Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

A four-component combination derived from Huang-Qin Decoction significantly enhances anticancer activity of irinotecan.

Huang-Qin Decoction (HQD) is a classic prescription for diarrhea in Chinese medicine treatment. Recent studies have demonstrated that HQD and its modified formulation PHY906 could ameliorate irinotecan (CPT-11) induced gastrointestinal (GI) toxicity and enhance its anticancer therapeutic efficacy. Nevertheless, which constituents in HQD are effective is still unclear so far. The study aims to screen out the key bioactive components combination from HQD that could enhance the anticancer effect of CPT-11. First, the potential bioactive constituents were obtained through system pharmacology strategy. Then the bioactivity of each constituent was investigated synthetically from the aspects of NCM460 cell migration, TNF-α release of THP-1-derived macrophage and MTT assay in HCT116 cell. The contribution of each constituent in HQD was evaluated using the bioactive index Ei, which taken the content and bioactivity into comprehensive consideration. And then, the most contributing constituents were selected out to form a key-component combination. At last, the bioefficacy of the key-component combination was validated in vitro and in vivo. As a result, a key-component combination (HB4) consisting of four compounds baicalin, baicalein, glycyrrhizic acid and wogonin was screened out. In vitro assessment indicated that HB4 could enhance the effect of CPT-11 on inhibiting cell proliferation and inducing apoptosis in HCT116. Furthermore, the in vivo study confirmed that HB4 and HQD have similar pharmacological activity and could both enhance the antitumor effect of CPT-11 in HCT116 xenograft model. Meanwhile, HB4 could also reduce the CPT-11 induced GI toxicity.

Network Pharmacology and Bioactive Equivalence Assessment Integrated Strategy Driven Q-markers Discovery for Da-Cheng-Qi Decoction to Attenuate Intestinal Obstruction.

BACKGROUND: Intestinal obstruction (IO) is a kind of acute abdomen with high morbidity and mortality. Patients suffer from poor quality of life and tremendous financial pressure. Da-Cheng-Qi decoction (DCQD), a classical purgation prescription, has clinically been proven to be an effective treatment for IO. PURPOSE: Network pharmacology integrated with bioactive equivalence assessment was used to discover the quality marker (Q-marker) of DCQD against IO. METHODS: As there is hardly any targets recorded in database, thus the collection of IO targets was conducted by searching those of alternative diseases which have similar pathological symptoms with IO. In order to improve the reliability of the obtained targets, IO metabolomics data was introduced. Active compounds combination (ACC) was focused as potential Q-markers via component-target network analysis and function query from the identified components corresponding to the common targets. Bioequivalence between ACC and DCQD was assessed from the aspects of intestine motility (somatostatin secretion), inflammation (IL-6 secretion) and injury (wound healing assay) in vitro and was further validated in ileus rat model. PPI network analysis of core targets followed by gene pedigree classification and experimental validation confirmed the potential intervention pathway. RESULTS: A combination of 11 ingredients, including emodin, physcion, aloe-emodin, rhein, chrysophanol, gallic acid, magnolol, honokiol, naringenin, tangeretin, and nobiletin was finally confirmed bioequivalence with DQCD to some extent and could serve as Q-markers for DCQD to attenuate IO. PI3K/AKT was verified as a possible affected pathway that DCQD exerted the effectiveness against IO. CONCLUSION: For the disease with few recorded targets, searching those of alternative diseases which have similar pathological symptoms could be a feasible and effective approach. The proposed network pharmacology integrated bioactive equivalence evaluation paradigm is efficient to discover Q-marker of herbal formulae.

Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity.

Renal injury is the main adverse reaction of cisplatin, and many traditional Chinese medicines (TCMs) were proven active against renal toxicity. Here, an integrated metabolomics and network pharmacology strategy was proposed to discover active TCM ingredients for the alleviation of cisplatin nephrotoxicity. First, by interrogating the Human Metabolome Database (HMDB) we collected targets connected to 149 cisplatin nephrotoxicity-related metabolites. Second, targets of kidney damage were obtained from the Therapeutic Target Database (TTD), PharmGKB, Online Mendelian Inheritance in Man (OMIM), and Genetic Association Database (GAD). Common targets of both dysregulated metabolites and kidney damage were then used for TCM active ingredient screening by applying the network pharmacology approach. Eventually, 22 ingredients passed screening criteria, and their antinephrotoxicity activity was assessed in human kidney tubular epithelial (HK2) cells. As a result, 14 ingredients were found to be effective, in which kaempferol showed relatively better activity. Further metabolomics analysis revealed that kaempferol exerted an antinephrotoxicity effect in rats by regulating amino acid, pyrimidine, and purine metabolism as well as lipid metabolism. Collectively, this proposed integrated strategy would promote the transformation of metabolomics research in the field of drug pair discovery for the purpose of reduced toxicity and increased efficiency.

Prostate cancer tends to metastasize in the bone-mimicking microenvironment via activating NF-κB signaling.

Prostate cancer preferentially metastasizes to the bone. However, the underlying molecular mechanisms are still unclear. To explore the effects of a bone-mimicking microenvironment on PC3 prostate cancer cell growth and metastasis, we used osteoblast differentiation medium (ODM; minimal essential medium alpha supplemented with L-ascorbic acid) to mimic the bone microenvironment. PC3 cells grown in ODM underwent epithelial-mesenchymal transition and showed enhanced colony formation, migration, and invasion abilities compared to the cells grown in normal medium. PC3 cells grown in ODM showed enhanced metastasis when injected in mice. A screening of signaling pathways related to invasion and metastasis revealed that the NF-κB pathway was activated, which could be reversed by Bay 11-7082, a NF-κB pathway inhibitor. These results indicate that the cells in different culture conditions manifested significantly different biological behaviors and the NF-κB pathway is a potential therapeutic target for prostate cancer bone metastasis.

Sinomenine activation of Nrf2 signaling prevents hyperactive inflammation and kidney injury in a mouse model of obstructive nephropathy.

Sinomenine is originally derived from medicinal herb and used preferentially in treatment of rheumatoid diseases in Far East regions. SIN has strong anti-inflammatory and immune-regulatory properties, acting mainly through inhibiting NF-kB signaling. Although the upstream target through which SIN affects NF-kB activity is unknown, evidence suggests that SIN might regulate inflammation through Nrf2 signaling. In this study we explored the role of Nrf2 in mediating SIN's anti-inflammation and kidney protection in a mouse model of obstructive nephropathy. We found that SIN is an activator of Nrf2 signaling. It markedly increased Nrf2 protein level, Nrf2 nuclear translocation, Nef2 transcription capacity, and the downstream protein expression. We further demonstrated that SIN activation of Nrf2 is likely due to its repression of the Nrf2 inhibitor Keap1 since it drastically reduced Keap1 protein through the PKC-sensitive ubiquitination-proteasomal degradation. SIN treatment of nephropathy mice effectively reduced the kidney damage and inflammatory responses, balanced renal oxidative stress, and improved the pathological protein expression in an Nrf2 dependent manner. In addition, SIN also Nrf2-dependently modulated macrophage M1/M2 polarization and inhibited the IkBα phosphorylation and NF-kB nuclear translocation, hence revealing an important upstream event that contributed to its anti-inflammation and tissue protection. Taken together our study has identified a novel pathway through which SIN exerts its anti-inflammation and renal protective functions, and provided a molecular basis for SIN potential applications in the treatment of kidney and other inflammatory disorders.