Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission.

Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression­enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.

[Herbal textual research on Rubi Fructus].

Rubi Fructus is a commonly used traditional Chinese medicine. The origin of Rubi Fructus is the dried fruit of Rubus chingii, a plant of the family Rosaceae, according to the 2015 edition of Chinese pharmacopoeia. There are some differences in the plant origin of Rubi Fructus in ancient herbal literature, to trace back its sources, we conducted a textual research on its origin, producing areas, quality evaluation, processing and concocting, properties, tastes and efficacy etc. based on the records of ancient herbal literatures and combined with plant morphology and related investigation. RESULTS:: showed that the variety of Rubi Fructus was more complex among ancient herbal literature, including R. coreanus, R. hirsutus, R. corchorifolius, R. foliolosus and other mixed varieties. Most scholars believe that the R. chingii has not been recorded in ancient herbal literature, while R. chingii was recorded as early as the Ming Dynasty in Compendium of materia medica through our textual research. Ancient Chinese herbs recorded that Rubi Fructus was mostly produced in Hubei, Shandong, Shanxi and Jiangsu provinces, while R. chingii mainly produced in Anhui, Jiangsu, Zhejiang, Jiangxi, Fujian and other provinces nowadays. Also, it was recorded that Rubi Fructus harvested in wheat field during May were the best. Besides, R. chingii with big, full, grain integrate, firm, yellow and green color, sour taste and impurity free possess the best quality in the contemporary. The ancient records of processing and concocting, properties, tastes and efficacy were basically the same as modern ones.These results provide the basis for the correct utilization and further development of Rubi Fructus.

Zi Shen Decoction Inhibits Growth and Metastasis of Lung Cancer via Regulating the AKT/GSK-3ß/ß-Catenin Pathway.

Lung cancer has become the leading cause of cancer-related death worldwide. Oxidative stress plays important roles in the pathogenesis of lung cancer. Many natural products show antioxidative activities in cancer treatment. Zi Shen decoction (ZSD) is a classic prescription for the treatment of lung disease. However, its effect on lung cancer lacks evidence-based efficacy. In this study, we investigated the anticancer effects of ZSD on lung cancer in vivo and in vitro. Our results showed that oral administration of ZSD suppressed the Lewis lung cancer (LLC) growth in a subcutaneous allograft model and promoted necrosis and inflammatory cell infiltration in the tumor tissues. Furthermore, ZSD not only inhibited tumor cell proliferation and migration but also induced cell apoptosis in lung cancer cells. PI3K/AKT signaling is well characterized in response to oxidative stress. The bioinformatics analysis and western blot assays suggested that ZSD decreased the enzyme activity of PI3K and AKT in vivo and in vitro. We also found that the AKT/GSK-3ß/ß-catenin pathway medicated anticancer effect of ZSD in lung cancer cells. In conclusion, we demonstrate for the first time that ZSD possesses antitumor properties, highlighting its potential use as an alternative strategy or adjuvant treatment for lung cancer therapy.

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy.

Phototherapy has been intensively investigated as a non-invasive cancer treatment option. However, its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity. To achieve high therapeutic efficiency and high security, a nanoassembly of Forster Resonance Energy Transfer (FRET) photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy. For proof-of-concept, an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6 (Ce6, FRET donor) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, FRET acceptor) is investigated for breast cancer treatment. Notably, Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy (PDT) only when DiR is photobleached by 808-nm laser. As a result, Ce6-caused phototoxicity could be well controlled. Under cascaded laser irradiation (808-660 nm), tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs, relieves tumor hypoxia, and promotes the PDT efficacy of Ce6. Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

HYR-2 plays an anti-lung cancer role by regulating PD-L1 and Akkermansia muciniphila.

