition efficiency than curcumol. Among them, compound 3 l shows the best inhibitory effect on the viability of SW620 with IC50 value of 19.90 ± 0.64 µM. The structure-activity relationships of these derivatives were discussed, which showed that the introduction of amino or aryl groups tended to increase the anti-cancer activity. In addition, compound 3 l may inhibit cancer cell proliferation through triggering cell apoptosis.

Design, synthesis, and anticancer activity evaluation of curcumol derivatives.

A new series of C-14 curcumol derivatives as potent anticancer agents were designed and synthesized by click reaction, whose structures were confirmed by 1H NMR,13C NMR, and HRMS analysis. All the synthesized compounds were evaluated for in vitro antitumor activity against colorectal cancer cell lines SW620 and HCT116. Most of them exhibited higher inhibitory activity than curcumol. Especially, compound 3j shows good inhibitory activity against SW620 with IC50 value of 8.10 ± 0.13 µM. The structure-activity relationships (SARs) of these derivatives were discussed. In addition, flow cytometry revealed that compound 3j induced SW620 cells apoptosis by facilitating apoptosis-related proteins expressions. Our findings suggested that fluorine functional group on phenyl ring tended to increase the anticancer activity.

LFZ-4-46, a tetrahydroisoquinoline derivative, induces apoptosis and cell cycle arrest via induction of DNA damage and activation of MAPKs pathway in cancer cells.

LFZ-4-46, that is [2-hydroxy-1-phenyl-1,5,6,10b-tetrahydropyrazolo(5,1-a) isoquinolin-3(2H)-yl](phenyl) methanone, a tetrahydroisoquinoline derivative with a pyrazolidine moiety, was synthetically prepared. The anti-cancer mechanism of the compound has not been clarified yet. In this study, the anticancer effects and potential mechanisms of LFZ-4-46 on human breast and prostate cancer cells were explored. (a) 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide assay was first performed to detect the effects of LFZ-4-46 on the viability of human cancer cells. (b) Comet assay was utilized to evaluate DNA damage. (c) Cell cycle, apoptosis and mitochondrial membrane potential were detected by flow cytometry. (d) The expression of relative proteins was detected by western blotting assay. LFZ-4-46 significantly inhibited the viability of cancer cells in a time- and dose-dependent manner and had no obviously inhibitory effect on the viability of mammary epithelial MCF-10A cells. Mechanistic studies demonstrated that LFZ-4-46-induced cell apoptosis and cycle arrest were mediated by DNA damage. It caused DNA damage through activating γ-H2AX and breaking DNA strands. Further studies showed that mitogen-activated protein kinasess pathway was involved in these activated several key molecular events. Finally, LFZ-4-46 showed a potent antitumor effect in vivo. These results suggest that LFZ-4-46 may be a potential lead compound for the treatment of breast and prostate cancer.

HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients.

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.

Targeting pharmacophore with probe-reactivity-guided fractionation to precisely identify electrophilic sesquiterpenes and its activity of anti-TNBC.

INTRODUCTION: Innovative strategy is urgently needed to precisely discover novel natural products as lead compounds for development of new drugs against orphan diseases such as triple-negative breast cancer (TNBC). Herein, we describe a targeting pharmacophore with probe-reactivity-guided strategy for the discovery of electrophilic sesquiterpene (ES), a class of bioactive natural product. OBJECTIVE: This study aimed to identify pharmacophore, based on pharmacophore with probe-reactivity-guided strategy for precisely discovering ESs from ethyl acetate extract of Eupatorium chinense L. (EEEChL) METHODOLOGY: MTT assay combined with ultra-performance liquid chromatography (UPLC) analysis was used to identify pharmacophore. UPLC-mass spectrometry (MS) was applied to carefully compare the intrinsic reactivity characteristics of two chemoselective nucleophilic probes: glutathione (GSH) and 4-bromothiophenol (BTP) reaction with ESs. ESs was isolated and identified from EEEChL by phytochemical methods. Furthermore, stoichiometric ratio and binding site of one typical ES 8ß-[4'-hydroxytigloyloxy]-5-desoxy-8-desacyleuparotin (HDDE) reaction with BTP were studied by UPLC-quadrupole time-of-flight (Q-TOF)-MS and two-dimensional nuclear magnetic resonance (NMR). RESULTS: Eleven ESs were identified from EEEChL, MTT assay illustrated that all of the 11 ESs possess fairly good anti-TNBC activity CONCLUSIONS: Electrophilic groups were confirmed as pharmacophore of bioactive compounds contained in EEEChL. An optimised halogenated aromatic probe BTP furnishes ES-BTP conjugates that are highly conspicuous via MS by virtue of a unique isotopic bromine signature, conjugates also have a considerable separation on C18 column. The new probe-reactivity-guided strategy can effectively improve the traditional bioassay-guided approaches, and significantly increase the probability of obtaining designated bioactive compounds.

