Nitric Oxide-Loaded Bioinspired Lipoprotein Normalizes Tumor Vessels To Improve Intratumor Delivery and Chemotherapy of Albumin-Bound Paclitaxel Nanoparticles.

The disorganized vasculatures in tumors represent a substantial challenge of intratumor nanomedicine delivery to exert the anticancer effects. Herein, we rationally designed a glutathione (GSH)-activated nitric oxide (NO) donor loaded bioinspired lipoprotein system (NO-BLP) to normalize tumor vessels and then promote the delivery efficiency of sequential albumin-bound paclitaxel nanoparticles (PAN) in tumors. NO-BLP exhibited higher tumor accumulation and deeper penetration versus the counterpart liposomal formulation (NO-Lipo) in 4T1 breast cancer tumors, thus producing notable vascular normalization efficacy and causing a 2.33-fold increase of PAN accumulation. The sequential strategy of NO-BLP plus PAN resulted in an 81.03% inhibition of tumor growth in 4T1 tumors, which was better than the NO-BLP monotherapy, PAN monotherapy, and the counterpart NO-Lipo plus PAN treatment. Therefore, the bioinspired lipoprotein of NO-BLP provides an encouraging platform to normalize tumor vessels and promote intratumor delivery of nanomedicines for effective cancer treatment.

Development of a sensitive UHPLC-MS/MS method for the pharmacokinetics study of a novel tyrosine kinase inhibitors, 1-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-phenyl)-piperazin-1-yl]-propenone in rats.

Targeted inhibition of epidermal growth factor receptor has become an important means of chemotherapy for nonsmall cell lung cancer, breast cancer, pancreatic cancer, colon cancer and other malignant tumors. Although remarkable curative effects have been achieved in the past few decades, the emergence of drug resistance is a problem. Therefore, new inhibitors need to be developed. XHL-31 is a new candidate with significant inhibitory activity against T790M and C797S mutations in vitro. In order to study the pharmacokinetics in vivo, a sensitive and efficient UHPLC-MS/MS method was developed for the determination of XHL-31 in rat plasma in this study. The lower limit of quantitation of this method was 1 ng/ml and the linear range was 1-2,000 ng/ml. Method validation showed a high accuracy and precision, a high stability, a high recovery and repeatability. The method was successfully applied to the pharmacokinetic study of XHL-31 in rats. The results indicated that there were significant gender differences in oral absorption and the absolute bioavailability of XHL-31 in female rats were extremely low (<10%).

Design, synthesis, antitumor activity and theoretical calculation of novel PI3Ka inhibitors.

PI3Kα has been identified as an ideal target to treat with PIK3CA gene mutation disease, including drugs such as Alpelisib and Copanlisib. Five purine analogues and four thiazole analogues were designed and synthesized. Their enzymaticactivity against PI3Ka/ß/γ/δ were tested, respectively. All compounds showed excellent selectivity in modulating PI3Ka activity, and parts of the compounds showed good inhibition. Meanwhile, we used Autodock 4.2 to explore the binding mode of the most potential compound Tg with the target protein. In addition, DFT was used to calculate the HOMO-LUMO maps of the compounds Tf, Tg and positive control. This paper will provide some useful information for further drug design of PI3Kα inhibitors.

A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis.

Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response.

Discovery of novel N,N-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo.

Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06 µM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett.2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem.2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69 µM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure-activity relationship (SAR) resulted in H16 (IC50 0.15 µM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal.

Design, synthesis and biological evaluation of N,N-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor.

