Lianhua Qingwen exerts anti-liver cancer effects and synergistic efficacy with sorafenib through PI3K/AKT pathway: Integrating network pharmacology, molecular docking, and experimental validation.

Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs that sensitize liver cancer patients to sorafenib is of great importance. Lianhua Qingwen (LHQW), a sort of Traditional Chinese Medicine (TCM) approved by the Chinese Food and Drug Administration (CFDA), is reported to exert synergistic effects with oseltamivir against Influenza virus. However, whether LHQW could exhibit anti-liver cancer effects and enhance the efficacy of sorafenib against liver cancer have not been reported. In the present study, the potential anti-liver cancer effects of LHQW and its synergistic effects with sorafenib were investigated via applying network pharmacology, molecular docking, and in vitro experiments. An "ingredient-compound- target-liver cancer" network was constructed which included 12 ingredients, 164 compounds, and 402 targets. AKT1 was identified as the most hub gene and the PI3K/AKT pathway was revealed as the most enriched pathway. Subsequently, the molecular docking results showed that kaempferol, luteolin, and quercetin were screened as the top 3 compounds which showed the tightest binding to AKT1. Further, the in vitro experiments verified that LHQW significantly inhibited liver cancer cell proliferation and induced apoptosis. Western blot assays confirmed that LHQW could attenuate the PI3K/AKT pathway. Interestingly, LHQW showed a synergistic effect with sorafenib against liver cancer via reducing cell viability, inducing apoptosis, and down- regulating PI3K/AKT pathway. This study broadens the potential application of LHQW and provides insights for liver cancer treatment.

Synergist for antitumor therapy: Astragalus polysaccharides acting on immune microenvironment.

Various new treatments are emerging constantly in anti-tumor therapies, including chemotherapy, immunotherapy, and targeted therapy. However, the efficacy is still not satisfactory. Astragalus polysaccharide is an important bioactive component derived from the dry root of Radix astragali. Studies found that astragalus polysaccharides have gained great significance in increasing the sensitivity of anti-tumor treatment, reducing the side effects of anti-tumor treatment, reversing the drug resistance of anti-tumor drugs, etc. In this review, we focused on the role of astragalus polysaccharides in tumor immune microenvironment. We reviewed the immunomodulatory effect of astragalus polysaccharides on macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes. We found that astragalus polysaccharides can promote the activities of macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes and induce the expression of a variety of cytokines and chemokines. Furthermore, we summarized the clinical applications of astragalus polysaccharides in patients with digestive tract tumors. We summarized the effective mechanism of astragalus polysaccharides on digestive tract tumors, including apoptosis induction, proliferation inhibition, immunoactivity regulation, enhancement of the anticancer effect and chemosensitivity. Therefore, in view of the multiple functions of astragalus polysaccharides in tumor immune microenvironment and its clinical efficacy, the combination of astragalus polysaccharides with antitumor therapy such as immunotherapy may provide new sparks to the bottleneck of current treatment methods.

Toll-like receptor 4: A potential therapeutic target for multiple human diseases.

The immune response plays a pivotal role in the pathogenesis of diseases. Toll-like receptor 4 (TLR4), as an intrinsic immune receptor, exhibits widespread in vivo expression and its dysregulation significantly contributes to the onset of various diseases, encompassing cardiovascular disorders, neoplastic conditions, and inflammatory ailments. This comprehensive review centers on elucidating the architectural and distributive characteristics of TLR4, its conventional signaling pathways, and its mode of action in diverse disease contexts. Ultimately, this review aims to propose novel avenues and therapeutic targets for clinical intervention.

Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis.

Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.

A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma.