[Mechanism and intervention of mucosal immune regulation based on "lung and large intestine being interior-exteriorly related" theory of traditional Chinese medicine].

The "lung and large intestine being interior-exteriorly related" is one of the classical theories in traditional Chinese medicine, which indicates a close correlation between the lung and large intestine in physiology and pathology, and plays a pivotal role in guiding the treatment of the lung and bowel diseases. Modern medicine has revealed some connections between the lung and large intestine in tissue origin and mucosal immunity, and preliminarily illuminated the material basis and possible regulatory mechanism of the theory. Recently, this theory has been applied to guide the treatment of refractory lung and intestine diseases such as COVID-19 and ulcerative colitis and has obtained reliable efficacy. Existing research results show that the anatomical homogeneity of lung and large intestine promotes the correlation between lung-bowel mucosal immunity, and mucosal immunity and migration and homing of innate lymphocytes are one of the physiological and pathological mechanisms for lung and large intestine to share. Under the guidance of this theory, Chinese medicines with heat-clearing and detoxifying or tonic effects are commonly used in the treatment of the lung and intestinal diseases by regulating lung-bowel mucosal immunity and they can be candidate drugs to treat lung/intestinal diseases simultaneously. However, the existing studies on immune regulation are mainly focused on the expression levels of sIgA and cytokines, as well as the changes in the number of immune cells such as innate lymphocytes and B lymphocytes. While the following aspects need further investigation: the airway/intestinal mucous hypersecretion, the functional changes of pulmonary and intestinal mucosal barrier immune cells, the dynamic process of lung/intestinal mucosal immune interaction, the intervention effect of local pulmonary/intestinal microecology, the correlation and biological basis between the heat-clearing and detoxifying effect and the tonic effect, and its regulation of pulmonary/intestinal mucosal immunity. In this paper, we try to analyze the internal relationship between lung and intestine related diseases from the point of view of the common mucosal immune system of lung and intestine, and summarize the characteristics and rules of traditional Chinese medicine compound and its active ingredients, which have regulatory effect on lung and intestine mucosal immune system, so as to further explain the theoretical connotation of "lung and large intestine being interior-exteriorly related" and provide reference for the research and development of drugs for related diseases.

Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells.

OBJECTIVE: Chronic hepatitis B (CHB) virus infection is a global health problem. Finding a cure for CHB remains a challenging task. DESIGN: In this study, poly I:C was employed as an adjuvant for HBV therapeutic vaccine (referred to as pHBV-vaccine) and the feasibility and efficiency of pHBV-vaccine in CHB treatment were evaluated in HBV-carrier mice. RESULTS: We found that pHBV-vaccine decreased HBsAg and HBV DNA efficiently and safely in HBV-carrier mice. Further investigation showed that pHBV-vaccine promoted maturation and antigen presentation ability of dendritic cells in vivo and in vitro. This vaccine successfully restored the exhaustion of antigen-specific CD8+ T cells and partly broke the immune tolerance established in HBV-carrier mice. pHBV-vaccine also enhanced the proliferation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells. Importantly, we observed that T cell activation molecule KLRG1 was only expressed on HBV specific CD11ahi CD8αlo cells. Furthermore, pHBV-vaccine reduced the expression of Eomes and increased the serum IL-12 levels, which in turn promoted the generation of effector memory short-lived effector cells (SLECs) to exhibit a critical role in HBV clearance. SLECs induced by pHBV-vaccine might play a crucial role in protecting from HBV reinfection. CONCLUSIONS: Findings from this study provide a new basis for the development of therapeutic pHBV-vaccine, which might be a potential candidate for clinical CHB therapy.

IFN-γ protects from apoptotic neutrophil-mediated tissue injury during acute Listeria monocytogenes infection.