A series of N,N-3-phenyl-3-benzylaminopropanamide derivatives were identified as novel CETP (cholesteryl ester transfer protein) inhibitors. In our previous study, lead compound L10 was discovered by pharmacophore-based virtual screening (Dong-Mei Zhao et al., 2014). Based on L10 (IC50 8.06 µM), compound HL6 (IC50 10.7 µM) was discovered following systematic structure variation and biological tests. Further optimization of the structure-activity relationship (SAR) resulted in N,N-3-phenyl-3-benzylaminopro panamides derivatives as novel CETP inhibitors. They were synthesized and evaluated against CETP by BODIPY-CE fluorescence assay. Among them, HL16 (IC50 0.69 µM) was a highly potent CETP inhibitor in vitro. In addition, HL16 exhibited favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. The molecular docking of HL16 into the CETP was performed. The binding mode demonstrated that HL16 occupied the CETP binding site and formed interactions with the key amino acid residues.

Detection of protein adduction derived from dauricine by alkaline permethylation.

Dauricine is a bisbenzylisoquinoline alkaloid derivative and has shown multiple pharmacological properties. Despite this, our previous study demonstrated that dauricine induced severe lung toxicity in experimental animals. Metabolic activation of dauricine to the corresponding quinone methide intermediate is suggested to play an important role in dauricine-induced cytotoxicity. Protein adduction derived from the reactive intermediate is considered to initiate the process of the toxicity. In the present study, we developed an alkaline permethylation- and mass spectrometry-based approach to detect dauricine-derived protein adduction. Protein samples were permethylated in the presence of NaOH and CH3I at 80 °C, followed by LC-MS/MS analysis. A thioether product was produced in the reaction. Not only does this technique quantify dauricine-derived protein adduction but also it tells the nature of the interaction between the target proteins and the reactive intermediate of dauricine. The recovery, precision, limit of detection, limit of quantity, and method detection limit were found to be 102.8 %±1.7 %, 1.89 %, 1.32 fmol/mL, 4.93 fmol/mL and 3.37 fmol/mL respectively. The surrogate recovery and surrogate RSD values were 81.5-103.0 % and 2.59 %, respectively. This analytical method has proven sensitive, selective, reliable, and feasible to assess total protein adduction derived from dauricine, and will facilitate the mechanistic investigation of dauricine and other bisbenzylisoquinoline toxicities. Graphical Abstract Alkaline permethylation of dauricine derived protein adduct.

Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study.

BACKGROUND: Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS: We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS: Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION: This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING: Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

Regulation of high mobility group box 1 and hypoxia in the migration of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have been increasingly offered for tissue regeneration with the premise that they can survive and thrive amidst the microenvironment of injured or degenerate tissues. The role of high mobility group box 1 (HMGB1) and hypoxia in the proliferation and migration of rat bone marrow MSCs (rBM-MSCs) has been investigated. First, the effect of HMGB1 on the proliferation of rBM-MSCs was determined. Second, to evaluate the regulation of hypoxia and HMGB1 in the migration of rBM-MSCs, cells in the wound healing model were exposed to four conditions: normoxia (20% O2) and complete medium, normoxia and HMGB1, hypoxia (1% O2) and complete medium, hypoxia and HMGB1. RT-PCR and Western blotting were used to measure the expression of migration-related genes and proteins. HMGB1 inhibited the proliferation of rBM-MSCs; HMGB1 alone or together with hypoxia and promoted the migration of MSCs and upregulated the expression of HIF-1α and SDF-1. These results demonstrated that HMGB1 arrested the proliferation of rBM-MSCs, but enhanced the migration of rBM-MSCs which could be further improved by hypoxia. This study strengthens current understanding of the interaction between MSCs and the microenvironment of damaged tissues.

Bioinspired Lipoproteins of Furoxans-Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy Resistance.

Radiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio-sensitizer and a CCL5 peptide-modified bioinspired lipoprotein system of NG (C-LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C-LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO- ) upon X-ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261-induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance.

Effect of progestin on thyroid function in female Wistar rats.

