Recent Advances on Direct Functionalization of Indoles in Aqueous Media.

Indoles and their derivatives have dominated a significant proportion of nitrogen-containing heterocyclic compounds and play an essential role in synthetic and medicinal chemistry, pesticides, and advanced materials. Compared with conventional synthetic strategies, direct functionalization of indoles provides straightforward access to construct diverse indole scaffolds. As we enter an era emphasizing green and sustainable chemistry, utilizing environment-friendly solvents represented by water demonstrates great potential in synthesizing valuable indole derivatives. This review aims to depict the critical aspects of aqueous-mediated indoles functionalization over the past decade and discusses the future challenges and prospects in this fast-growing field. For the convenience of readers, this review is classified into three parts according to the bonding modes (C-C, C-N, and C-S bonds), which focus on the diversity of indole derivatives, the prominent role of water in the chemical process, and the types of catalyst systems and mechanisms. We hope this review can promote the sustainable development of the direct functionalization of indoles and their derivatives and the discovery of novel and practical organic methods in aqueous phase.

Assembly of spirocyclic pyrazolone-pyrrolo[4,3,2-de]quinoline skeleton via cascade [1,5] hydride transfer/cyclization by C(sp3)-H functionalization.

Herein, a highly efficient, scalable, and cascade [1,5] hydride transfer/cyclization method for constructing unique spirocyclic pyrazolone-pyrrolo[4,3,2-de]quinoline structures via C(sp3)-H functionalization is achieved, using pyrazolones and oxindoles attached to C4 amines. This strategy represents a limited approach utilizing C-H activation to construct spirocyclic pyrazolone scaffolds with moderate to excellent reaction performance.

Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus.

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE-/-) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE-/- mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.

Advanced Glycation End Products Induce Vascular Smooth Muscle Cell-Derived Foam Cell Formation and Transdifferentiate to a Macrophage-Like State.

BACKGROUND: Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. METHODS: Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. RESULTS: In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. CONCLUSIONS: CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.

Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque.

Vascular calcification is a key character of advanced plaque in diabetic atherosclerosis. Microcalcification induces plaque rupture, whereas macrocalcification contributes to plaque stability. However, there is still no clear explanation for the formation and transition of these two types of calcification. Based on existing work and the latest international progress, this article provides a brief review of four aspects: calcification transition in plaque; matrix vesicle-mediated calcification transition in plaque; regulation mechanism of matrix vesicle-mediated calcification transition in diabetic plaque; and proposal of a new hypothesis, which may offer a new perspective on the study of the mechanism of calcification transition in plaque.

Role of Matrix Vesicles in Bone-Vascular Cross-Talk.

Matrix mineralization can be divided into physiological mineralization and pathological mineralization. There is a consensus among existing studies that matrix vesicles (MVs) are the starting sites of bone mineralization, and each component of MVs serves a certain function in mineralization. In addition, ectopic MVs pathologically promote undesired calcification, the primary focus of which is the promotion of vascular calcification. However, the specific mechanisms of the actions of MVs in bone-vascular axis cross-talk have not been fully elucidated. This review summarizes the latest research in this field and explores the roles of MVs in the bone-vascular axis with the aim of generating new ideas for the prevention and treatment of vascular calcification and bone metabolic disease.

Role of AGEs in the progression and regression of atherosclerotic plaques.

The formation of advanced glycation end-products(AGEs) is an important cause of metabolic memory in diabetic patients and a key factor in the formation of atherosclerosis(AS) plaques in patients with diabetes mellitus. Related studies showed that AGEs could disrupt hemodynamic steady-state and destroy vascular wall integrity through the endothelial barrier damage, foam cell(FC) formation, apoptosis, calcium deposition and other aspects. At the same time, AGEs could initiate oxidative stress and inflammatory response cascade via receptor-depended and non-receptor-dependent pathways, promoting plaques to develop from a steady state to a vulnerable state and eventually tend to rupture and thrombosis. Numerous studies have confirmed that these pathological processes mentioned above could lead to acute coronary heart disease(CHD) and other acute cardiovascular and cerebrovascular events. However, the specific role of AGEs in the progression and regression of AS plaques has not yet been fully elucidated. In this paper, the formation, source, metabolism, physical and chemical properties of AGEs and their role in the migration of FCs and plaque calcification are briefly described, we hope to provide new ideas for the researchers that struggling in this field.

Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.

Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.

Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research.

Targeted protein degradation (TPD) technology is based on a unique pharmacological mechanism that has profoundly revolutionized medicinal research by overcoming limitations associated with traditional small-molecule drugs. Autophagy, a mechanism for intracellular waste disposal and recovery, is an important biological process in medicinal research. Recently, studies have demonstrated that several emerging autophagic degraders can treat human diseases. Herein we summarize the progress in medicinal research on autophagic degraders, including autophagosome-tethering compounds (ATTEC), autophagy-targeting chimeras (AUTAC), and AUTOphagy-TArgeting chimeras (AUTOTAC), for treating human diseases. These autophagic degraders exhibit excellent potential for treating neurodegenerative diseases. Our research on autophagic degraders provides a new avenue for medicinal research on TPD via autophagy.

Gut microbiota: A magical multifunctional target regulated by medicine food homology species.

BACKGROUND: The relationship between gut microbiota and human health has gradually been recognized. Increasing studies show that the disorder of gut microbiota is related to the occurrence and development of many diseases. Metabolites produced by the gut microbiota are responsible for their extensive regulatory roles. In addition, naturally derived medicine food homology species with low toxicity and high efficiency have been clearly defined owing to their outstanding physiological and pharmacological properties in disease prevention and treatment. AIM OF REVIEW: Based on supporting evidence, the current review summarizes the representative work of medicine food homology species targeting the gut microbiota to regulate host pathophysiology and discusses the challenges and prospects in this field. It aims to facilitate the understanding of the relationship among medicine food homology species, gut microbiota, and human health and further stimulate the advancement of more relevant research. KEY SCIENTIFIC CONCEPTS OF REVIEW: As this review reveals, from the initial practical application to more mechanism studies, the relationship among medicine food homology species, gut microbiota, and human health has evolved into an irrefutable interaction. On the one hand, through affecting the population structure, metabolism, and function of gut microbiota, medicine food homology species maintain the homeostasis of the intestinal microenvironment and human health by affecting the population structure, metabolism, and function of gut microbiota. On the other hand, the gut microbiota is also involved in the bioconversion of the active ingredients from medicine food homology species and thus influences their physiological and pharmacological properties.

Construction of Oxo-Bridged Diazocines via Rhodium-Catalyzed (4+3) Cycloaddition of Carbonyl Ylides with Azoalkenes.

Developing efficient strategies for synthesizing novel diazocine compounds is valuable because their use has been limited by their synthetic accessibility. This work describes the catalytic (4+3) cycloaddition reaction of carbonyl ylides with azoalkenes generated in situ. The rhodium-catalyzed cascade reaction features good atom and step economy, providing the first access to oxo-bridged diazocines. The product could be synthesized on a gram scale and converted into diversely substituted dihydroisobenzofurans.

The emerging role of radical chemistry in the amination transformation of highly strained [1.1.1]propellane: Bicyclo[1.1.1]pentylamine as bioisosteres of anilines.

Bicyclo[1.1.1]pentylamines (BPCAs), emerging as sp3-rich surrogates for aniline and its derivatives, demonstrate unique structural features and physicochemical profiles in medicinal and synthetic chemistry. In recent years, compared with conventional synthetic approaches, the rapid development of radical chemistry enables the assembly of valuable bicyclo[1.1.1]pentylamines scaffold directly through the amination transformation of highly strained [1.1.1]propellane. In this review, we concisely summarize the emerging role of radical chemistry in the construction of BCPAs motif, highlighting two different and powerful radical-involved strategies including C-centered and N-centered radical pathways under appropriate conditions. The future direction concerning BCPAs is also discussed at the end of this review, which aims to provide some inspiration for the research of this promising project.

Nε-Carboxymethyl-Lysine Negatively Regulates Foam Cell Migration via the Vav1/Rac1 Pathway.