Traditional Chinese medicine (TCM) plays a vital part in cancer treatment due to its unique superiority. Huoxue Yiqi Recipe-2 (HYR-2) was supposed to have therapeutic effect on lung cancer, which came from Ze Qi Decoction in one of the four great classics of TCM called "Synopsis of Prescriptions of the Golden Chamber". Network pharmacology demonstrated that the targets of active components from HYR-2 were significantly enriched in the signaling pathways, which were closely associated with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1). Then, data about NSCLC was downloaded from Gene Expression Omnibus database (GEO). The Cancer Genome Atlas (TCGA) and DisGeNET was analyzed by bioinformatics, and 214 biomarkers for NSCLC were obtained, containing 14 targets of active components from HYR-2 (which were significantly enriched in the PD-L1 related signaling pathway). In vivo and in vitro experiments showed that HYR and HYR-2 could inhibit the growth of lung cancer and down-regulate the expression of PD-L1, which might be related to the blocking effect of HYR-2 on the PI3K/Akt signaling pathway. Furthermore, HYR-2 promoted the transformation of M2 macrophages into M1 macrophages as well. It is deserved to be mentioned that the level of Akkermansia muciniphila was also significantly elevated by HYR-2, which was believed to enhance the therapeutic effect of PD-L1 antibodies. To sum up, HYR-2 might play an anti-lung cancer effect by down-regulating PD-L1 together with up-regulating Akkermansia muciniphila.

Self-Assembly of a Pure Photosensitizer as a Versatile Theragnostic Nanoplatform for Imaging-Guided Antitumor Photothermal Therapy.

Imaging-guided diagnosis and phototherapy has been emerging as promising theragnostic strategies for detection and treatment of cancer. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) has been widely investigated for in vivo imaging and photothermal therapy (PTT). However, the tumor-homing ability and PTT efficiency of DiR is greatly limited by its extremely low water solubility and nonspecific distribution in off-target tissues. Herein, a facile nanoassembly of pure DiR is reported as a theragnostic nanocarrier platform for imaging-guided antitumor phototherapy. Self-assembly of DiR has almost no effect on its in vitro photothermal efficacy when compared with DiR solution. Interestingly, the PEGylated nanoassemblies of DiR showed distinct advantages over DiR solution and non-PEGylated nanoassemblies in terms of systemic circulation and tumor-homing capability in vivo. As a result, PEGylated DiR nanoassemblies demonstrate potent photothermal tumor therapy in BALB/c mice bearing 4T1 xenograft tumors. Such a pure photosensitizer-based nanoassembly holds great potential as a versatile platform for efficient imaging-guided cancer therapy.

Effects of ulinastatin on early postoperative cognitive function after one-lung ventilation surgery in elderly patients receiving neoadjuvant chemotherapy.

We investigated the effects of ulinastatin on early postoperative cognitive dysfunction (POCD) after one-lung ventilation (OLV) surgery in elderly patients receiving neoadjuvant chemotherapy. Eighty elderly patients with preoperative neoadjuvant chemotherapy scheduling for radical esophagectomy under OLV were recruited. They were randomly divided into an ulinastatin pretreatment group (U group, n = 40) and a control group (C group, n = 40). The U group received 10,000 U/kg ulinastatin before anesthesia and 5000 U/kg daily on postoperative days 1 to 3, while C group received saline. Levels of interleukin (IL)-6, IL-10, C-reactive protein (CRP), and S-100ß protein were assayed before surgery, at the end of surgery, and on postoperative days 1 and 3. Patients underwent cognitive assessment 1 day before and 7 days after surgery. 38 patients in U group and 37 patients in C group completed the neuropsychological tests. The U group had a lower incidence of POCD than C group (23.7 % versus 45.9 %, P = 0.043). The levels of S-100ß protein, IL-6, IL-10, and CRP in both groups increased after surgery. The postoperative concentrations of S-100ß protein, IL-6, and CRP in U group were lower than those in C group. On postoperative day 3, compared with C group, the level of CRP in U group was lower, while that of IL-10 was higher. These findings demonstrate that ulinastatin can attenuate the elevation of S100ß protein levels and the incidence of POCD, most likely by the mechanism of reducing serum IL-6 and CRP levels and increasing IL-10 levels.

Specific aptamer-conjugated mesoporous silica-carbon nanoparticles for HER2-targeted chemo-photothermal combined therapy.

