Atomically Resolved Transition Pathways of Iron Redox.

The redox transition between iron and its oxides is of the utmost importance in heterogeneous catalysis, biological metabolism, and geological evolution. The structural characteristics of this reaction may vary based on surrounding environmental conditions, giving rise to diverse physical scenarios. In this study, we explore the atomic-scale transformation of nanosized Fe3O4 under ambient-pressure H2 gas using in-situ environmental transmission electron microscopy. Our results reveal that the internal solid-state reactions dominated by iron diffusion are coupled with the surface reactions involving gaseous O or H species. During reduction, we observe two competitive reduction pathways, namely Fe3O4 → FeO → Fe and Fe3O4 → Fe. An intermediate phase with vacancy ordering is observed during the disproportionation reaction of Fe2+ → Fe0 + Fe3+, which potentially alleviates stress and facilitates ion migration. As the temperature decreases, an oxidation process occurs in the presence of environmental H2O and trace amounts of O2. A direct oxidation of Fe to Fe3O4 occurs in the absence of the FeO phase, likely corresponding to a change in the water vapor content in the atmosphere. This work elucidates a full dynamical scenario of iron redox under realistic conditions, which is critical for unraveling the intricate mechanisms governing the solid-solid and solid-gas reactions.

S-allylmercaptocysteine inhibits mucin overexpression and inflammation via MAPKs and PI3K-Akt signaling pathways in acute respiratory distress syndrome.

Cytokine storm is an important cause of acute respiratory distress syndrome and multiple organ failure. Excessive secretion and accumulation of mucins on the surface of airway cause airway obstruction and exacerbate lung infections. MUC5AC and MUC5B are the main secreted mucins and overexpressed in various inflammatory responses. S-allylmercaptocysteine, a water-soluble organic sulfur compound extracted from garlic, has anti-inflammatory and anti-oxidative effects for various pulmonary diseases. The aim of this work was to investigate the therapeutic effects of SAMC on mucin overproduction and inflammation in 16HBE cells and LPS-induced ARDS mice. Results show that SAMC treatment ameliorated inflammatory cell infiltration and lung histopathological changes in the LPS-induced ARDS mice. SAMC also inhibited the expressions of MUC5AC and MUC5B, decreased the production of pro-inflammatory markers (IL-6, TNF-α, CD86 and IL-12) and increased the production of anti-inflammatory markers (IL-10, CD206 and TGF-ß). These results confirm that SAMC had potential beneficial effects on suppressed hyperinflammation and mucin overexpression. Furthermore, SAMC exerted the therapeutic effects through the inhibition of phosphorylation of MAPKs and PI3K-Akt signaling pathways in the 16HBE cells and mice. Overall, our results demonstrate the effects of SAMC on the LPS-induced mucin overproduction and inflammation both in the 16HBE cells and mice.

Biomimetic Phosphate-Catalyzed Pictet-Spengler Reaction for the Synthesis of 1,1'-Disubstituted and Spiro-Tetrahydroisoquinoline Alkaloids.

Tetrahydroisoquinoline (THIQ) alkaloids are an important group of compounds that exhibit a range of bioactivities. Here, a phosphate buffer-catalyzed Pictet-Spengler reaction (PSR) using unreactive ketone substrates is described. A variety of 1,1'-disubstituted and spiro-tetrahydroisoquinoline alkaloids were readily prepared in one-step and high yields, highlighting the general applicability of this approach. This study features the role of phosphate in the aqueous-based PSR and provides an atom-efficient, sustainable route to new THIQs.

2-Arylthio-5-iodo pyrimidine derivatives as non-nucleoside HBV polymerase inhibitors.

In this study, a series of 2-arylthio-5-iodo pyrimidine derivatives, as non-nucleoside hepatitis B virus inhibitors, were evaluated and firstly reported as potential anti-HBV agents. To probe the mechanism of active agents, DHBV polymerase was isolated and a non-radioisotopic assay was established for measuring HBV polymerase. The biological results demonstrated that 2-arylthio-5-iodo pyrimidine derivatives targeted HBV polymerase. In addition, pharmacophore models were constructed for future optimization of lead compounds. Further study will be performed for the development of non-nucleoside anti-HBV agents.