Introduction: To characterize the influence of female-specific hormones on women's thyroid function, the study investigated the influence of extra progestin from oral contraceptives on inducing thyroid dysfunction. Methods: Sixty female Wistar rats were divided into six groups based on levonorgestrel or desogestrel administration as the main active agents: control, low (0.0039 mg*20-fold), medium (0.0039 mg*100-fold), high (0.0318 mg*100-fold) levonorgestrel (pure product); and low (0.0083 mg*20-fold) and high (0.0083 mg*100-fold) desogestrel (pure product). Progestin was administered by gavage every 4 days for 1 month. Statistical analysis was performed using one-way analysis of variance and the Kruskal-Wallis test. Results: Following levonorgestrel gavage, serum free T4 and thyroidstimulating hormone levels were significantly lower in the experimental group than that in the control group (p=0.013 and 0.043). After desogestrel gavage, the serum free T4 and free T3 levels were lower in the experimental group than that in the control group (p=0.019 and 0.030). Thyroid hormone antibody concentrations were lower in rats administered levonorgestrel and desogestrel than that in control rats. Moreover, exposure to progestin upregulated the expression of the thyroid-stimulating hormone receptor and sodium iodide symporter in thyroid. Discussion: Progestin stimulation enhanced the proliferation of follicular epithelial cells in rat thyroid tissues. Progestin exposure could cause thyroid dysfunction by upregulating the transcription of thyroid-stimulating hormone receptor and sodium iodide symporter in thyroid, thus inducing pathomorphological changes in rats' thyroid.

Discovery of a Novel Benzothiadiazine-Based Selective Aldose Reductase Inhibitor as Potential Therapy for Diabetic Peripheral Neuropathy.

Aldose reductase 2 (ALR2), an activated enzyme in the polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for complications of diabetes, especially in diabetic peripheral neuropathy (DPN). However, many of the ALR2 inhibitors have shown serious side effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we describe the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c, carrying a carbonyl group at the 3-position of the thiadiazine ring, showed high potent inhibition against ALR2 (IC50 = 33.19 nmol/L) and ∼16,109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated that 15c had a good pharmacokinetic feature (t1/2 = 5.60 h, area under the plasma concentration time curve [AUC(0-t)] = 598.57 ± 216.5 µg/mL * h), which was superior to epalrestat (t1/2 = 2.23 h, AUC[0-t] = 20.43 ± 3.7 µg/mL * h). Finally, in a streptozotocin-induced diabetic rat model, 15c significantly increased the nerve conduction velocities of impaired sensory and motor nerves, achieved potent inhibition of d-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold. By combining the above investigations, we propose that 15c might represent a promising lead compound for the discovery of an antidiabetic peripheral neuropathy drug.

Species variation in the spontaneous calcification of bone marrow-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) hold great promise for tissue regeneration. With increasing numbers of clinical trials, the safety of BM-MSCs attracts great interest. Previously, we determined that rat BM-MSCs possessed spontaneous calcification without osteogenic induction after continuous culture. However, it is unclear whether BM-MSCs from other species share this characteristic. In this study, spontaneous calcification of BM-MSCs from rat, goat, and human specimens was investigated in vitro. BM-MSCs were cultured in complete medium, and calcification was determined by morphologic observation and alizarin red staining. It was demonstrated that rat BM-MSCs possessed a typically spontaneous calcification, whereas goat and human BM-MSCs under the same system proliferated significantly but did not calcify spontaneously. The significant species variation in spontaneous calcification of BM-MSCs described in this study provides useful information regarding evaluation of numerous BM-MSC-based approaches for bone regeneration and the safety of BM-MSCs.

Experimental study on the control effects of different strategies on particle transportation in a conference room: Mechanical ventilation, baffle, portable air cleaner, and desk air cleaner.

