Antineuroblastoma Activity Evaluation and Mechanism of Novel PD-L1 Small Molecule Inhibitors through Immune and Non-Immune Pathways.

Neuroblastoma (NB) is a pediatric solid tumor originating in the sympathetic nervous system, primarily affecting children under 10 years old. Metastatic, high-risk NB often exhibits elevated PD-L1 expression, which is linked to poor prognosis. In this study, we screened 41 newly synthesized biphenyl small molecules for activity against PD-L1 highly expressed NB cell lines.

Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction.

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure-activity relationship of the degraders, we identified two highly active compounds, 9i and 9j.

The role of tumor-associated macrophages in lung cancer: From mechanism to small molecule therapy.

Tumor-associated macrophages (TAMs) are the main component of tumor-infiltrating immune cells in the lung tumor microenvironment. TAMs recruited to the lung cancer can create a suitable microenvironment for the growth and metastasis of lung cancer by secreting tumor promoting factors and interfering with the function of T cells. Currently, numerous studies have reported that small molecular drugs affect lung cancer progression by selectively targeting TAMs.

Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer.

Unlabelled: This research found that the clinical outcomes (PFS, ORR, OS) of the non-platinum-based doublet regimen (docetaxel capecitabine combination) were similar to those of the platinum-based (oxaliplatin capecitabine combination) when used as first line therapy for MGC patients.

Background: Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes of the docetaxel capecitabine combination and the oxaliplatin capecitabine combination as first-line therapy in MGC patients.

Design, synthesis and anti-tumor activity of novel benzothiophenonaphthalimide derivatives targeting mitochondrial DNA (mtDNA) G-quadruplex.

A series of new naphthalimide derivatives, benzothiophenonaphthalimides (7a-7g, 8a-8g), were designed and synthesized, of which compounds 8a-8g are hydrochloride salts of corresponding compounds 7a-7g. All compounds presented different anti-tumor activities for tumor cells tested by the CCK-8 assay. In particular, compound 7c displayed the strongest anti-tumor activity with an IC value of 0.

The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target.

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance.

A 1,10-phenanthroline derivative selectively targeting telomeric G-quadruplex induces cytoprotective autophagy, causing apoptosis of gastric cancer cells.

Aims: This study aimed to evaluate the ability of compound 13d to induce autophagy and to promote apoptosis of tumor cells and its interaction mechanism.

Materials And Methods: Using CCK-8 assay, transwell assay, fluorescence resonance energy transfer melting analysis (FRET), transmission electron microscopy, flow cytometry assay, immunofluorescence assay, Western blot analysis, and wound healing assay.

Key Findings: The results indicated that compound 13d could induce autophagy and apoptosis of gastric cancer cells.

Achieving and control of partial denitrification in anoxic-oxic process of real municipal wastewater treatment plant.

Partial denitrification is an alternative process to provide stable nitrite for anammox. In this study, based on full-scale and lab-scale experiments, achieving and control of partial denitrification and the microbial mechanism were studied for 17 months in municipal wastewater treatment plant (MWWTP). Using glucose (GLC) as sole carbon source, partial denitrification was successfully achieved with nitrite accumulation percentage (NAP) higher than 90%; whereas, using sodium acetate (NaAc) as sole carbon source, nitrite accumulation was effectively controlled with economic and efficient carbon usage.

Discovery of Pyrrole-imidazole Polyamides as PD-L1 Expression Inhibitors and Their Anticancer Activity via Immune and Nonimmune Pathways.

In recent years, PD-1 immune checkpoint inhibitors based on monoclonal antibodies have revolutionized cancer therapy, but there still exist unresolved issues, such as the high cost, the relatively low response rates, and so on, compared with small-molecule drugs. Herein a type of pyrrole-imidazole (Py-Im) polyamide as a small-molecule DNA binder was designed and synthesized, which could competitively bind to the same double-stranded DNA stretch in the PD-L1 promoter region as the STAT3 binding site and thus downregulate PD-L1 expression. It was demonstrated that the Py-Im polyamides directly caused apoptosis in tumor cells and retarded cell migration in the absence of T cells through inhibiting the Akt/caspase-3 pathway.