Enzymatic and Chemoenzymatic Three-Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines.

Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3-hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet-Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)-metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo- and biocatalysts for optimal results.

A stereo configuration-activity study of 3-iodo-4-(2-methylcyclohexyloxy)-6-phenethylpyridin-2(2H)-ones as potency inhibitors of HIV-1 variants.

3-Iodo-4-(2'-methylcyclohexyloxy)-6-phenethylpyridin-2(1H)-ones, as effective non-nucleoside reverse transcriptase inhibitors, were synthesized and resolved with different configurations. Biological results revealed that the trans-racemate 2b exhibited more potent activity than the cis-isomers. Noticeably, the trans-(S,S)-enantiomer 2e turned out to be significantly more potent than its counterpart enantiomer 2d against wild-type and double-mutant strains with high selectivity indexes.

[Density functional theory investigation on antioxidation activity of four flavonoids from Rhododendri Daurici Folium].

Four main flavonoids of the Chinese medicine Rhododendri Daurici Folium were studied using the density functional theory (DFT) B3LYP method with 6-311 + + G (d, p) basis set．Their activities were analyzed based on molecular structure, bond dissociation energy (BDE) and the energy gap between HOMO and LUMO. As a result, the antioxidant ability order of the four flavonoids compounds is farrerol

The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50 of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 10(4). A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants, in vitro resistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, these in vitro data indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs.

A novel 2-pyridinone scaffold was rationally designed and synthesized based on the active anti-HIV agent 1 (LAM-trans) via an efficient method. The biological results revealed that some target compounds inhibited HIV-1 reverse transcriptase in the lower micromolar concentration range (IC50 0.089-0.68 µm). Notably, the most promising compound 25b exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.0563 µM and the viral selectivity index amounted to 3466.8. Molecular modeling studies were performed, and some SARs were rationalized.

[Synthesis of 6-benzyl-1-[(benzyloxy)methyl]-3-hydroxy-5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione].

OBJECTIVE: To find the best synthesis method of 6-benzyl-1-[(benzyloxy)methyl]-3-hydroxy-5-(hydroxymethyl) pyrimidine-2,4(1H,3H)-dione e for observing the change of its biological activity after N-3 hydroxylation. METHODS: After trying some N-hydroxylation methods, the target compound was successfully synthesized via one-pot oxidizing process by sodium hydride (NaH) and 3-chloroperbenzoic acid(m-CPBA); the anti-HIV reverse transcriptase (RT) activity and integrase (IN) activity of the target compound was assayed via enzyme-linked immunesorbent assay (ELISA) and phosphorylation of DNA package method. RESULTS: The target compound could be obtained through the improved m-CPBA oxidative method by only one step, and the yield of the reaction could reach 60%-70%. And the structure of this compound was identified by 1H NMR, 13C NMR and MS; The activity result showed it added the anti-HIV IN activity after N-3 hydroxylation as well as retained the anti-HIV RT activity. CONCLUSION: The improved m-CPBA oxidative method is a convenient and efficient way to prepare the compound 6-benzyl-1-[(benzyloxy)methyl]-3-hydroxy-5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione e which has both anti-HIV RT and IN activity.

Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodine-6-substituted-benzyl-pyrimidine-4(3H)-ones as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

A novel series of 2-arylalkylthio-5-iodine-6-substitutedbenzyl-pyrimidine-4(3H)-ones (S-DABOs) 8a-x had been synthesized via an efficient method. Their biological activity against HIV virus and RT assay were evaluated. Some compounds, especially 8h, 8l and 8n, displayed promising activity against HIV-1 RT with IC50 values in a range of 0.41 µM to 0.71 µM, which were much better than that of nevirapine. Molecular modeling studies revealed that the binding mode would be affected via forming an additional hydrogen bond by incorporating an oxygen atom on the C-2 side chain. The biological activity was in accordance with the docking results.