Background: Hepatocellular carcinoma is the third most deadly malignant tumor in the world with a poor prognosis. Although immunotherapy represents a promising therapeutic approach for HCC, the overall response rate of HCC patients to immunotherapy is less than 30%. Therefore, it is of great significance to explore prognostic factors and investigate the associated tumor immune microenvironment features. Methods: By analyzing RNA-seq data of the TCGA-LIHC cohort, the set of cuproptosis related genes was extracted via correlation analysis as a generalization feature. Then, a random forest cox prognostic model was constructed and the cuproptosis random forest cox score was built by random forest feature filtering and univariate multivariate cox regression analysis. Subsequently, the prognosis prediction of CRFCS was evaluated via analyzing data of independent cohorts from GEO and ICGC by using KM and ROC methods. Moreover, mutation characterization, immune cell infiltration, immune evasion, and drug sensitivity of CRFCS in HCC were assessed. Results: A cuproptosis random forest cox score was built based on a generalization feature of four cuproptosis related genes. Patients in the high CRFCS group exhibited a lower overall survival. Univariate multivariate Cox regression analysis validated CRFCS as an independent prognostic indicator. ROC analysis revealed that CRFCS was a good predictor of HCC (AUC =0.82). Mutation analysis manifested that microsatellite instability (MSI) was significantly increased in the high CRFCS group. Meanwhile, tumor microenvironment analysis showed that the high CRFCS group displayed much more immune cell infiltration compared with the low CRFCS group. The immune escape assessment analysis demonstrated that the high CRFCS group displayed a decreased TIDE score indicating a lower immune escape probability in the high CRFCS group compared with the low CRFCS group. Interestingly, immune checkpoints were highly expressed in the high CRFCS group. Drug sensitivity analysis revealed that HCC patients from the high CRFCS group had a lower IC50 of sorafenib than that from the low CRFCS group. Conclusions: In this study, we constructed a cuproptosis random forest cox score (CRFCS) model. CRFCS was revealed to be a potential independent prognostic indicator of HCC and high CRFCS samples showed a poor prognosis. Interestingly, CRFCS were correlated with TME characteristics as well as clinical treatment efficacy. Importantly, compared with the low CRFCS group, the high CRFCS group may benefit from immunotherapy and sorafenib treatment.

Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma in vitro and in vivo.

Nasopharyngeal carcinoma (NPC) is a malignant tumor that mainly occurs in East and Southeast Asia. Although patients benefit from the main NPC treatments (e.g., radiotherapy and concurrent chemotherapy), persistent and recurrent diseases still occur in some NPC patients. Therefore, investigating the pathogenesis of NPC is of great clinical significance. In the present study, replication factor c subunit 4 (RFC4) is a key potential target involved in NPC progression via bioinformatics analysis. Furthermore, the expression and mechanism of RFC4 in NPC were investigated in vitro and in vivo. Our results revealed that RFC4 was more elevated in NPC tumor tissues than in normal tissues. RFC4 knockdown induced G2/M cell cycle arrest and inhibited NPC cell proliferation in vitro and in vivo. Interestingly, HOXA10 was confirmed as a downstream target of RFC4, and the overexpression of HOXA10 attenuated the silencing of RFC4-induced cell proliferation, colony formation inhibition, and cell cycle arrest. For the first time, this study reveals that RFC4 is required for NPC cell proliferation and may play a pivotal role in NPC tumorigenesis.

Recruitment Maneuver to Reduce Postoperative Pulmonary Complications after Laparoscopic Abdominal Surgery: A Systematic Review and Meta-Analysis.

Background: Lung-protective ventilation strategies are recommended for patients undergoing mechanical ventilation. However, there are currently no guidelines to follow regarding recruitment maneuvers (RMs). We attempted to identify the effects of RMs on patients undergoing laparoscopic abdominal surgery. Methods: We searched for randomized controlled trials (RCTs) in PubMed, the Cochrane Library databases, Embase, Web of Science and the ClinicalTrials.gov registry for trials published up to December 2021. The primary outcome was postoperative pulmonary complications (PPCs). The secondary outcomes consisted of the static lung compliance, driving pressure (DP), intraoperative oxygenation index (OI), OI in the post-anesthesia care unit (PACU), mean arterial pressure (MAP) and heart rate (HR). Seventeen RCTs with a total of 3480 patients were examined. Results: Patients who received RMs showed a considerable reduction in PPCs (risk ratio (RR) = 0.70; 95% confidence interval (CI): 0.62 to 0.79; p < 0.01), lower DP (weighted mean difference (WMD) = −3.96; 95% CI: −5.97 to −1.95; p < 0.01), elevated static lung compliance (WMD = 10.42; 95% CI: 6.13 to 14.71; p < 0.01) and improved OI (intraoperative: WMD = 53.54; 95% CI: 21.77 to 85.31; p < 0.01; PACU: WMD = 59.40; 95% CI: 39.10 to 79.69; p < 0.01) without substantial changes in MAP (WMD = −0.16; 95% CI −1.35 to 1.03; p > 0.05) and HR (WMD = −1.10; 95% CI: −2.29 to 0.10; p > 0.05). Conclusions: Recruitment maneuvers reduce postoperative pulmonary complications and improve respiratory mechanics and oxygenation in patients undergoing laparoscopic abdominal surgery. More data are needed to elucidate the effect of recruitment maneuver on the circulatory system.

