Visible-light photoredox-catalyzed radical aryldifluoromethylation of N-arylacrylamides with S-(difluoromethyl)sulfonium salt.

A facile and highly efficient visible-light photoredox-catalyzed protocol for aryldifluoromethylation of acrylamides was developed using S-(difluoromethyl)sulfonium salt as the difluoromethyl source. With this method, pharmaceutically interesting CF2H-containing oxindoles were readily accessed from N-arylacrylamides, and this method featured mild reaction conditions, a broad scope of substrates, good tolerance of functional groups, and good to excellent yields. Control experiments revealed that this protocol proceeded through a difluoromethylation/cyclization cascade process.

[Preparation of hydrophilic Indigo Naturalis based on polyethylene glycol( PEG) surface film-forming method and evaluation].

Polyethylene glycol (PEG) surface film-forming method was used to prepare hydrophilic Indigo Naturalis decoction pieces with stable effect.The preparation process of modified Indigo Naturalis was optimized and its microscopic properties,hydrophilicity,antipyretic efficacy,and safety were systematically evaluated.With equilibrium contact angle as assessment index,the influence of modifier type,modifier dosage,dispersant dosage,and co-grinding time on water solubility of Indigo Naturalis was investigated by single factor test.The results showed that the optimal preparation process was as follows.The 6%PEG6000 is dissolved in 10%anhydrous ethanol solution by sonification and then the mixture is ground with Indigo Naturalis for 2 min.The resultant product is dried on a square tray in an oven at 60℃to remove ethanol and thereby the PEG-modified hydrophilic Indigo Naturalis decoction pieces are yielded.The morphological observation under scanning electron microscope (SEM) indicated that the modified Indigo Naturalis had smoother surface than Indigo Naturalis,and energy spectrometer measurement showed that the nitrogen (N),calcium(Ca),oxygen (O),and silicon (Si) on the surface of modified Indigo Naturalis powder were less than those of Indigo Naturalis powder.Modified Indigo Naturalis had the equilibrium contact angle 18.96°smaller,polar component 22.222 m J·m~(-2)more,and nonpolar component 7.277 m J·m~(-2)smaller than the Indigo Naturalis powder.Multiple light scattering technique was employed to evaluate the dispersion in water and the result demonstrated that the transmittance of Indigo Naturalis and modified Indigo Naturalis was about85%and 75%,respectively,suggesting the higher dispersity of modified Indigo Naturalis.The suspension rate of modified Indigo Naturalis in water was determined by reflux treatment.The result showed that 57%of Indigo Naturalis was not wetted after refluxing for1 h,while the modified Indigo Naturalis was all wetted and dispersed into water.The dissolution of indigo and indirubin of modified Indigo Naturalis increased and the process was more stable.Then,rats were randomized into the blank group,model group,acetaminophen group,Indigo Naturalis group,and hydrophilic Indigo Naturalis group.The temperature changes of rats were observed after administration and the concentration of IL-1ßand TNF-αin serum and IL-1ßand PGE_2in hypothalamus was measured.The results indicated that the temperature of Indigo Naturalis group and hydrophilic Indigo Naturalis group dropped and the IL-1ßlevel of the hydrophilic Indigo Naturalis group decreased (P<0.05) as compared with those in the model group.Thus,both Indigo Naturalis and hydrophilic Indigo Naturalis had antipyretic effect,particularly the hydrophilic Indigo Naturalis.The acute toxicity test of hydrophilic Indigo Naturalis verified that it had no toxicity to rats.In this study,the hydrophilic Indigo Naturalis decoction pieces were prepared with the PEG surface film-forming method,and the antipyretic efficacy and safety were evaluated,which expanded the technological means of powder modification for Chinese medicine and provided a method for clinical use of Chinese medicine.

Immunotherapy for Sepsis Induced by Infections: Clinical Evidence and Potential Targets.

Sepsis is a life-threatening organ dysfunction caused by the maladjustment of the body's response to infection. Abnormal immune response plays an important role in the progression of sepsis, and immunomodulatory therapy is a promising therapeutic strategy for sepsis. Great efforts have been made recently to elucidate the mechanism by which immune dysfunction contributes to sepsis, and identify potential biomarkers and targets for the diagnosis and therapy of sepsis induced by emerging pathogens, especially for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19. In this review, we summarize recent progress on the understanding of immune dysregulation involved in sepsis, and highlight potential biomarkers and targets to evaluate immune status of the patients with sepsis for individualized and precise immunotherapy.

TREML4: a Potential Target for Immunotherapy of Sepsis.