Listeria monocytogenes (LM) is a foodborne Gram-positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN-γ-producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN-γ. IFN-γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng-/- mice. Moreover, IFN-γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM-induced neutrophil apoptosis and spleen damage. In addition to this, IFN-γ could effectively drive macrophage-mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF-ß secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN-γ at the early stage of LM infection, which is characterized by both LM elimination and tissue-protective effects.

Alisol A Suppresses Proliferation, Migration, and Invasion in Human Breast Cancer MDA-MB-231 Cells.

Natural products are a precious source of promising leads for the development of novel cancer therapeutics. Recently, triterpenoids in Alismatis rhizoma has been widely demonstrated for their anti-cancer activities in cancer cells. In this study, we examined the inhibitory effects of alisol A in human breast cancer cells. We demonstrated that alisol A exhibited significant anti-proliferative effects in MDA-MB-231 cells and this response was related to autophagy induction. Alisol A-induced autophagy was supported by the triggered autophagosome formation and increased LC3-II levels. Interestingly, autophagy inhibitor 3-MA significantly reversed the cytotoxic effects induced by alisol A. Meanwhile, alisol A-induced autophagy was significantly inhibited by 3-MA in MDA-MB-231 cells. Cell cycle analysis revealed that alisol A arrested the cell cycle at G0/G1 phase. The expression level of cell cycle regulatory proteins cyclin D1 was significantly down regulated. In addition, the suppression of NF-κB and PI3K/Akt/mTOR pathways in MDA-MB-231 cells was observed. Furthermore, alisol A significantly suppressed the migration and invasion of MDA-MB-231 cells by inhibiting the expression levels of MMP-2 and MMP-9. Taken together, our results demonstrated that alisol A could inhibit the proliferation and metastasis of MDA-MB-231 cells. It could be a promising agent for breast cancer therapy.

Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist.

Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small-molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR-expressing cells, including 32D-MPL and human hematopoietic stem cells, with low nanomolar EC50 values through stimulation of STAT, PI3K and ERK signalling pathways. Notably, hetrombopag effectively up-regulated G1 -phase-related proteins, including p-RB, Cyclin D1 and CDK4/6, normalized progression of the cell cycle, and prevented apoptosis by modulating BCL-XL/BAK expression in 32D-MPL cells. Moreover, hetrombopag and TPO acted additively in stimulating TPOR-dependent signalling, promoting cell viability, and preventing apoptosis. Orally administered hetrombopag specifically promoted the viability and growth of 32D-MPL cells in hollow fibres implanted into nude mice with much higher potency than that of the well-known TPOR agonist, eltrombopag, in association with activation of TPOR-dependent signal transduction in vivo. Taken together, our findings indicate that, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small-molecule TPOR agonist for patients with thrombocytopenia.

Combined inhibition of EGFR and c-ABL suppresses the growth of fulvestrant-resistant breast cancer cells through miR-375-autophagy axis.

Fulvestrant is the FDA-approved "pure anti-estrogen" agent for malignant breast cancer therapy. But endocrine resistance causes drug failure. A new approach is desired for fulvestrant-resistant breast cancer (FRBC) therapy. This study aims to find an effective approach to inhibit FRBC for patients with advanced breast cancer. MTT assay was first performed to detect the effect of inhibitors of c-ABL (imatinib) and EGFR (lapatinib) on FRBC cells. Microarray analysis was carried out to identify microRNA which is significantly changed between parental and FRBC cells. The related mechanisms were analyzed by qRT-PCR, MTT, AO staining and western blotting. Dual treatment significantly inhibited cell growth of FRBC and upregulated microRNA-375 (miR-375). Overexpression of miR-375 inhibited growth of FRBC cells, reduced autophagy, and decreased expression of ATG7 and LC3-II. Dual treatment elevated expression of miR-375 more than any single one of these two inhibitors. Overexpression of miR-375 increased cell growth inhibition induced by dual treatment, and the effect was attenuated when miR-375 was inhibited. In conclusion, we identified that combined inhibition of EGFR and c-ABL can suppress the growth of FRBC cells and elucidated a mechanism within FRBC cells involving regulation of miR-375 and autophagy. Dual treatment may be useful for inhibiting fulvestrant-resistant breast cancer.