Bioactive polyketides and meroterpenoids from the mangrove-derived fungus Talaromyces flavus TGGP35.

Six new polyketides, which includes three new lactones (talarotones A-C) (1-3), one new polyketide (talarotide A) (4), two new polyenes (talaroyenes A, B) (5, 6), together with one new meroterpenoid (talaropenoid A) (7) and 13 known compounds (8-20) were isolated from the mangrove-derived fungus Talaromyces flavus TGGP35. The structure and configuration of the compounds 1-7 were elucidated from the data obtained from HR-ESI-MS, IR, 1D/2D NMR spectroscopy, Mo2 (OAc)4-induced electronic circular dichroism (ECD), CD spectroscopy, and modified Mosher's method. Compounds 5 and 20 displayed antioxidant activity with IC50 values of 0.40 and 1.36 mM, respectively. Compounds 3, 6, 11, 16, and 17 displayed cytotoxic activity against human cancer cells Hela, A549, and had IC50 values ranging from 28.89 to 62.23 µM. Compounds 7, 10-12, and 14-18 exhibited moderate or potent anti-insect activity against newly hatched larvae of Helicoverpa armigera Hubner, with IC50 values in the range 50-200 µg/mL. Compound 18 showed antibacterial activity against Ralstonia solanacearum with the MIC value of 50 µg/mL.

Acid-Resistant Near-Infrared II Ag2Se Quantum Dots for Gastrointestinal Imaging.

With the development of near-infrared II (NIR-II) fluorescence imaging, Ag2Se quantum dots (QDs) have become promising label candidates due to their negligible toxicity and narrow band gap. Despite their potential for gastrointestinal (GI) imaging, the application of Ag2Se QDs still presents significant challenges due to issues such as fluorescence extinction or poor stability in the complex digestive microenvironment. Herein, we have proposed a novel approach to the continuous production of Se precursors using glutathione (GSH) as the reductant under acidic conditions, realizing the continuous growth of water-dispersible Ag2Se QDs. The Ag2Se QDs emitting at 600-1100 nm have been successfully synthesized. Meanwhile, the silver-rich surface of the synthesized NIR-II Ag2Se QDs has been passivated well with the dense GSH, resulting in exceptional colloidal stability and photostability and endowing them with acid resistance. As a result, the obtained NIR-II Ag2Se QDs have exhibited remarkable stability in gastric acid, thus enabling their utilization for long-term real-time monitoring of GI peristalsis via NIR-II fluorescence imaging. Moreover, in contrast to conventional barium meal-based X-ray imaging, NIR-II fluorescence imaging with as-prepared NIR-II Ag2Se QDs can offer clearer visualization of fine intestinal structures, with a width as small as 1.07 mm. The developed strategy has offered a new opportunity for the synthesis of acid-resistant nanocrystals, and the acid-resistant, low-toxicity, and biocompatible NIR-II Ag2Se QDs synthesized in this work show a great promise for GI imaging and diagnosis of GI diseases in vivo.

How different are the surfaces of semiconductor Ag2Se quantum dots with various sizes?

The surface of nanocrystals plays a dominant role in many of their physical and chemical properties. However, controllability and tunability of nanocrystal surfaces remain unsolved. Herein, we report that the surface chemistry of nanocrystals, such as near-infrared Ag2Se quantum dots (QDs), is size-dependent and composition-tunable. The Ag2Se QDs tend to form a stable metal complex on the surface to minimize the surface energy, and therefore the surface chemistry can be varied with particle size. Meanwhile, changes in surface inorganic composition lead to reorganization of the surface ligands, and the surface chemistry also varies with composition. Therefore, the surface chemistry of Ag2Se QDs, responsible for the photoluminescence (PL) quantum yield and photostability, can be tuned by changing their size or composition. Accordingly, we demonstrate that the PL intensity of the Ag2Se QDs can be tuned reversely by adjusting the degree of surface Ag+ enrichment via light irradiation or the addition of AgNO3. This work provides insight into the control of QD surface for desired PL properties.

Mst1 silencing alleviates hypertensive myocardial injury associated with the augmentation of microvascular endothelial cell autophagy.

