End-expiratory lung volumes as a potential indicator for COVID-19 associated acute respiratory distress syndrome: a retrospective study.

BACKGROUND: End-expiratory lung volume (EELV) has been observed to decrease in acute respiratory distress syndrome (ARDS). Yet, research investigating EELV in patients with COVID-19 associated ARDS (CARDS) remains limited. It is unclear whether EELV could serve as a potential metric for monitoring disease progression and identifying patients with ARDS at increased risk of adverse outcomes. STUDY DESIGN AND METHODS: This retrospective study included mechanically ventilated patients diagnosed with CARDS during the initial phase of epidemic control in Shanghai. EELV was measured using the nitrogen washout-washin technique within 48 h post-intubation, followed by regular assessments every 3-4 days. Chest CT scans, performed within a 24-hour window around each EELV measurement, were analyzed using AI software. Differences in patient demographics, clinical data, respiratory mechanics, EELV, and chest CT findings were assessed using linear mixed models (LMM). RESULTS: Out of the 38 patients enrolled, 26.3% survived until discharge from the ICU. In the survivor group, EELV, EELV/predicted body weight (EELV/PBW) and EELV/predicted functional residual capacity (EELV/preFRC) were significantly higher than those in the non-survivor group (survivor group vs. non-survivor group: EELV: 1455 vs. 1162 ml, P = 0.049; EELV/PBW: 24.1 vs. 18.5 ml/kg, P = 0.011; EELV/preFRC: 0.45 vs. 0.34, P = 0.005). Follow-up assessments showed a sustained elevation of EELV/PBW and EELV/preFRC among the survivors. Additionally, EELV exhibited a positive correlation with total lung volume and residual lung volume, while demonstrating a negative correlation with lesion volume determined through chest CT scans analyzed using AI software. CONCLUSION: EELV is a useful indicator for assessing disease severity and monitoring the prognosis of patients with CARDS.

Myofibroblast-derived exosomes enhance macrophages to myofibroblasts transition and kidney fibrosis.

A critical event in the pathogenesis of kidney fibrosis is the transition of macrophages into myofibroblasts (MMT). Exosomes play an important role in crosstalk among cells in the kidney and the development of renal fibrosis. However, the role of myofibroblast-derived exosomes in the process of MMT and renal fibrosis progression remains unknown. Here, we examined the role of myofibroblast-derived exosomes in MMT and kidney fibrogenesis. In vitro, transforming growth factor-ß1 stimulated the differentiation of kidney fibroblasts into myofibroblasts and promoted exosome release from myofibroblasts. RAW264.7 cells were treated with exosomes derived from myofibroblasts. We found purified exosomes from myofibroblasts trigger the MMT. By contrast, inhibition of exosome production with GW4869 or exosome depletion from the conditioned media abolished the ability of myofibroblasts to induce MMT. Mice treatment with myofibroblast-derived exosomes (Myo-Exo) exhibited severe fibrotic lesion and more abundant MMT cells in kidneys with folic acid (FA) injury, which was negated by TANK-banding kinase-1 inhibitor. Furthermore, suppression of exosome production reduced collagen deposition, extracellular matrix protein accumulation, and MMT in FA nephropathy. Collectively, Myo-Exo enhances the MMT and kidney fibrosis. Blockade of exosomes mediated myofibroblasts-macrophages communication may provide a novel therapeutic target for kidney fibrosis.

Remimazolam attenuates inflammation and kidney fibrosis following folic acid injury.

The transition of acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by intense inflammation and progressive fibrosis. Remimazolam is widely used for procedural sedation in intensive care units, such as AKI patients. Remimazolam has been shown to possess anti-inflammatory and organ-protective properties. However, the role of remimazolam in inflammation and renal fibrosis following AKI remains unclear. Here, we explored the effects of remimazolam on the inflammatory response and kidney fibrogenesis of mice subjected to folic acid (FA) injury. Our results showed that remimazolam treatment alleviated kidney damage and dysfunction. Mice treated with remimazolam presented less collagen deposition in FA-injured kidneys compared with FA controls, which was accompanied by a reduction of extracellular matrix proteins accumulation and fibroblasts activation. Furthermore, remimazolam treatment reduced inflammatory cells infiltration into the kidneys of mice with FA injury and inhibited proinflammatory or profibrotic molecules expression. Finally, remimazolam treatment impaired the activation of bone marrow-derived fibroblasts and blunted the transformation of macrophages to myofibroblasts in FA nephropathy. Additionally, the benzodiazepine receptor antagonist PK-11195 partially reversed the protective effect of remimazolam on the FA-injured kidneys. Overall, remimazolam attenuates the inflammatory response and renal fibrosis development following FA-induced AKI, which may be related to the peripheral benzodiazepine receptor pathway.

