Dual-targeted delivery of temozolomide by multi-responsive nanoplatform via tumor microenvironment modulation for overcoming drug resistance to treat glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.

Bacteria Synergized with PD-1 Blockade Enhance Positive Feedback Loop of Cancer Cells-M1 Macrophages-T Cells in Glioma.

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti-PD-1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD-1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells-M1 macrophages-T cells. Collectively, the bacteria synergized with PD-1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma.

Hydrogen production promotion and energy saving in anaerobic co-fermentation of heat-treated sludge and food waste.

The objective of this paper is to gain insights into the synergistic advantage of anaerobic co-fermentation of heat-treated sludge (HS) with food waste (FW) and heat-treated food waste (HFW) for hydrogen production. The results showed that, compared with raw sludge (RS) mixed with FW (RS-FW), the co-substrate of HS mixed with either FW (HS-FW) or HFW (HS-HFW) effectively promoted hydrogen production, with HS-HFW promoted more than HS-FW. The maximum specific hydrogen production (MSHP) and the maximum hydrogen concentration (MHC) of HS-HFW were 40.53 mL H2/g dry weight and 57.22%, respectively, and 1.21- and 1.45-fold as high as those from HS-FW. The corresponding fermentation was ethanol type for HS-HFW and butyric acid type for HS-FW. The net energy production from RS-FW and HS-FW was both negative, but it was positive (2.57 MJ) from 40% HFW addition to HS-HFW. Anaerobic fermentation was more viable for HS-HFW.

30-norlanostane triterpenoids and steroid derivatives from the endophytic fungus Aspergillus nidulans.

Two undescribed 30-norlanostane triterpenoids, named nidulanoids A and B, one ergostane-type steroid with an unusual double bond between C-17 and C-20 designated (17E,22E,24R)-3ß,5α-dihydroxyergosta-7,17,22-trien-6,16-dione, and one pregnane, (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al, along with six known steroids were isolated from the extract of the fungus Aspergillus nidulans. Among them, nidulanosides A and B represents the first example of naturally occurred 30-norlanostane triterpenoids featuring a C9 side-chain moiety at C-17 and a hemiacetal system formed between C-3 and C-19, as an intermediate between lanostane and the regular steriods; the structure of (17E,22E,24R)-3ß,5α-dihydroxyergosta-7,17,22-trien-6,16-dione possesses an untypical Δ17,20 double bond; meanwhile, (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al represents the first example of C-21 steroid with an aldehyde group at C-13. Their structures and absolute stereochemistry were elucidated based on spectroscopic data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al showed moderate inhibitory activities against rat brain cancer (PC12) cell lines, with IC50 value of 7.34 µM. This study enriches the diversified structures of triterpenoids and steroids analogues from A. nidulans and indicated (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17(20)-trien-18-al to be a promising lead compound against PC12 cell lines.

Four undescribed ergostane-type steroids from Lasiodiplodia pseudotheobromae and their neuroprotective activity.

Four undescribed ergostane-type steroids, (22E,24R)-4α,5α-epoxyergosta-9α,14ß-dihydroxy-7,22-diene-3,6-dione, (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione, 12α-hydroxyergosta-7,22,24(28)-triene-3-one, and 3ß,12α-dihydroxyergosta-7,24(28)-diene, along with a known congener (22E,24R)-9α,14ß-dihydroxyergosta-4,7,22-triene-3,6-dione, were isolated from the fungus Lasiodiplodia pseudotheobromae. Their structures were elucidated using NMR, HRESIMS, ECD calculation, and X-ray diffraction analyses. (22E,24R)-4α,5α-epoxyergosta-9α,14ß-dihydroxy-7,22-diene-3,6-dione and (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione are a pair of C-14 epimers possessing an unusual epoxy group between C-4 and C-5, which was demonstrated using single-crystal X-ray diffraction analyses. The absolute configurations of 12α-hydroxyergosta-7,22,24(28)-triene-3-one and 3ß,12α-dihydroxyergosta-7,24(28)-diene were determined by ECD calculations. Moreover, 3ß,12α-dihydroxyergosta-7,24(28)-diene exhibited neuroprotective activity in vitro in glutamate-treated SH-SY5Y cell lines.

Effects of fulvic acid size on microcystin-LR photodegradation and detoxification in the chlorine/UV process.

Microcystin-LR (MC-LR), a polypeptide toxin generated by cyanobacteria, threatens the safety of drinking water supplies. In this study, fulvic acid (FA) was separated into two molecular weight (MW) ranges to evaluate the effects of FA size on MC-LR degradation in the chlorine/UV process. The rates of MC-LR degradation were significantly reduced in FA-containing water (3.7 × 10-3 s-1 for small MW FA; 4.3 × 10-3 s-1 for large MW FA) as compared with FA free water (4.9 × 10-3 s-1). The contributions of ClO• to MC-LR degradation were dramatically lower in small MW FA water (0.4%) than large MW FA (13.9%) and FA free water (17.4%), suggesting inhibition by lignin-like substances in FA in the transformation of Cl• to ClO• and scavenging ClO•. Monochlorination and hydroxylation occurred in the first step of the MC-LR degradation process. The accumulation of intermediate products in the chlorine/UV process indicated that small MW FA inhibited further degradation of MC-LR. Small MW FA, rather than MC-LR degradation, was the dominant factor in minimizing MC-LR cytotoxicity toward a human intestinal epithelial cell line.