Integrated analysis identified NPNT as a potential key regulator in tumor metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the lethal malignancies worldwide. Tumor metastasis is the main cause of HCC related death. Although progress has been made in the mechanism study of HCC in the past decades, the underlying mechanism of HCC metastasis has not been fully illustrated. In the present study, bioinformatic analysis including weighted gene co-expression network analysis (WGCNA), differentially expressed gene analysis, and gene enrichment analysis were applied to discover genes correlated with HCC metastasis. Immunohistochemistry (IHC) assays were applied to detect the expression of NPNT in HCC samples. Cell transfection, wound healing, matrigel transwell assays, and western blot assays were utilized to evaluate the effects of NPNT on cell migration and invasion and signaling pathway variation. We found that NPNT was up-regulated in HCC tumor tissues compared with normal tissues. Especially, NPNT was highly expressed in metastatic tumor compared with non-metastatic HCC tumors. Down-regulation of NPNT via siRNA transfection inhibited cell migration, invasion, and FAK/PI3K/AKT signaling pathway in HCC. Our results demonstrate that NPNT is a potential key regulator in HCC metastasis.

Design, Synthesis, Molecular Docking, and Tumor Resistance Reversal Activity Evaluation of Matrine Derivative with Thiophene Structure.

Nasopharyngeal carcinoma (NPC) frequently occurs in Southern China. The main treatments of NPC are chemotherapy and radiotherapy. However, chemo-resistance arises as a big obstacle in treating NPC. Therefore, there is a great need to develop new compounds that could reverse tumor drug resistance. In this study, eight matrine derivatives containing thiophene group were designed and synthesized. Structures of these 8 compounds were characterized by 1H-NMR, 13C-NMR, and high-resolution mass spectrometer (HRMS). The cytotoxicity and preliminary synergistic effects of these 8 compounds were detected against nasopharyngeal carcinoma (NPC) cells and cisplatin-resistant NPC cells (CNE2/CDDP), respectively. Furthermore, the in vivo and in vitro tumor resistance reversal effects of compound 3f were evaluated. Moreover, docking studies were performed in Bclw (2Y6W). The results displayed that compound 3f showed synergistic inhibitory effects with cisplatin against CNE2/CDDP cells proliferation via apoptosis induction. Docking results revealed that compound 3f may exert its effects via inhibiting anti-apoptosis protein Bcl-w.

Chemotherapy and chemo-resistance in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) and occurs frequently in the south of China and Southeast Asian countries. Concurrent chemo-radiotherapy is one of the main treatments for NPC. Although, the combined treatment of chemo-radiotherapy produces a satisfying survival rate, the chemo-resistance arises as a big obstacle in curing recurrent NPC patients. The acquirement of chemo-resistance is usually along with a poor prognosis. So far, the mechanism of chemo-resistance in NPC has not been fully elucidated and there have not been a comprehensive review on this issue. Thus, it is of great significance to summarize the mechanisms involved in NPC chemo-resistance. In this review, the importance and limitations of chemotherapy and the mechanisms of chemo-resistances in NPC were discussed.

Synthesis of a series of benzothiazole amide derivatives and their biological evaluation as potent hemostatic agents.

A series of benzothiazole amide derivatives were synthesized through a facile and efficient method via a nucleophilic acyl substitution reaction between 2-aminobenzothiazole and various cinnamic acid compounds. The obtained products exhibited good thermal stabilities. All compounds were evaluated for their in vitro hemostatic activities using the commercially available standard drug etamsylate as a positive control. The results showed that compound Q2 had a significant partial coagulation activity, reduced capillary permeability at 5, 10 and 50 µmol L-1, activated thrombin activity, and a more potent platelet aggregation activity than the positive control group (etamsylate, up to 1283.9 times in the nanomole range). A molecular modeling study revealed that compound Q2 was a competitive thrombin activator. Therefore, Q2 may be a potential lead for further biological screening and for the generation of drug molecules. Moreover, the structure-activity relationship of the prepared compounds is also discussed herein.