To control the spread and transmission of airborne particles (especially SARS-CoV-2 coronavirus, recently) in the indoor environment, many control strategies have been employed. Comparisons of these strategies enable a reasonable choice for indoor environment control and cost-effectiveness. In this study, a series of experiments were conducted in a full-scale chamber to simulate a conference room. The control effects of four different strategies (a ventilation system (320 m3/h) with and without a baffle, a specific type of portable air cleaner (400 m3/h) and a specific type of desk air cleaner (DAC, 160 m3/h)) on the transportation of particles of different sizes were studied. In addition, the effects of coupling the ventilation strategies with five forms of indoor airflow organization (side supply and side or ceiling return, ceiling supply and ceiling or side return, floor supply and ceiling return) were evaluated. The cumulative exposure level (CEL) and infection probability were selected as evaluation indexes. The experimental results showed that among the four strategies, the best particle control effect was achieved by the PAC. The reduction in CEL for particles in the overall size range was 22.1% under the ventilation system without a baffle, 34.3% under the ventilation system with a baffle, 46.4% with the PAC, and 10.1% with the DAC. The average infection probabilities under the four control strategies were 11.3-11.8%, 11.1-11.8%, 9.1-9.5%, and 18.2-19.7%, respectively. Among the five different forms of airflow organization, the floor supply and ceiling return mode exhibited the best potential ability to remove particles.

Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy.

The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO-) were largely produced, which could diffuse into regions over 400 µm away from the tumor vessels and be detectable after 24 h of radiation, thereby exhibiting superior efficacy in improving the spatiotemporal distribution in tumors versus common reactive oxygen species (ROS). Moreover, M-PFO mediated chemo-radiotherapy caused notable inhibition of tumor growth, with an 89.45% inhibition in HT-29 tumor models and a 92.69% suppression in CT-26 tumor models. Therefore, this bioinspired design provides an encouraging platform to improve intratumor spatiotemporal distribution to synergize chemo-radiotherapy.

Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells.

MSCs (mesenchymal stem cells) may be promising seed cells for tissue regeneration because of their self-renewal and multi-differentiation potential. Shh (sonic hedgehog) is involved in the skeletal formation during embryo development and skeletal regeneration. However, how Shh regulates the biological characteristics of BM-MSCs (bone marrow-derived MSCs) is poorly understood. We have investigated the effect of rShh-N (recombinant N-terminal Shh) on the proliferation and osteogenic differentiation of rBM-MSCs (rat BM-MSCs) in vitro. rBM-MSCs were treated with rShh-N at concentrations up to 200 ng/ml. Proliferation and colony-forming ability of rBM-MSCs were increased in a dose-dependent manner. rShh-N increased the ratio of cells in S and G2/M phase, as well as the number of Ki-67+ cells. In addition, ALP (alkaline phosphatase) activity and matrix mineralization were enhanced by 200 ng/ml rShh-N. Real-time PCR showed that rShh-N (200 ng/ml) up-regulated the expression of genes encoding Cbfa-1 (core-binding factor α1), osteocalcin, ALP and collagen type I in rBM-MSCs. This information reveals some potential of rShh-N in the therapeutics of bone-related diseases.

Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors.

Ergosterol exert the important function in maintaining the fluidity and osmotic pressure of fungal cells, and its key biosynthesis enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) displayed the obvious synergistic effects. Therefore, we expected to discover the novel antifungal compounds with dual-target (SE/CYP51) inhibitory activity. In the progress, we screened the different kinds of potent fragments based on the dual-target (CYP51, SE) features, and the method of fragment-based drug discovery (FBDD) was used to guide the construction of three different series of benzodioxane compounds. Subsequently, their chemical structures were synthesized and evaluated. These compounds displayed the obvious biological activity against the pathogenic fungal strains. Notably, target compounds 10a-2 and 22a-2 possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125-2.0 µg/mL) and the activity against drug-resistant strains (MIC50, 0.5-2.0 µg/mL). Preliminary mechanism studies have confirmed that these compounds effectively inhibited the dual-target (SE/CYP51) activity, they could cause fungal rupture and death by blocking the bio-synthetic pathway of ergosterol. Further experiments discovered that compounds 10a-2 and 22a-2 also maintained a certain of anti-fungal effect in vivo. In summary, this study not only provided the new dual-target drug design strategy and method, but also discover the potential antifungal compounds.

