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Abstract Despite the massive efforts to develop the treatment of pancreatic cancers, no effective application exhibits satisfactory clinical outcome. Macropinocytosis plays a critical role for continuous proliferation of pancreatic ductal adenocarcinoma (PDAC). In this study, we generated a screening method and identified phellodendrine chloride (PC) as a potential macropinocytosis inhibitor. PC significantly inhibited the viability of KRAS mutant pancreatic cancer cells (PANC-1 and MiaPaCa-2) in a dose-dependent manner; however, it did not affect the wild type KRAS pancreatic cancer cells (BxPC-3). Further experiments indicated that PC reduced the growth of PANC-1 cells through inhibition of macropinocytosis and diminishing the intracellular glutamine level. Disruption of glutamine metabolism led to enhance the reactive oxygen species level and induce mitochondrial membrane potential depolarization in PANC-1 cells. PC treatment caused increased Bax and decreased Bcl-2 expression, along with the activation of cleaved caspase-3, 7, 9 and cleaved-PARP, thus induced mitochondrial apoptosis. Moreover, PC inhibited macropinocytosis in vivo and effectively reduced the growth of PANC-1 xenograft tumors. All together, we demonstrated that inhibition of macropinocytosis might be an effective strategy to treat pancreatic cancers. Thus, PC could be a potential compound with improved therapeutic efficacy in patients with pancreatic cancers. [ABSTRACT FROM AUTHOR]

Nowadays, more and more attention has been paid to osteoporosis caused by diabetes mellitus. Elevated levels of pro-inflammatory cytokines in diabetic patients activate the activity of osteoclasts through the RANKL/OPG pathway. The nuclear transcription factor SREBP2, a master regulator of cholesterol metabolism, has been found involved in osteoclastogenesis. In our previous study, we have identified anhydroicaritin as a potent inhibitor of transcription factor SREBPs, which improves dyslipidemia and insulin resistance. In this study, we demonstrated that anhydroicaritin could also decrease the level of SREBP2 and its target genes in osteoclasts induced by RANKL without significant cytotoxicity. Moreover, anhydroicaritin suppressed RANKL-induced osteoclasts differentiation. In STZ-induced diabetic mice model, we found that the osteoclasts were largely increased accompanied with deterioration of bone structure. Anhydroicaritin decreased the level of blood glucose and alleviated insulin resistance. More importantly, anhydroicaritin inhibited osteoclast differentiation and rescued diabetes-induced bone loss in vivo . In conclusion, anhydroicaritin, a potent SREBP2 inhibitor, inhibits the osteoclasts formation and improves diabetes-induced bone loss. [ABSTRACT FROM AUTHOR]

Cyclopamine, an inhibitor of the Hedgehog (Hh) signaling pathway, has been paid much attention in treating a wide variety of tumors. However, isolation and purification of cyclopamine analogs from medicinal plants remain challengeable. We herein proposed an efficient strategy using liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) and liquid chromatography triple-quadrupole mass spectrometry (LC-QqQ-MS) for rapid screening and targeted isolation of cyclopamine analogs in Fritillaria and Veratrum plants. Firstly, fifteen reference compounds were characterized by LC-Q-TOF-MS and their characteristic fragment ions were summarized. Secondly, according to the characteristic fragment ions at m / z 67.1, 84.1, 109.1 and 114.1, rapid chemical screening of plant extracts was carried out by LC-QqQ-MS using precursor ion scan mode and 69 pre-target compounds were screened out. Thirdly, 24 real target compounds were verified by LC-Q-TOF-MS based on relative abundances (over 20%) of characteristic fragment ions. Fourthly, the targeted isolation of Fritillaria ussuriensis bulb and Veratrum dahuricum rhizome afforded a novel cyclopamine analog namely 15 β -hydroxy-23-isopengbeisine B as well as four known ones, whose structures were determined by nuclear magnetic resonance (NMR) analysis. Additionally, these five analogs were evaluated for the inhibitory activity of Hh signaling pathway in NIH/3T3 cell and cytotoxicity in PANC-1 and HepG2 cells. These results indicated that the proposed strategy was reliable for rapid discovery and targeted isolation of important natural products from chemically complex plant matrices. [ABSTRACT FROM AUTHOR]

SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice, AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia. In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases. [ABSTRACT FROM AUTHOR]

As the first histone acetyltransferase to be cloned and identified in yeast, general control non-depressible 5 (GCN5) plays a crucial role in epigenetic and chromatin modifications. It has been extensively studied for its essential role in regulating and causing various diseases. There is mounting evidence to suggest that GCN5 plays an emerging role in human diseases and its therapeutic potential is promising. In this paper, we begin by providing an introduction GCN5 including its structure, catalytic mechanism, and regulation, followed by a review of the current research progress on the role of GCN5 in regulating various diseases, such as cancer, diabetes, osteoporosis. Thus, we delve into the various aspects of GCN5 inhibitors, including their types, characteristics, means of discovery, activities, and limitations from a medicinal chemistry perspective. Our analysis highlights the importance of identifying and creating inhibitors that are both highly selective and effective inhibitors, for the future development of novel therapeutic agents aimed at treating GCN5-related diseases. [Display omitted] • Introduce structure, catalytic mechanism, and regulation of GCN5. • GCN5 modulating the acetylation levels of histones, non-histones and numerous transcription factors. • Systematic reviewing GCN5 inhibitors from a medicinal chemistry perspective. • The current challenges and future perspectives of GCN5 inhibitors. • Regulating GCN5 actions can be a promising treatments on some human diseases. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic endocrine disease result from absolute or relative insulin secretion deficiency, insulin resistance, or both, and has become a major and growing public healthy menace worldwide. Currently, clinical antidiabetic drugs still have some limitations in efficacy and safety such as gastrointestinal side effects, hypoglycemia, or weight gain. Rosmarinus officinalis is an aromatic evergreen shrub used as a food additive and medicine, which has been extensively used to treat hyperglycemia, atherosclerosis, hypertension, and diabetic wounds. A great deal of pharmacological research showed that rosemary extract and its phenolic constituents, especially carnosic acid, rosmarinic acid, and carnosol, could significantly improve diabetes mellitus by regulating glucose metabolism, lipid metabolism, anti-inflammation, and anti-oxidation, exhibiting extremely high research value. Therefore, this review summarizes the pharmacological effects and underlying mechanisms of rosemary extract and its primary phenolic constituents on diabetes and relative complications both in vitro and in vivo studies from 2000 to 2020, to provide some scientific evidence and research ideas for its clinical application. [ABSTRACT FROM AUTHOR]

The development and application of traditional drugs represented by small molecule chemical drugs and biological agents, especially inhibitors, have become the mainstream drug development. In recent years, targeted protein degradation (TPD) technology has become one of the most promising methods to remove specific disease-related proteins using cell self-destruction mechanisms. Many different TPD strategies are emerging based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), including but not limited to proteolysis-targeting chimeras (PROTAC), molecular glues (MG), lysosome targeting chimeras (LYTAC), chaperone-mediated autophagy (CMA)-targeting chimeras, autophagy-targeting chimera (AUTAC), autophagosome-tethering compound (ATTEC), and autophagy-targeting chimera (AUTOTAC). The advent of targeted degradation technology can change most protein targets in human cells from undruggable to druggable, greatly expanding the therapeutic prospect of refractory diseases such as metabolic syndrome. Here, we summarize the latest progress of major TPD technologies, especially in metabolic syndrome and look forward to providing new insights for drug discovery. [Display omitted] [ABSTRACT FROM AUTHOR]