The activation of mammalian ste20­like kinase1 (Mst1) is a crucial event in cardiac disease development. The inhibition of Mst1 has been recently suggested as a potential therapeutic strategy for the treatment of diabetic cardiomyopathy. However, whether silencing Mst1 also protects against hypertensive (HP) myocardial injury, or the mechanisms through which this protection is conferred are not yet fully understood. The present study aimed to explore the role of Mst1 in HP myocardial injury using in vivo and in vitro hypertension (HP) models. Angiotensin II (Ang II) was used to establish HP mouse and cardiac microvascular endothelial cell (CMEC) models. CRISPR/adenovirus vector transfection was used to silence Mst1 in these models. Using echocardiography, hematoxylin and eosin staining, Masson's trichrome staining, the enzyme­linked immunosorbent assay detection of inflammatory factors, the enzyme immunoassay detection of oxidative stress markers, terminal deoxynucleotidyl transferase dUTP nick­end labeling staining, scanning electron microscopy, transmission electron microscopy, as well as immunofluorescence and western blot analysis of the autophagy markers, p62, microtubule­associated proteins 1A/1B light chain 3B and Beclin­1, it was found that Ang II induced HP myocardial injury with impaired cardiac function, increased the expression of inflammatory factors, and elevated oxidative stress in mice. In addition, it was found that Ang II reduced autophagy, enhanced apoptosis, and disrupted endothelial integrity and mitochondrial membrane potential in cultured CMECs. The silencing of Mst1 in both in vivo and in vitro HP models attenuated the HP myocardial injury. On the whole, these findings suggest that Mst1 is a key contributor to HP myocardial injury through the regulation of cardiomyocyte autophagy.

Quantum Dots with a Compact Amphiphilic Zwitterionic Coating.

Generally speaking, it is difficult to keep nanomaterials encapsulated in amphiphilic polymers like octylamine-grafted poly(acrylic acid) (OPA) compact in coating-layer, with a small hydrodynamic size. Here, we prepared stable hydrophilic quantum dots (QDs) via encapsulation in ∼3 nm-long amphiphilic and zwitterionic (AZ) molecules. After encapsulation with AZ molecules, the coated QDs are only 2.1 nm thicker in coating, instead of 5.4 nm with OPA. Meanwhile, the hydrodynamic sizes of CdSe/CdS, ZnCdSeS, ZnCdSe/ZnS, and CdSe/ZnS QDs encapsulated in AZ molecules (AZ-QDs) are less than 15 nm, and 6-7 nm smaller than those of QDs in OPA (OPA-QDs). Notably, both extracellular and intracellular nonspecific binding of AZ-QDs is approximately 100-folds lower than that of OPA-QDs.

Breaking through the Size Control Dilemma of Silver Chalcogenide Quantum Dots via Trialkylphosphine-Induced Ripening: Leading to Ag2Te Emitting from 950 to 2100 nm.

Ag2Te is one of the most promising semiconductors with a narrow band gap and low toxicity; however, it remains a challenge to tune the emission of Ag2Te quantum dots (QDs) precisely and continuously in a wide range. Herein, Ag2Te QDs emitting from 950 to 2100 nm have been synthesized via trialkylphosphine-controlled growth. Trialkylphosphine has been found to induce the dissolution of small-sized Ag2Te QDs due to its stronger ability to coordinate to the Ag ion than that of 1-octanethiol, predicated by the density functional theory. By controlling this dissolution effect, the monomer supply kinetics can be regulated, achieving precise size control of Ag2Te QDs. This synthetic strategy results in state-of-the-art silver-based QDs with emission tunability. Only by taking advantage of such an ultrawide emission has the sizing curve of Ag2Te been obtained. Moreover, the absolute photoluminescence quantum yield of Ag2Te QDs can reach 12.0% due to their well-passivated Ag-enriched surface with a density of 5.0 ligands/nm2, facilitating noninvasive in vivo fluorescence imaging. The high brightness in the long-wavelength near-infrared (NIR) region makes the cerebral vasculature and the tiny vessel with a width of only 60 µm clearly discriminable. This work reveals a nonclassical growth mechanism of Ag2Te QDs, providing new insight into precisely controlling the size and corresponding photoluminescence properties of semiconductor nanocrystals. The ultrasmall, low-toxicity, emission-tunable, and bright NIR-II Ag2Te QDs synthesized in this work offer a tremendous promise for multicolor and deep-tissue in vivo fluorescence imaging.