Enhancement of Carbon Conversion and Value-Added Compound Production in Heterotrophic Chlorella vulgaris Using Sweet Sorghum Extract.

High-cost carbon sources are not economical or sustainable for the heterotrophic culture of Chlorella vulgaris. In order to reduce the cost, this study used sweet sorghum extract (SE) and its enzymatic hydrolysate (HSE) as alternative carbon sources for the heterotrophic culture of Chlorella vulgaris. Under the premise of the same total carbon concentration, the value-added product production performance of Chlorella vulgaris cultured in HSE (supplemented with nitrogen sources and minerals) was much better than that in the glucose medium. The conversion rate of the total organic carbon and the utilization rate of the total nitrogen were both improved in the HSE system. The biomass production and productivity using HSE reached 2.51 g/L and 0.42 g/L/d, respectively. The production of proteins and lipids using HSE reached 1.17 and 0.35 g/L, respectively, and the production of chlorophyll-a, carotenoid, and lutein using HSE reached 30.42, 10.99, and 0.88 mg/L, respectively. The medium cost using HSE decreased by 69.61% compared to glucose. This study proves the feasibility and practicability of using HSE as a carbon source for the low-cost heterotrophic culture of Chlorella vulgaris.

Bioinspired Lipoproteins of Furoxans-Oxaliplatin Remodel Physical Barriers in Tumor to Potentiate T-Cell Infiltration.

The infiltration of cytotoxic T lymphocytes (CTLs) in tumors is critically challenged by the intricate intratumor physical barriers, which is emerging as an important issue of anticancer immunotherapy. Herein, a reduction-sensitive nitric oxide donor conjugate of furoxans-oxaliplatin is synthesized and a stroma-cell-accessible bioinspired lipoprotein system (S-LFO) is designed, aiming to facilitate CTL infiltration in tumors for anticancer immunotherapy. S-LFO treatment significantly promotes tumor vessel normalization and eliminates multiple components of tumor stroma, ultimately producing a 2.96-fold, 5.02-fold, and 8.65-fold increase of CD3+ CD8+ T cells, their interferon-γ- and granzyme B-expressing subtypes when comparing to the negative control, and considerably facilitating their trafficking to the cancer cell regions in tumors. Moreover, the combination of S-LFO with an antiprogrammed death ligand-1 produces notable therapeutic benefits of retarded tumor growth and extends survivals in three murine tumor models. Therefore, this study provides an encouraging strategy of remodeling the intratumor physical barriers to potentiate CTL infiltration for anticancer immunotherapy.

Protection of Vitamin C on Oxidative Damage Caused by Long-Term Excess Iodine Exposure in Wistar Rats.

Vitamin C was reported to be able to protect against oxidative damage due to its reducibility. 120 Wistar rats were randomly divided into 4 × 2 groups, including normal iodine (NI), high iodine (HI), low vitamin C (HI + LC), and high vitamin C (HI + HC); potassium iodide (KI) and potassium iodate (KIO3) were commonly used as additives for iodized salt, so every group was also divided into KI and KIO3 groups. After 6 months' feed, the activities of antioxidant enzymes and Lipid Peroxide (MDA) content in serum, liver, kidney, brain, thyroid and lens were determined. In serum, for males, long-term excess iodine intake caused oxidative damage; in the liver, male rats in the HI + LC group had the highest MDA content, which showed that low-dose vitamin C might promote oxidative damage; in kidneys, the MDA content in the HI and HI + LC groups of females was higher; in the brain, high-dose vitamin C could increase the activity of superoxide dismutase (SOD), which was decreased by high iodine intake, and it also decreased MDA content; in the thyroid, for KIO3, the activity of SOD in the HI group was lower than NI and HI + LC; in the lens, the MDA content in females was lower than males. Long-term excess iodine exposure caused oxidative damage and showed sex difference, and vitamin C had a protective effect on it, especially for high-dose vitamin C.