Sepsis is a serious syndrome with a series of abnormalities caused by dysfunctional host response to infection. Toll-like receptor 4 (TLR-4) has been considered as a key regulator of inflammatory response and immune cell apoptosis in lipopolysaccharides (LPS) challenged models. However, in clinical trials, monoclonal antibodies of TLR-4 have not shown therapeutic effects as expected. Moreover, clinical trials based on immunotherapy by regulating inflammatory cytokines during the acute phase of sepsis have also failed. Recent evidence indicates that the fast-acting innate immune system plays a bigger role in blocking the fast progression of sepsis upon infection than the adaptive immune system. Consequently, the strategies for clinical management of sepsis should be shifted from targeting adaptive immune system to targeting innate immune system. In this review, we summarize our understanding of the role of TREML4 in sepsis, and highlight potential value of TREML4 in clinical management of sepsis. Further mechanistic studies on TREML4 such as the identification of its ligand will provide more clues on the development of novel and effective approaches to the prevention and therapy of sepsis.

Laboratory Biomarkers for the Diagnosis and Management of Patients with COVID-19: an Updated Review.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global crisis due to strong infectivity and fast transmission speed. Some patients with Coronavirus Disease 2019 (COVID-19) progress rapidly and may develop fatal complications, which brings serious challenges in disease assessment and treatment. Recent progress in the understanding of the molecular biology of SARS-CoV-2 has led to the identification of a variety of laboratory biomarkers that could be potentially applied to clinical practice for the diagnosis, treatment, and prognosis of patients with COVID-19. In this review we summarize the updated status on the identification of COVID-19 related laboratory markers, and propose further direction on the application of these markers to clinical diagnosis and management of patients with COVID-19.

Clinical management of sepsis resulting from infections including COVID-19.

Sepsis is an important disorder in intensive care medicine, and the emphasis is not on infections but the imbalance in body reactions and life-threatening organ dysfunction. The infection, the imbalance in the body's reaction, and the deadly organ dysfunction are three aspects of sepsis. Currently, there is still a debate on suitable criteria for the diagnosis of patients with sepsis with continuing changes in the guidelines on sepsis management. Here we summarize recent advances on the definitions, diagnosis, and treatment in the clinical practice of sepsis management in the emergency department. We also highlight future research directions on sepsis. In particular, given the global outbreak of coronavirus disease 2019 (COVID-19), we briefly describe the relationship between COVID-19 and sepsis. How to manage sepsis caused by emerging pathogens such as COVID-19 is a new challenge for care professionals in the emergency department.

Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner.

Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays an important pathogenic role. However, the current drugs for IBD treatment are far from optimal. Previous researches indicated that parthenolide (PTL) had not only anti-cancer properties but also strong anti-inflammatory activities. Rationale: To investigate the protective effect of PTL on colon inflammation and demonstrate the underlying gut microbiota-dependent mechanism. Methods: Colon inflammation severity in mouse model was measured by body weight change, mortality, colon length, disease activity index (DAI) score, H&E staining and colonoscopy evaluation. Gut microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA sequencing and targeted metabolomics. Luminex cytokine microarray and Enzyme-linked immunosorbent assay (ELISA) were conducted to measure the colon cytokines profile. The frequency of immune cells in lamina propria (LP) and spleen were phenotyped by flow cytometry. Results: The PTL-treated mice showed significantly relieved colon inflammation, as evidenced by a reduction in body weight loss, survival rate, shortening of colon length, DAI score, histology score and colonoscopy score. Notably, when the gut microbiota was depleted using antibiotic cocktails, the protective effect of PTL on colon inflammation disappeared. PTL treatment downregulated the level of proinflammatory cytokines, including IL-1ß, TNF-α, IL-6, and IL-17A and upregulated the immunosuppressive cytokine IL-10 in colon tissue. 16S rRNA sequencing indicated that PTL-treated mice exhibited much more abundant gut microbial diversity and flora composition. Targeted metabolomics analysis manifested the increased SCFAs production in PTL-treated mice. Additionally, PTL administration selectively upregulated the frequency of colonic regulatory T (Treg) cells as well as downregulated the ratio of colonic T helper type 17 (Th17) cells, improving the Treg/Th17 balance to maintain intestinal homeostasis. Gut microbiota depletion and fecal microbiota transplantation (FMT) was performed to confirm this gut microbiota-dependent mechanism. Conclusions: PTL ameliorated colon inflammation in a gut microbiota-dependent manner. The underlying protective mechanism was associated with the improved Treg/Th17 balance in intestinal mucosa mediated through the increased microbiota-derived SCFAs production. Collectively, our results demonstrated the role of PTL as a potential gut microbiota modulator to prevent and treat IBD.

Topological states from topological crystals.

We present a scheme to explicitly construct and classify general topological states jointly protected by an onsite symmetry group and a spatial symmetry group. We show that all these symmetry-protected topological states can be adiabatically deformed into a special class of states we call topological crystals. A topological crystal in, for example, three dimensions is a real-space assembly of finite-sized pieces of topological states in one and two dimensions protected by the local symmetry group alone, arranged in a configuration invariant under the spatial group and glued together such that there is no open edge or end. As a demonstration of principle, we explicitly enumerate all inequivalent topological crystals for noninteracting time-reversal symmetric electronic insulators with spin-orbit coupling and any one of the 230 space groups. This enumeration gives topological crystalline insulators a full classification.