Synthesis and biological evaluation of a new series of cinnamic acid amide derivatives as potent haemostatic agents containing a 2-aminothiazole substructure.

Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC50=1.87µmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC50=46.22µmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study.

Matrine derivative YF-18 inhibits lung cancer cell proliferation and migration through down-regulating Skp2.

Lung cancer is the leading cause of cancer related death which needs novel drugs to improve patient outcomes. In this study, we examined the ability of YF-18, a novel matrine derivative to inhibit the growth and migration of lung cancer cells. By cell cycle analysis, wound healing and transwell assays, we found that YF-18 induced G2/M cell cycle arrest and inhibited migration of lung cancer cells in a dose-dependent manner. Further results indicated that YF-18 inhibited cell proliferation and migration through down-regulating Skp2 and up-regulating its substrates, p27 and E-cadherin. Moreover, YF-18 inhibited A549-luciferase cell xenograft tumor growth in a dose-dependent manner. The findings indicate that YF-18 bears therapeutic potentials for lung cancer.

Synthesis and biological evaluation of matrine derivatives containing benzo-α-pyrone structure as potent anti-lung cancer agents.

Matrine, an active component of root extracts from Sophora flavescens Ait, is the main chemical ingredient of Fufang Kushen injection which was approved by Chinese FDA (CFDA) in 1995 as an anticancer drug to treat non-small cell lung cancer and liver cancer in combination with other anticancer drugs. Owning to its druggable potential, matrine is considered as an ideal lead compound for modification. We delineate herein the synthesis and anticancer effects of 17 matrine derivatives bearing benzo-α-pyrone structures. The results of cell viability assays indicated that most of the target compounds showed improved anticancer effects. Further studies showed that compound 5i could potently inhibit lung cancer cell proliferation in vitro and in vivo with no obvious side effects. Moreover, compound 5i could induce G1 cell cycle arrest and autophagy in lung cancer cells through up-regulating P27, down-regulating CDK4 and cyclinD1 and attenuating PI3K/Akt/mTOR pathway. Suppression of autophagy attenuated 5i induced proliferation inhibition. Collectively, our results infer that matrine derivative 5i bears therapeutic potentials for lung cancer.

Synthesis and biological evaluation of matrine derivatives as anti-hepatocellular cancer agents.

We delineate herein the synthesis and anti-cancer effects of 15 matrine derivatives. The in vitro growth inhibitory assays showed that most of the prepared compounds exhibited improved anti-proliferative activities towards cancer cells with IC50 17-109 times lower than that of matrine. Compounds CH6 showed the most potent anti-proliferative activities in the four tested cancer cell lines. Moreover, compound CH6 could induce G1 cell cycle arrest and inhibit cell migration in human hepatocellular cancer cell lines Bel-7402 and HepG2 through up-regulation of P21, P27 and E-cadherin and down-regulation of N-cadherin.

Study of the interaction between sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine and bovine serum albumin by fluorescence spectroscopy.

Three sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine (CCSCP) were synthesized and their structures were determined by (1)H and (13)C NMR, LC-MS and IR. The binding properties between CCSCPs and bovine serum albumin (BSA) were studied using fluorescence spectroscopy in combination with UV-vis absorbance spectroscopy. The results indicate that the fluorescence quenching mechanisms between BSA and CCSCPs were static quenching at low concentrations of CCSCPs or combined quenching (static and dynamic) at higher CCSCP concentrations of 298, 303 and 308 K. The binding constants, binding sites and corresponding thermodynamic parameters (ΔH, ΔS, ΔG) were calculated at different temperatures. All ΔG values were negative, which revealed that the binding processes were spontaneous. Although all CCSCPs had negative ΔH and positive ΔS, the contributions of ΔH and ΔS to ΔG values were different. When the 4'-substituent was fluorine or chlorine, van der Waals interactions and hydrogen bonds were the main interaction forces. However, when the halogen was bromine, ionic interaction and proton transfer controlled the overall energetics. The binding distances between CCSCPs and BSA were determined using the Förster non-radiation energy transfer theory and the effects of CCSCPs on the conformation of BSA were analyzed by synchronous fluorescence spectroscopy.