LYSMD3: A mammalian pattern recognition receptor for chitin.

Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, it is unclear how mammals recognize chitin and the principal receptor(s) on epithelial cells that sense chitin remain to be determined. In this study, we show that LYSMD3 is expressed on the surface of human airway epithelial cells and demonstrate that LYSMD3 is able to bind chitin, as well as ß-glucan, on the cell walls of fungi. Knockdown or knockout of LYSMD3 also sharply blunts the production of inflammatory cytokines by epithelial cells in response to chitin and fungal spores. Competitive inhibition of the LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 also blocks chitin signaling. Our study reveals LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and establishes its role in epithelial cell inflammatory responses to chitin and fungi.

Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic.

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.

Liver failure in pregnancy: a review of 25 cases.

We retrospectively reviewed the medical records from 25 pregnant women with liver failure from May 2009 to July 2019. Data describing clinical symptoms and manifestations, routine blood analyses, coagulation, and liver and kidney function were extracted. Swansea criteria were assessed to identify variables with prognostic significance for maternal mortality. The results showed that acute fatty liver was the primary cause of liver failure and 8 (88.89%) patients died within 7 days. Swansea diagnostic criteria for assessing the severity of liver failure were consistent with Chinese guidelines and were more systematic and convenient. The incidence of postpartum haemorrhage was 76%, and the velocity of bleeding was approximately 600 mL per hour. Increased Swansea score, hepatic encephalopathy and decreased PWR were important prognostic indicators for mortality. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes.Impact statementWhat is already known on this subject? Liver failure in pregnant women is a rare but potentially devastating disease with a high rate of short-term morbidity and mortality. There are limited reports about clinical predictors of maternal-foetal outcomes and the dilemmas faced in the term of delivery.What the results of this study add? The incidence of postpartum haemorrhage was 76% in pregnant women with liver failure, but the velocity of bleeding was approximately 600 mL per hour. Our study revealed the Swansea score and the ratio of hepatic encephalopathy were significantly higher and platelet-to-white blood cell ratio (PWR) was lower in women who died compared to those who survived. During treatment period, 8 (88.89%) patients died within 7 days.What the implications are of these findings for clinical practice and/or further research? Swansea score, hepatic encephalopathy and PWR were important prognostic indicators for mortality in pregnant women with liver failure. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes. Our findings may prompt researchers to conduct a large multicentre study to evaluate the prognostic indicators for mortality in pregnant women with liver failure.

Near-Infrared IIb Emitting Nanoprobe for High-Resolution Real-Time Imaging-Guided Photothermal Therapy Triggering Enhanced Anti-tumor Immunity.

The change of tumor vessels is an important indicator for the evolution of cancer, which largely reflects the curative degrees. Therefore, in situ monitoring of the change of tumor vessels during the course of medical treatment becomes an urgent need for the implementation of therapy. Photothermal therapy (PTT), a promising treatment for cancer, has attracted extensive attention. So far, it lacks precise methods for visualizing tumor vessels during the PTT treatment in a noninvasive way. Herein, the quantum-dot-based nanoprobes emitting in the 1500-1700 nm range of the second near-infrared region (NIR-IIb window) with good photothermal conversion performance are conjugated with arginine-glycine-aspartate peptide and successfully applied to imaging-guided photothermal therapy. Owing to the high resolution of NIR-IIb fluorescence imaging, the process of significant reduction of tumor-associated vessels and abnormal angiogenesis is clearly demonstrated. Encouragingly, the immune response can be activated after the photothermal therapy. Excellent therapeutic efficacy with suppressed recurrence is achieved under the synergistic effect of destroying tumor tissues and enhancing immunity. This work provides a noninvasive method to evaluate the changes of tumor microvessel density for anti-angiogenesis therapy and affords a powerful tool for in vivo research of preclinical animal models and precise cancer therapies.

Molecular Targeting Nanoprobes with Non-Overlap Emission in the Second Near-Infrared Window for in Vivo Two-Color Colocalization of Immune Cells.

