CXCL12/CXCR4 axis in the microenvironment of solid tumors: A critical mediator of metastasis.

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.

https://www.pnas.org/content/pnas/118/13/e2015433118.full.pdf

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment.

Gout represents a metabolic ailment resulting from the accumulation of monosodium urate crystals within joints, causing both inflammation and, harm to tissues. The primary contributor to gout’s emergence is an elevated presence of serum urate, which is under the regulation of kidney and, gut urate transporters. Mitigating this risk factor is crucial for averting gout’s onset. Several treatments rooted in TCM and related active compounds have demonstrated efficacy in managing gout, skillfully regulating serum uric acid (UA) levels and curbing inflammation’s progression. This analysis compiles key foundational research concerning the molecular signaling pathways and UA transporters linked to gout, under the regulation of TCM. The focus includes individual botanical drug, active compounds, and TCM formulations, which have been consolidated and examined in this overview. The primary keywords chosen were “gout, hyperuricemia, gouty arthritis, traditional Chinese medicine, Chinese botanical drug, medicinal botanical drug, and natural plant”. Various relevant literature published within the last 5 years were gathered from electronic databases, including PubMed, Web of Science, CNKI, and others. The findings revealed that TCM has the capacity to modulate various signaling pathways, including MAPK, NF-κB, PI3K/Akt, NLRP3 and JAK/STAT. Additionally, it impacts UA transporters like URAT1, GLUT9, ABCG2, as well as OATs and OCTs, thereby contributing to gout treatment. TCM helps maintain a balanced inflammatory interaction and facilitates UA excretion. This study enhances our understanding of TCM’s anti-gout mechanisms and introduces novel perspectives for establishing the clinical significance and future prospects of TCM-based gout treatment.

TCM and related active compounds in the treatment of gout: the regulation of signaling pathway and urate transporter

Triterpenoids derived from natural products can exert antihyperuricemic effects. Here, we investigated the antihyperuricemic activity and mechanism of quinoa bran saponins (QBSs) in hyperuricemic mouse and cell models. The QBS4 fraction, with the highest saponin content, was used. Fourier-transform infrared, high-performance liquid chromatography, and ultrahigh-performance liquid chromatography-mass spectrometry identified 11 individual saponins in QBS4, of which the main components were hederagenin and oleanolic acid. The QBS4 effects on hyperuricemic mice (induced by adenine and potassium oxonate) were then studied. QBS4 reduced the levels of uric acid (UA), serum urea nitrogen, creatinine, and lipids in mice with hyperuricemia (HUA) and decreased renal inflammation and renal damage. Molecular analysis revealed that QBS4 may alleviate HUA by regulating the expression of key genes involved in the transport of UA and by inhibiting the activation of the PI3K/AKT/NFκB inflammatory signaling pathway. In conclusion, QBS4 has promise for using as a natural dietary supplement to treat and prevent HUA.

Quinoa (Chenopodium quinoa Willd) Bran Saponins Alleviate Hyperuricemia and Inhibit Renal Injury by Regulating the PI3K/AKT/NFκB Signaling Pathway and Uric Acid Transport.

Amide-sulfamide modulators as effective anti-tumor metastatic agents targeting CXCR4/CXCL12 axis.

Development of CXCR4 modulators based on the lead compound RB-108.

Synthesis and bioactivity evaluation of novel nuciferine derivatives with antihyperuricemia and nephroprotective effects.

To explore potential indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, we designed a series of compounds incorporating urea and 1,2,3-triazole structures. IDO1 enzymatic activity experiments with the synthesized compounds were used to verify their molecular-level activity; for instance, the half maximal inhibitory concentration value of compound 3c was 0.07 μM. Our research has yielded a series of novel IDO1 inhibitors which may be beneficial in the development of drugs targeting IDO1 for cancer treatment.

Novel Compounds with Promising IDO1 Inhibitory Activity As New Cancer Drug Candidates: Derivatives Of N, N'-diphenylurea Linked With 1,2,3-triazole.

Synthesis and Bioactivity Evaluation of Novel Nuciferine Derivatives with Antihyperuricemia and Nephroprotective Effects

Abstract Based on 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione as a raw material, a series of novel pomalidomide linked with diphenylcarbamide derivatives were synthesized through several step reactions of substitution, click reaction, and addition reaction. The structures of these compounds were confirmed by 1H NMR, 13C NMR, and MS. We discovered that some of the compounds are capable of suppressing indoleamine pyrrole-2,3-dioxygenase-1 activities in in vitro experiments, in which the inhibitory activity of 5b reached the level of benefits. Graphical abstract

Design, synthesis, and biological activity of novel pomalidomide linked with diphenylcarbamide derivatives

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