BACKGROUND: Macrophage-derived foam cells play a central role in atherosclerosis, and their ultimate fate includes apoptosis, promotion of vascular inflammation, or migration to other tissues. Nε-Carboxymethyl-lysine (CML), the key active component of advanced glycation end products, induced foam cell formation and apoptosis. Previous studies have shown that the Vav1/Rac1 pathway affects the macrophage cytoskeleton and cell migration, but its role in the pathogenesis of diabetic atherosclerosis is unknown. METHODS AND RESULTS: In this study, we used anterior tibiofibular vascular samples from diabetic foot amputation patients and accident amputation patients, and histological and cytological tests were performed using a diabetic ApoE-/- mouse model and primary peritoneal macrophages, respectively. The results showed that the atherosclerotic plaques of diabetic foot amputation patients and diabetic ApoE-/- mice were larger than those of the control group. Inhibition of the Vav1/Rac1 pathway reduced vascular plaques and promoted the migration of macrophages to lymph nodes. Transwell and wound healing assays showed that the migratory ability of macrophage-derived foam cells was inhibited by CML. Cytoskeletal staining showed that advanced glycation end products inhibited the formation of lamellipodia in foam cells, and inhibition of the Vav1/Rac1 pathway restored the formation of lamellipodia. CONCLUSION: CML inhibits the migration of foam cells from blood vessels via the Vav1/Rac1 pathway, and this process affects the formation of lamellipodia.

CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver.

Non-alcoholic fatty liver disease (NAFLD) has become a common chronic disease in the world. NAFLD is not only a simple intrahepatic lesion, but also affects the occurrence of a variety of extrahepatic complications. In particular, cardiovascular complications are particularly serious, which is the main cause of death in patients with NAFLD. To study the relationship between NAFLD and AS may be a new way to improve the quality of life in patients with NAFLD. As we all known, inflammatory response plays an important role in the occurrence and development of NAFLD and AS. In this study, we found that the accumulation of Nε-carboxymethyllysine (CML) in the liver leads to hepatic steatosis. CML can induce the expression of interleukin (IL-1ß), interleukin (IL-6), tumor necrosis factor (TNF-α), C-reactionprotein (CRP) by binding with advanced glycosylation end-product receptor (RAGE) and accelerate the development of AS. After silencing RAGE expression, the expression of pro-inflammatory cytokines was inhibited and liver and aorta pathological changes were relieved. In conclusion, CML/RAGE signal promotes the progression of non-alcoholic fatty liver disease and atherosclerosis. We hope to provide new ideas for the study of liver vascular dialogue in multi organ communication.

RAGE/galectin-3 yields intraplaque calcification transformation via sortilin.

AIMS: Macrocalcification and microcalcification present different clinical risks, but the regulatory of their formation was unclear. Therefore, this study explored the underlying mechanisms of macrocalcification and microcalcification in diabetes mellitus. METHODS: Anterior tibial arteries of amputated diabetic feet were collected. According to the calcium content, patients were divided into less-calcification group and more-calcification group. And calcification morphology in plaques was observed. For further study, an in vivo mouse diabetic atherosclerosis model and an in vitro primary mouse aortic smooth muscle cell model were established. After the receptors for AGEs (RAGE) or galectin-3 were silenced, calcified nodule sizes and sortilin expression were determined. Scanning electron microscopy (SEM) was performed to detect the aggregation of matrix vesicles with the inhibition or promotion of sortilin. RESULTS: Both macro- and microcalcification were found in human anterior tibial artery plaques. Macrocalcification formed after the silencing of RAGE, and microcalcification formed after the silencing of galectin-3. In the process of RAGE- or galcetin-3-induced calcification, sortilin played an important role downstream. SEM showed that sortilin promoted the aggregation of MVs in the early stage of calcification and formed larger calcified nodules. CONCLUSION: RAGE downregulated sortilin and then transmitted microcalcification signals, whereas galectin-3 upregulated sortilin, which accelerated the aggregation of MVs in the early stage of calcification and mediated the formation of macrocalcifications, These data illustrate the progression of two calcification types and suggest sortilin as a potential target for early intervention of calcification and as an effective biomarker for the assessment of long-term clinical risk and prognosis.