Myofibroblasts are central mediators of fibrosis. Typically derived from resident fibroblasts, myofibroblasts represent a heterogeneous population of cells that are principally defined by acquired ...contractile function and high synthetic ability to produce extracellular matrix (ECM). Current literature sheds new light on the critical role of ECM signaling coupled with mechanotransduction in driving myofibroblastic activation. In particular, transforming growth factor β1 (TGF-β1) and extra domain A containing fibronectin (EDA-FN) are thought to be the primary ECM signaling mediators that form and also induce positive feedback loops. The outside-in and inside-out signaling circuits are transmitted and integrated by TGF-β receptors and integrins at the cell membrane, ultimately perpetuating the abundance and activities of TGF-β1 and EDA-FN in the ECM. In this review, we highlight these conceptual advances in understanding myofibroblastic activation, in hope of revealing its therapeutic anti-fibrotic implications.
The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such ...as carbohydrates, small-molecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges.This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and
-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various
-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries.We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck-Matsuda arylation, palladium-catalyzed
-arylation, and regiodivergent 3 + 2 cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.
Macrocycles with bent π‐conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with ...synthetically challenging bent π‐conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5‐triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5‐triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring‐closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5‐triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland–Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2–13.3 μM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.
The first asymmetric total synthesis of spirotetronate polyketides spirohexenolides A and B is reported. This synthesis features a ring‐closing metathesis macrocyclization followed by double dehydration to achieve the C15 macrocycle with the unprecedented deformed nonplanar 1,3,5‐triene conjugation.
Paspaline‐derived indole diterpenes (IDTs) are structurally complex mycotoxins with unique tremorgenic activity. Reported are asymmetric total syntheses of three paspaline‐derived IDTs paspalicine, ...paspalinine and paspalinine‐13‐ene. Our synthesis features a green Achmatowicz rearrangement/bicycloketalization for the efficient construction of FG rings (75 % yield) and a cascade ring‐closing metathesis of dienyne for highly regioselective formation of CD rings (72 % yield). Other highlights include four palladium‐mediated reactions (Stille, aza‐Wacker, Suzuki, and Heck) to forge the BE rings and the installation of two continuous all‐carbon quaternary stereocenters via reductive ring‐opening of cyclopropane and α‐methylation of the conjugate ester. Our new synthetic strategy is expected to be applicable to the chemical synthesis of other paspaline‐derived IDTs and will facilitate the bioactivity studies of these agriculturally and pharmacologically important IDTs.
The asymmetric total synthesis of three paspaline‐derived indole diterpenes paspalicine, paspalinine and paspalinine‐13‐ene is reported. This synthesis features a green Achmatowicz rearrangement/bicycloketalization for the efficient construction of FG rings, a cascade ring‐closing metathesis of dienyne for highly regioselective formation of CD rings, and four palladium‐mediated reactions to forge BE rings.
Epigenetic mechanisms involve the placing (writing) or removal (erasing) of histone modifications that allow heterochromatin to transition to the open, activated euchromatin state necessary for ...transcription. A third, less studied epigenetic pathway involves the reading of these specific histone marks once placed. The BETs (bromodomain and extraterminal-containing protein family), which includes BRD2, BRD3, and BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ-1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension, and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes, and elsewhere suggest BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity, and cell state transitions, whether physiological or pathological, adaptive, or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.
The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. ...Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.
Background
The impacts of chronic airway diseases on coronavirus disease 2019 (COVID‐19) are far from understood.
Objective
To explore the influence of asthma and chronic obstructive pulmonary ...disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID‐19 patients.
Methods
A total of 961 hospitalized COVID‐19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin‐converting enzyme II (ACE2) expression. BEAS‐2B cell line was stimulated with various cytokines.
Results
In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525‐360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461‐267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID‐19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF‐α, IL‐2 receptor, IL‐10, IL‐8, and IL‐6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐4 and IL‐13 downregulated, but TNF‐α, IL‐12, and IL‐17A upregulated ACE2 expression in BEAS‐2B cells.