A cisplatin and disulphiram co-loaded inclusion complex overcomes drug resistance by inhibiting cancer cell stemness in non-small cell lung cancer.

Introduction: Non-small cell lung cancer (NSCLC) accounting for about 80-85% of all lung cancer cases is one of the fastest-growing malignancies in terms of incidence and mortality worldwide and is commonly treated with cisplatin (DDP). Although treatment may initially be effective, the DDP therapy often leads to the development of chemoresistance and treatment failure. Disulphiram (DSF), an old alcohol-aversion drug, has been revealed to help reverse drug resistance in several cancers. In addition, several studies have shown a close relationship between drug resistance and cancer cell stemness.Methods: In this study, DDP and DSF were embedded in hydroxypropyl-ß-cyclodextrin (CD) to prepare a co-loaded inclusion complex of DDP and DSF (DDP-DSF/CD) with enhanced solubility and therapeutic effects. The effects and mechanism of DSF on the DDP resistance from the perspective of cancer cell stemness were determined.Results: Our data show that DDP-DSF/CD increased cytotoxicity and apoptosis of DDP-resistant A549 (A549/DDP) cells, inhibited stem cell transcriptional regulatory genes and drug resistance-associated proteins and reversed the DDP resistance in vitro and in vivo.Discussion: Overall, DDP-DSF/CD could be a promising formulation for the reversal of DDP resistance in NSCLC by inhibiting cancer cell stemness.

S-allylmercaptocysteine promotes anti-tumor immunity by suppressing PD-L1 expression.

SAMC (S-allylmercaptocysteine) possesses significant anti-tumor effects and is proven to inhibit inflammation in chronic obstructive pulmonary disease. The potential to regulate the immune system of SAMC inspired us to detect whether SAMC can promote anti-tumor immunity. Here we found that SAMC inhibits tumor development and progression by boosting CD8+ T cell and NK cell infiltration and decreasing the frequency of immune suppressing Treg cells in tumor tissue and enhancing the systemic immune function. Mechanistically, we found that SAMC suppresses PD-L1 expression at transcriptional level to increase the activation of anti-tumor cytotoxic T cells. Finally, we proved that SAMC inhibits PD-L1 transcription by suppressing the phosphorylation activation of STAT3. In conclusion, our findings reveal that SAMC is a potent immunity regulator and a potential agent for immune checkpoint inhibition in tumor therapy.

Ultralarge anti-Stokes lasing through tandem upconversion.

Coherent ultraviolet light is important for applications in environmental and life sciences. However, direct ultraviolet lasing is constrained by the fabrication challenge and operation cost. Herein, we present a strategy for the indirect generation of deep-ultraviolet lasing through a tandem upconversion process. A core-shell-shell nanoparticle is developed to achieve deep-ultraviolet emission at 290 nm by excitation in the telecommunication wavelength range at 1550 nm. The ultralarge anti-Stokes shift of 1260 nm (~3.5 eV) stems from a tandem combination of distinct upconversion processes that are integrated into separate layers of the core-shell-shell structure. By incorporating the core-shell-shell nanoparticles as gain media into a toroid microcavity, single-mode lasing at 289.2 nm is realized by pumping at 1550 nm. As various optical components are readily available in the mature telecommunication industry, our findings provide a viable solution for constructing miniaturized short-wavelength lasers that are suitable for device applications.

[Influence of SGHWJN particles on mediators of inflammation in esophageal tissues of rat with reflux esophagitis].