Tumor-specific therapeutic platforms designed for combined tumor therapy has recently received wide attention. In this work, a new HB5 aptamer-functionalized mesoporous silica-carbon based doxorubicin (DOX)-loaded system (MSCN-PEG-HB5/DOX) was successfully constructed and characterized for chemo-photothermal combined therapy of human epithelial growth factor receptor 2 (HER2)-positive breast cancer cells. The in vitro release result showed that MSCN-PEG-HB5/DOX exhibited pH-sensitive and NIR-triggered release manner. HB5-modified nanoparticles showed significant higher cellular uptake in HER2-positive breast cancer cells (SK-BR-3) but not in normal breast epithelial cells (MCF-10A), compared to unmodified counterparts. The intracellular uptake of functional nanoparticles was mainly based on the receptor-mediated mechanism which was energy-dependent. Cytotoxicity experiments demonstrated that combined therapy induced highest cell killing effect compared to chemotherapy and photothermal therapy alone. The combination index (CI) was 0.253 indicating the synergistic effect of chemotherapy and photothermal therapy. These findings suggested that MSCN-PEG-HB5/DOX was a potential chemo-photothermal therapeutic platform targeting to HER2-positive breast cancers.

Synthesis of core-shell graphitic carbon@silica nanospheres with dual-ordered mesopores for cancer-targeted photothermochemotherapy.

Tumor site-directed multifunctional therapeutic platforms such as photothermochemotherapy that respond to tumor-focused physical and biological stimuli are highly demanded for effective cancer therapy. Herein, targeting peptide-conjugated core­shell graphitic carbon@silica nanospheres with dual-ordered mesopores (MMPS) were successfully fabricated and developed as antitumoral doxorubicin (DOX) delivery system (MMPSD) for synergistic targeted photothermal chemotherapy of breast cancer. The hydrophilic mesoporous silica shell guarantees good water dispersity of MMPSD. The hydrophobic graphitic mesoporous carbon core provides excellent hydrophobic drug loading, immediate contact between the drug and photothermal hotspots, and high NIR photothermal conversion efficiency. SP13 peptide facilitates MMPSD for targeted and enhanced delivery of DOX within HER2-positive SK-BR-3 breast cancer cells, while PEGylation ensures biocompatibility. Thus, the MMPSD system exhibited efficient drug loading capacity, high targeting ability, sensitive NIR/pH-responsive DOX release, sustained release, and excellent combined antitumor activity.

A general strategy for dual-triggered combined tumor therapy based on template semi-graphitized mesoporous silica nanoparticles.

A general strategy is developed for dual-triggered chemo-photothermal tumor therapy based on template semi-graphitized mesoporous silica nanoparticles (TsGMSN). The strategy endues classic MSN with new charming properties, while easily escaping from toxicity of the surfactant. The doxorubicin-loaded system (TsGMSND) exhibits synergistic heat-stimulative, pH-responsive, and sustained release, and effective combined tumor therapy.

Multifunctional mesoporous silica-coated graphene nanosheet used for chemo-photothermal synergistic targeted therapy of glioma.

Current therapy of malignant glioma in clinic is unsatisfactory with poor patient compliance due to low therapeutic efficiency and strong systemic side effects. Herein, we combined chemo-photothermal targeted therapy of glioma within one novel multifunctional drug delivery system. A targeting peptide (IP)-modified mesoporous silica-coated graphene nanosheet (GSPI) was successfully synthesized and characterized, and first introduced to the drug delivery field. A doxorubicin (DOX)-loaded GSPI-based system (GSPID) showed heat-stimulative, pH-responsive, and sustained release properties. Cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of glioma cells compared to that of single chemotherapy or photothermal therapy. Furthermore, the IP modification could significantly enhance the accumulation of GSPID within glioma cells. These findings provided an excellent drug delivery system for combined therapy of glioma due to the advanced chemo-photothermal synergistic targeted therapy and good drug release properties of GSPID, which could effectively avoid frequent and invasive dosing and improve patient compliance.