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"Fu, Ping"
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Kidney fibrosis: from mechanisms to therapeutic medicines
Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD.
Journal Article
Photoelectrochemical oxidative C(sp3)−H borylation of unactivated hydrocarbons
Organoboron compounds are of high significance in organic synthesis due to the unique versatility of boryl substituents to access further modifications. The high demand for the incorporation of boryl moieties into molecular structures has witnessed significant progress, particularly in the C(sp
3
)−H borylation of hydrocarbons. Taking advantage of special characteristics of photo/electrochemistry, we herein describe the development of an oxidative C(sp
3
)−H borylation reaction under metal- and oxidant-free conditions, enabled by photoelectrochemical strategy. The reaction exhibits broad substrate scope (>57 examples), and includes the use of simple alkanes, halides, silanes, ketones, esters and nitriles as viable substrates. Notably, unconventional regioselectivity of C(sp
3
)−H borylation is achieved, with the coupling site of C(sp
3
)−H borylation selectively located in the distal methyl group. Our method is operationally simple and easily scalable, and offers a feasible approach for the one-step synthesis of high-value organoboron building blocks from simple hydrocarbons, which would provide ample opportunities for drug discovery.
Organoboron compounds are of high interest in organic synthesis due to the versatility of boryl substituents that allows access to further modifications. Here, the authors report on the development of an oxidative C(sp
3
)−H borylation reaction under metal- and oxidant-free conditions, enabled by photoelectrochemical strategy
Journal Article
Ion adsorption-induced reversible polarization switching of a van der Waals layered ferroelectric
Solid-liquid interface is a key concept of many research fields, enabling numerous physical phenomena and practical applications. For example, electrode-electrolyte interfaces with electric double layers have been widely used in energy storage and regulating physical properties of functional materials. Creating a specific interface allows emergent functionalities and effects. Here, we show the artificial control of ferroelectric-liquid interfacial structures to switch polarization states reversibly in a van der Waals layered ferroelectric CuInP
2
S
6
(CIPS). We discover that upward and downward polarization states can be induced by spontaneous physical adsorption of dodecylbenzenesulphonate anions and N,N-diethyl-N-methyl-N-(2-methoxyethyl)-ammonium cations, respectively, at the ferroelectric-liquid interface. This distinctive approach circumvents the structural damage of CIPS caused by Cu-ion conductivity during electrical switching process. Moreover, the polarized state features super-long retention time (>1 year). The interplay between ferroelectric dipoles and adsorbed organic ions has been studied systematically by comparative experiments and first-principles calculations. Such ion adsorption-induced reversible polarization switching in a van der Waals ferroelectric enriches the functionalities of solid-liquid interfaces, offering opportunities for liquid-controlled two-dimensional ferroelectric-based devices.
Whether it is possible to achieve polarization inversion in a ferroelectric without any energy consumption is an open question. Here, the authors demonstrate an energy-free approach to control the polarization state of CuInP
2
S
6
, a typical room-temperature van der Waals layered ferroelectric.
Journal Article
GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy
Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.
Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.
GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.
Journal Article
Optimal decision for the satellite navigation system under navigation countermeasures based on spoofing effect evaluation results
This paper realizes the evaluation and optimal decision of the spoofing effect on the global navigation satellite system (GNSS) under navigation countermeasures based on the game perspective, to overcome the limitations of current relevant research findings and maintain the secure application of the GNSS and maximize its defensive benefit during countering. An evaluation system based on the perspective of the game between spoofing strategies and defense measures is created to build the benefit matrix, which can solve the limitation in building a benefit matrix (the vital element in a game) that conforms to the confrontation‐oriented GNSS spoofing properties. Based on the built benefit matrix, a method integrating the grey expert‐based system with the hybrid evolutionary method is developed to realize quantifying the matrix and further make the optimal decision stably, which can solve the uncertainties of qualitative indices during quantifying and no global optimal solution for benefit equations deduced from the quantified matrix. Finally, based on various judgment principles, simulation and testing results verify the effectiveness of the obtained results and the superiority of the proposed method by comparing the results solved by the method in this paper with the results obtained by other decision‐making processing methods. This paper realizes the evaluation and optimal decision of the spoofing effect on the global navigation satellite system (GNSS) under navigation countermeasures based on the game perspective, to overcome the limitations of the current relevant research findings and maintain the secure application of the GNSS and maximize its defensive benefit during countering. Specifically, it proposes and verifies a method related to the effective evaluation and dynamic decision of GNSS spoofing effect under the satellite navigation confrontation, it selects and updates the optimal defense measure according to the known spoofing strategies under different information conditions, and it minimizes the damage to GNSS. In conclusion, the safety protection ability of GNSS can be enhanced.
Journal Article
Functional roles of circular RNAs during epithelial-to-mesenchymal transition
Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.
Journal Article
Direct radical functionalization of native sugars
Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity
1
,
2
. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies
3
to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transformation of native sugars to complex saccharides remains a notable challenge. Here we describe a photoinduced approach to achieve site- and stereoselective chemical glycosylation from widely available native sugar building blocks, which through homolytic (one-electron) chemistry bypasses unnecessary hydroxyl group masking and manipulation. This process is reminiscent of nature in its regiocontrolled generation of a transient glycosyl donor, followed by radical-based cross-coupling with electrophiles on activation with light. Through selective anomeric functionalization of mono- and oligosaccharides, this protecting-group-free ‘cap and glycosylate’ approach offers straightforward access to a wide array of metabolically robust glycosyl compounds. Owing to its biocompatibility, the method was extended to the direct post-translational glycosylation of proteins.
A radical-based method for functionalizing native sugars shows a way to remove typical protecting-group manipulations.
Journal Article
Development of bifunctional organocatalysts and application to asymmetric total synthesis of naucleofficine I and II
The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps). As a practical application, the asymmetric total synthesis of naucleofficine I (
1a
) and II (
1b
) in ten steps have been accomplished.
Natural products often contain complex N-fused polycyclic structures with multiple substituents and stereocentres. Here, the authors developed a bifunctional organocatalyst that is instrumental in obtaining such structures and applied it to the total synthesis of naucleofficine I and II in 6 steps.
Journal Article
Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes
Difluorocarbene has important applications in pharmaceuticals, agrochemicals and materials, but all these applications proceed using just a few types of reaction by taking advantage of its intrinsic electrophilicity. Here, we report a palladium-catalysed strategy that confers the formed palladium difluorocarbene (Pd=CF
2
) species with both nucleophilicity and electrophilicity by switching the valence state of the palladium centre (Pd(0) and Pd(
ii
), respectively). Controllable catalytic difluorocarbene transfer occurs between readily available arylboronic acids and the difluorocarbene precursor diethyl bromodifluoromethylphosphonate (BrCF
2
PO(OEt)
2
). From just this simple fluorine source, difluorocarbene transfer enables access to four types of product: difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones. The transfer can also be applied to the modification of pharmaceuticals and agrochemicals as well as the one-pot diversified synthesis of fluorinated compounds. Mechanistic and computational studies consistently reveal that competition between nucleophilic and electrophilic palladium difluorocarbene ([Pd]=CF
2
) is the key factor controlling the catalytic difluorocarbene transfer.
Difluorocarbene transfer is mostly limited to reactions that utilize its intrinsic electrophilicity. Now, a controllable palladium-catalysed difluorocarbene transfer reaction is reported that involves nucleophilic and electrophilic palladium difluorocarbene species. The selective reactions between arylboronic acids and the difluorocarbene precursor BrCF
2
PO(OEt)
2
give four different products—difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones.
Journal Article