Monitoring specific immune cells in vivo will provide significant information for improving the therapeutic effect of immunotherapy. Herein, the in vivo two-color fluorescence molecular imaging of an important immune cell, myeloid-derived suppressor cell (MDSC), was realized by using quantum dot (QD)-based nanoprobes with non-overlap emission in the second near-infrared window (NIR-II, 1000-1700 nm). NIR-IIa and NIR-IIb QDs were conjugated with two MDSC-specific antibodies, respectively, and targeted the in vivo MDSCs together. Due to the suppressed photon scattering and diminished autofluorescence in the NIR-II window, the distribution of MDSCs in different organs and tissues was clearly revealed in a non-invasive way by the colocalization of two-color fluorescence from nanoprobes. The high-resolution imaging further confirmed the exact distribution of MDSCs in tumor immune microenvironment (TIME). Our results demonstrated that NIR-II fluorescence nanoprobes with molecular targeting ability provided a powerful tool for monitoring the dynamic change of immune cell populations in TIME in vivo, thus guiding the choice of clinical medicine and evaluating the therapeutic effect.

Cell Membrane-Camouflaged NIR II Fluorescent Ag2 Te Quantum Dots-Based Nanobioprobes for Enhanced In Vivo Homotypic Tumor Imaging.

The advantages of fluorescence bioimaging in the second near-infrared (NIR II, 1000-1700 nm) window are well known; however, current NIR II fluorescent probes for in vivo tumor imaging still have many shortcomings, such as low fluorescence efficiency, unstable performance under in vivo environments, and inefficient enrichment at tumor sites. In this study, Ag2 Te quantum dots (QDs) that emit light at a wavelength of 1300 nm are assembled with poly(lactic-co-glycolic acid) and further encapsulated within cancer cell membranes to overcome the shortcomings mentioned above. The as-prepared ≈100 nm biomimetic nanobioprobes exhibit ultrabright (≈60 times greater than that of free Ag2 Te QDs) and highly stable (≈97% maintenance after laser radiation for 1 h) fluorescence in the NIR II window. By combining the active homotypic tumor targeting capability derived from the source cell membrane with the passive enhanced permeation and retention effect, improved accumulation at tumor sites ((31 ± 2)% injection dose per gram of tumor) and a high tumor-to-normal tissue ratio (13.3 ± 0.7) are achieved. In summary, a new biomimetic NIR II fluorescent nanobioprobe with ultrabright and stable fluorescence, homotypic targeting and good biocompatibility for enhanced in vivo tumor imaging is developed in this study.

Innate Immunity Induced by the Major Allergen Alt a 1 From the Fungus Alternaria Is Dependent Upon Toll-Like Receptors 2/4 in Human Lung Epithelial Cells.

Allergens are molecules that elicit a hypersensitive inflammatory response in sensitized individuals and are derived from a variety of sources. Alt a 1 is the most clinically important secreted allergen of the ubiquitous fungus, Alternaria. It has been shown to be a major allergen causing IgE-mediated allergic response in the vast majority of Alternaria-sensitized individuals. However, no studies have been conducted in regards to the innate immune eliciting activities of this clinically relevant protein. In this study, recombinant Alt a 1 was produced, purified, labeled, and incubated with BEAS-2B, NHBE, and DHBE human lung epithelial cells. Alt a 1 elicited strong induction of IL-8, MCP-1, and Gro-a/b/g. Using gene-specific siRNAs, blocking antibodies, and chemical inhibitors such as LPS-RS, it was determined that Alt a 1-induced immune responses were dependent upon toll-like receptors (TLRs) 2 and 4, and the adaptor proteins MYD88 and TIRAP. Studies utilizing human embryonic kidney cells engineered to express single receptors on the cell surface such as TLRs, further confirmed that Alt a 1-induced innate immunity is dependent upon TLR4 and to a lesser extent TLR2.

Pranlukast, a novel binding ligand of human Raf1 kinase inhibitory protein.

OBJECTIVES: To study the binding of pranlukast to hRKIP and its regulatory role in the Raf1/MEK/ERK signal pathway. RESULTS: NMR and fluorescence experiments demonstrated hRKIP could bind pranlukast with a binding constant of 1016 mM(-1). Residues (Y81, S109 and Y181) on the conserved ligand-binding pocket of hRKIP played a crucial role in binding pranlukast, and their mutations reduced the binding affinity more than 85 %. Furthermore, 25 µM pranlukast could up-regulate the ERK phosphorylation by about 17 %. CONCLUSION: Pranlukast may be used as a potential drug precursor for treating hRKIP involved diseases.