Conclusion
Patients with asthma and COPD likely have different risk of severe COVID‐19, which may be associated with different ACE2 expression.
After adjusting for confounding factors, COVID‐19 patients with COPD have higher risks of developing severe illness and acute respiratory distress syndrome than COVID‐19 patients with asthma. COPD patients have increased, whereas asthmatics have decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐17A, TNF‐α, and IL‐12 promote, while IL‐4 and IL‐13 suppress ACE2 expression in airway BEAS‐2B cells. Abbreviations: ACE2, angiotensin‐converting enzyme II; ARDS, acute respiratory distress syndrome; BEAS‐2B, adenovirus‐12 SV40 hybrid virus transformed bronchial epithelial cells; COPD, chronic obstructive pulmonary disease; COVID‐19, coronavirus disease 2019.
The daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are ...highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (−)‐himalensine A, which was accomplished in 14 steps. Key features of this strategy include a Cu‐catalyzed nitrile hydration, a Heck reaction to construct the challenging 2‐azabicyclo3.3.1nonane motif, a Meinwald rearrangement reaction, six, pot‐economic reactions, and the minimal use of protecting groups, which significantly improved the overall synthetic efficiency.
A concise strategy to provide diversifiable access to various daphniphyllum alkaloids is described and used in the asymmetric synthesis of (−)‐himalensine A, which was accomplished in only 14 steps. Key features include a Cu‐catalyzed nitrile hydration, a Heck reaction to form the 2‐azabicyclo3.3.1nonane motif, a Meinwald rearrangement, and the minimal use of protecting groups, which improved the overall synthetic efficiency.
Abstract
Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the
Daphniphyllum
alkaloids. Despite ...extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type
Daphniphyllum
alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products.
Pro-inflammatory cytokine production by the retinal pigment epithelium (RPE) is a key etiology in retinal degenerative diseases, yet the underlying mechanisms are not well understood. TMEM97 is a ...scarcely studied transmembrane protein recently implicated in retinal degeneration. BAH domain coiled coil 1 (BAHCC1) is a newly discovered histone code reader involved in oncogenesis. A role for TMEM97 and BAHCC1 in RPE inflammation was not known. Here we found that they constitute a novel axis regulating pro-inflammatory cytokine expression in RPE cells. Transcriptomic analysis using a TMEM97−/− ARPE19 human cell line and the validation via TMEM97 loss- and gain-of-function revealed a profound role of TMEM97 in promoting the expression of pro-inflammatory cytokines, notably IL1β and CCL2, and unexpectedly BAHCC1 as well. Moreover, co-immunoprecipitation indicated an association between the TMEM97 and BAHCC1 proteins. While TMEM97 ablation decreased and its overexpression increased NFκB (p50, p52, p65), the master transcription factor for pro-inflammatory cytokines, silencing BAHCC1 down-regulated NFκB and downstream pro-inflammatory cytokines. Furthermore, in an RPE-damage retinal degeneration mouse model, immunofluorescence illustrated down-regulation of IL1β and CCL2 total proteins and suppression of glial activation in the retina of Tmem97−/− mice compared to Tmem97+/+ mice. Thus, TMEM97 is a novel determinant of pro-inflammatory cytokine expression acting via a previously unknown TMEM97- > BAHCC1- > NFκB cascade.
Retinal pigment epithelium (RPE) inflammation can lead to blindness. We identify here a previously uncharacterized cascade that underlies RPE cell production of pro-inflammatory cytokines. Specifically, transmembrane protein TMEM97 positively regulates the recently discovered histone code reader BAHCC1, which in turn enhances pro-inflammatory cytokine expression via the transcription factor NFκB.
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•TMEM97 promotes the expression of pro-inflammatory cytokines, most notably IL1β and CCL2.•TMEM97 positively regulates BAHCC1 expression and the two proteins co-immunoprecipitate.•The TMEM97/BAHCC1 axis positively regulates NFκB expression.•Retinal IL1β, CCL2, and glial activation are suppressed in oxidant-treated Tmem97−/− mice.
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