Estimated Number of Acupuncture Practitioners in Mainland China in 2018: Multiperspectives.

Acupuncture and Oriental medicine are widespread, practiced in >183 countries and regions. As such, it has played an important role in the world health care system. However, there are no official statistics available on the number of acupuncture practitioners in China.

Design, synthesis and anti-cancer activity of pyrrole-imidazole polyamides through target-downregulation of c-kit gene expression.

Pyrrole-imidazole polyamide (PIP) can specifically bind in the B-DNA minor groove that has been used in several biological applications, such as anti-cancer activity, gene expression and translation control, and visualization of complex genomic areas. c-kit is a family member of the Tyrosine Kinase (RTK) type III receptor and plays a vital role in tumor growth, proliferation, differentiation, and cell apoptosis; however, its mutations and overexpression induce tumor dysfunction. Here, we designed and synthesized five matched PIPs that can recognize and bind to the DNA sequence in the oncogene c-kit promoter region, and evaluated their anti-cancer activity.

Anti-cancer activity of benzoxazinone derivatives via targeting c-Myc G-quadruplex structure.

Aims: This study aimed to analyze the impact of four synthesized benzoxazinone derivatives as screening drugs on c-Myc-overexpressed cancer cells (H7402, HeLa, SK-RC-42, SGC7901, and A549) and to explore their interaction mechanisms in detail.

Materials And Methods: Using morphological analysis, real-time cytotoxicity analysis, wound healing assay, reverse transcription PCR, electrophoretic mobility shift assay, and circular dichroism spectroscopy techniques.

Key Findings: Results revealed that these four compounds could inhibit proliferation of SK-RC-42, SGC7901, and A549 cells in five cancer cell lines to varying degrees and significantly hinder migration.

Design, synthesis and biological evaluation of 2-methyl-(1,1'-biphenyl)-pyrimidine conjugates.

Small molecule inhibitors of biphenyl structure as core backbone have shown a significant effect on PD-1/PD-L1 axis, and 2-amino-pyrimidine structure is a promising privileged scaffold in medicinal chemistry and drug discovery. We designed by combination principles and synthesized 27 novel compounds with N-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrimidin-2-amine as a basic skeletal structure, and their anti-cancer activity was evaluated. Among compounds, 15a-d and 16b displayed strong anti-cancer effects on 9 tested cancer cell lines, in particular, the 16b did the highest inhibitive activity, but against HepG2 cells, and possessed the lowest IC value of 2.

Exosomes as drug carriers for cancer therapy and challenges regarding exosome uptake.

With the development of biomedicine, exosomes are rapidly developing as a new therapy for tumors. As biological carriers, exosomes possess biological activity and can transport their contents between cells. The contents are natural or artificially loaded with biomolecules or chemical drugs.

Design, synthesis of 4,5-diazafluorene derivatives and their anticancer activity via targeting telomeric DNA G-quadruplex.

In our work, 19 novel 4,5-diazafluorene derivatives (11a-d, 12a-d, 13a-d, 14a-c, 15c, 16a-c) bearing a 1,3-disubstituted pyrazol/thioxothiazolidinone or thioxothiazolidinone-oxadiazole moieties were designed, synthesized, preliminarily explored for their antitumor activities and in vitro mechanism. All compounds showed different values of antiproliferative activity against A549, AGS, HepG2 and MCF-7 cell lines through CCK-8. Especially, the compound 14c exhibited the strongest activity and best selectivity against A549 cells with an IC 1.

Knockdown of TGF-β1 expression in human umbilical cord mesenchymal stem cells reverts their exosome-mediated EMT promoting effect on lung cancer cells.