OBJECTIVE: To study the influence of SGHWJN particles on inflammation and the mediators of inflammation in esophageal tissues of rat with reflux esophagitis. METHOD: Fifty SD rats were randomly divided into 5 groups, namely, a control group, a sham-operated group, a model group, a SGHWJN particles group and a PPI group. Reflux esophagitis was induced by adopting partial pyloric ligation plus cardiomyotomy. One week later, the rats were orally administered twice daily for 28 days. Pathological changes of esophagus mucous membrane were evaluated by using HE staining and Harry S. Cooper's method in every groups. MDA and SOD contents in esophageal tissues were measured by colorimetric method. Expression of TNF-alpha in esophageal tissues were examined by real-time fluorescent quantitative reverse transcriptase polymerase chain reaction (RT-FQ-PCR) with SYBR Green. RESULT: Model group, esophageal inflammation scores, expression of TNF-alpha in esophageal tissues and MDA contents compared with the normal group and sham operation group were significantly higher (P < 0.05). SOD contents in the esophageal tissues of the model group was significantly lower than that of control group and sham-operated group (P < 0.05). SGHWJN particles group and PPI group of esophageal tissue inflammation scores, expression of TNF-a in esophageal tissues and MDA levels than those in model group decreased significantly (P < 0.05). SOD content was significantly higher than that of model group (P < 0.05), SGHWJN particles group and PPI group showed no statistically significant difference between the above-mentioned indicators. The above-mentioned indicators showed no statistically significant difference between the normal group and sham-operated group. MDA content and expression of TNF-alpha in esophageal tissue was positively correlated with inflammatory scores of model group (r = 0.813). Model group esophageal tissue SOD content and inflammation scores were negatively correlated (r = -0.847). Esophageal tissue SOD levels were negatively correlated with MDA levels (r = -0.863). CONCLUSION: SGHWJN particles can effectively inhibit inflammation in rat with reflux esophagitis through regulating TNF-alpha, SOD and MDA.

Identification of TNFAIP8 as an Immune-Related Biomarker Associated With Tumorigenesis and Prognosis in Cutaneous Melanoma Patients.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which is associated with inflammation and tumorigenesis. The potential role of TNFAIP8 in a tumor immune microenvironment in skin cutaneous melanoma (SKCM) has not yet been investigated. The TNFAIP8 expression was evaluated via gene expression profiling interactive analysis (GEPIA). We also evaluated the influence of TNFAIP8 on overall survival via GEPIA and PrognoScan. After GO and KEGG pathway analyses, the correlation between the TNFAIP8 expression level and immune cells or gene markers of the immune infiltration level was explored by R-language. The result showed the TNFAIP8 expression was significantly reduced in SKCM in comparison with normal control. In SKCM, the TNFAIP8 expression in higher levels was associated with the better overall survival. The high expression of TNFAIP8 was positively correlated with the immune score and promoted immune cell infiltration in SKCM patients. TNFAIP8 can be a positive prognosis marker or new immunotherapy target in SKCM.

ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target.

Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.

An erythrocyte-delivered photoactivatable oxaliplatin nanoprodrug for enhanced antitumor efficacy and immune response.

The outcome of conventional platinum (Pt)-based chemotherapy is limited by reduced circulation, failure to accumulate in the tumor, and dose-limiting toxicity arising from non-controllable activation. To address these limitations, we present an erythrocyte-delivered and near-infrared (NIR) photoactivatable PtIV nanoprodrug for advanced cancer treatment. Compared with small molecule PtIV prodrugs, this nanoprodrug exhibits significantly enhanced stability, prolonged circulation in the blood, and minimized side effects. The hitchhiking of the nanoprodrug on erythrocytes dramatically increases Pt accumulation in the tumor. Upon irradiation, the nanoprodrug releases oxaliplatin in a controllable manner, resulting in significant antitumor activity against breast tumors in vivo, as evidenced by the complete elimination of tumors from a single-dose injection. Additionally, this nanoprodrug is associated with remarkably enhanced immunopotentiation. Our study highlights an efficient strategy to overcome the shortcomings of traditional Pt-based chemotherapy via the erythrocyte-mediated delivery of an NIR-activatable nanoprodrug of oxaliplatin, a clinically used anticancer drug.