Decarboxylative Negishi Coupling of Redox-Active Aliphatic Esters by Cobalt Catalysis.

A cobalt-catalyzed decarboxylative Negishi coupling reaction of redox-active aliphatic esters with organozinc reagents was developed. The method enabled efficient alkyl-aryl, alkyl-alkenyl, and alkyl-alkynyl coupling reactions under mild reaction conditions with no external ligand or additive needed. The success of an in situ activation protocol and the facile synthesis of the drug molecule (±)-preclamol highlight the synthetic potential of this method. Mechanistic studies indicated that a radical mechanism is involved.

Three-Component Catalytic Carboxygenation of Activated Alkenes Enabled by Bimetallic Rh(III)/Cu(II) Catalysis.

A novel cascade Cp*Rh(III)-catalyzed C-H alkylation/Cu(II)-promoted α-oxygenation which enabled a three-component carboxygenation of activated alkene is reported. Mild reaction conditions, broad substrate scope, and good functional group tolerance were observed. The synthetic utility of the protocol was showcased by the facile transformations of the product to a variety of structurally diverse molecules. Preliminary mechanistic studies were conducted.

Regioselective Synthesis of 5-Aminooxazoles via Cp*Co(III)-Catalyzed Formal [3 + 2] Cycloaddition of N-(Pivaloyloxy)amides with Ynamides.

A simple and efficient protocol for the regioselective synthesis of 5-aminooxazoles is disclosed. The reaction, catalyzed by a cheap Cp*Co(III) catalyst, starts from easily accessible N-(pivaloyloxy)amides and ynamides. Mild reaction conditions, a broad substrate scope, good functional group tolerance, and good to excellent yields were observed.

Psiguajadials A-K: Unusual Psidium Meroterpenoids as Phosphodiesterase-4 Inhibitors from the Leaves of Psidium guajava.

Bioassay-guided fractionation of the ethanolic extract of the leaves of Psidium guajava led to the isolation of 11 new Psidium meroterpenoids, psiguajadials A-K (1-11), along with 17 known ones (12-28). Their structures and absolute configurations were elucidated by spectroscopic methods and comparison of experimental and calculated ECD. Compounds 1 and 2 represent two unprecedented skeletons of 3,5-diformyl-benzyl phloroglucinol-coupled sesquiterpenoid, while 3 is the first example of Psidium meroterpenoids coupling via an oxepane ring. Putative biosynthetic pathways towards 1 and 2 are proposed. Compounds 1-13 and 16-26 exhibited moderate inhibitory activities against phosphodiesterase-4 (PDE4), a drug target for asthma and chronic obstructive pulmonary disease, with IC50 values in the range of 1.34-7.26 µM.

Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles.

Fluorinated heterocycles play an important role in pharmaceutical and agrochemical industries. Herein, we report on the synthesis of four types of fluorinated heterocycles via rhodium(III)-catalyzed C-H activation of arenes/alkenes and versatile coupling with 2,2-difluorovinyl tosylate. With N-OMe benzamide being a directing group (DG), the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones and 5-fluoropyridin-2(1H)-ones. When N-OPiv benzamides were used, however, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones. Synthetic applications have been demonstrated and the ready availability of both the arene and the coupling partner highlighted the synthetic potentials of these protocols. Mechanistically, these two processes share a common process involving N-H deprotonation, C-H activation, and olefin insertion to form a 7-membered rhodacycle. Thereafter, different reaction pathways featuring ß-F elimination and C-N bond formation are followed on the basis of density functional theory (DFT) studies. These two pathways are DG-dependent and led to the open chain and cyclization products, respectively. The mechanistic rationale was supported by detailed DFT studies. In particular, the origins of the intriguing selectivity in the competing ß-F elimination versus C-N bond formation were elucidated. It was found that ß-F elimination is a facile event and proceeds via a syn-coplanar transition state with a low energy barrier. The C-N bond formation proceeds via a facile migratory insertion of the Rh-C(alkyl) into the Rh(V) amido species. In both reactions, the migratory insertion of the alkene is turnover-limiting, which stays in good agreement with the experimental studies.

Total synthesis of (±)-ganocins B and C.

The first total synthesis of structurally unique polycyclic phenolic meroterpenoids, ganocins B and C is reported. The synthesis features gold-catalyzed intramolecular cascade cyclization to construct the C/D ring bearing an angular methyl group, diastereoselective Michael addition, and acid-mediated one-pot Robinson cyclization/deprotection/isomerization.