The effect of mesenchymal stem cells (MSCs) on lung cancer cells is controversial, and the underlying mechanisms remain unclear, which harms the utilization of MSCs in tumor therapy. In this study, we found that human umbilical cord MSC-conditioned medium (MSC-CM) promotes EMT, invasion, and migration, yet inhibits proliferation and promotes apoptosis of lung cancer cells. The EMT-promoting effect of MSCs was mediated by exosomes derived from MSCs (MSC-exo) and eliminated by inhibiting exosome release.

Synthesis and the interaction of 2-(1H-pyrazol-4-yl)-1H-imidazo[4,5-f][1,10]phenanthrolines with telomeric DNA as lung cancer inhibitors.

A novel series of 2-(1H-pyrazol-4-yl)-1H-imidazo[4,5-f][1,10]phenanthrolines were designed, synthesized and evaluated for their antitumor activity against lung adenocarcinoma by CCK-8 assay, electrophoretic mobility shift assay (EMSA), UV-melting study, wound healing assay and docking study. These compounds showed good inhibitory activities against lung adenocarcinoma. Especially compound 12c exhibited potential antiproliferative activity against A549 cell line with the half maximal inhibitory concentration (IC) value of 1.

Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1β-Primed Mesenchymal Stem Cells Against Sepsis.

Improving the immunomodulatory efficacy of mesenchymal stem cells (MSCs) through pretreatment with pro-inflammatory cytokines is an evolving field of investigation. However, the underlying mechanisms have not been fully clarified. Here, we pretreated human umbilical cord-derived MSCs with interleukin-1β (IL-1β) and evaluated their therapeutic effects in a cecal ligation and puncture-induced sepsis model.

A Comprehensive Review on the Biological and Pharmacological Activities of Rhodanine Based Compounds for Research and Development of Drugs.

At present, diseases resulting from various reasons have been causing deadly fears to humans and previously incogitable losses to health. Meanwhile, the patient compliance has been weakening because of drug resistance and serious drug adverse effects. There is therefore an urgent need for the development of novel structural agents.

Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs.

Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a remarkable elevation in various proinflammatory cytokines, including IL-1, IL-6, CXCL15 (human IL-8 homolog), IL-10, TNF-α, and monocyte chemotactic protein 1 (chemokine ligand 2 (CCL2)); decrease in TGF-β1 and TGFβRI receptor in the lungs; and spillover of IL-6 and CXCL15 into the bronchoalveolar lavage fluids.

Mesenchymal stem cells-regulated Treg cells suppress colitis-associated colorectal cancer.

Introduction: Previous studies have produced controversial results regarding whether mesenchymal stem cells (MSCs) promote or inhibit tumor development. Given the dual role of MSCs in inflammation and cancer, in this study the colitis-associated colorectal cancer (CAC) model was used to examine whether umbilical cord tissue-derived MSCs could prevent neoplasm by inhibiting chronic inflammation.

Methods: MSCs were obtained and identified using flow cytometry.

LRP5 polymorphism-A potential predictor of the clinical outcome in advanced gastric cancer patients treated with EOF regimen.

Purpose: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. The present study analyzed the polymorphism of lipoprotein-related receptor 5 (LRP5) (gene with key functions in Wnt signaling) and its impact on the response to chemotherapy and survival of patients with advanced gastric cancer (AGC).

Methods: A total of 107 consecutive patients with AGC treated with first-line chemotherapy of EOF regimen were enrolled in the present retrospective study.

Mesenchymal stem cells ameliorate Th1-induced pre-eclampsia-like symptoms in mice via the suppression of TNF-α expression.

Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua.

The toll-like receptor 3 ligand, poly(I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143.

Mesenchymal stem cells (MSCs) are attractive candidates for clinical therapeutic applications. Recent studies indicate MSCs express active Toll-like receptors (TLRs), but their effect on MSCs and the underlying mechanisms remain unclear. In this study, we found that, after treating human umbilical cord MSCs with various TLR ligands, only TLR3 ligand, poly(I:C), could significantly increase the expression of cyclooxygenase-2 (COX-2).