Leptin, an adipose tissue-derived hormone, exhibits potent tumor promoting effects through various mechanisms. Cathepsin B, a member of the lysosomal cysteine proteases, has been shown to modulate the growth of cancer cells. In this study, we have investigated the role of cathepsin B signaling in leptin-induced hepatic cancer growth. Leptin treatment caused significant increase in the levels of active cathepsin B through the axis of endoplasmic reticulum stress and autophagy induction without significant effects on pre- and pro-forms of cathepsin B. Interestingly, inhibition of cathepsin B signaling by gene silencing or treatment with a selective pharmacological inhibitor (CA-074) prevented leptin-enhanced viability of hepatic cancer cell and suppressed progression of cell cycle, indicating the critical role of cathepsin B in leptin-induced hepatic cancer growth. We have further observed that maturation of cathepsin B is required for NLRP3 inflammasomes activation, which is implicated in the growth of hepatic cancer cell. The crucial roles of cathepsin B maturation in leptin-induced hepatic cancer growth and NLRP3 inflammasomes activation were confirmed in an in vivo HepG2 tumor xenograft model. Taken together, these results demonstrate that cathepsin B signaling plays a pivotal role in leptin-induced hepatic cancer cell growth by activating NLRP3 inflammasomes.

E2F 1, 2, and 3a, (refer to as E2Fs) are a subfamily of E2F transcription factor family that play essential roles in cell-cycle progression, DNA replication, DNA repair, apoptosis, and differentiation. Although the transcriptional regulation of E2Fs has focused on pocket protein retinoblastoma protein complex, recent studies indicate that post-translational modification and stability regulation of E2Fs play key roles in diverse cellular processes. In this study, we found that FBXO1, a component of S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) complex, is an E2Fs binding partner. Furthermore, FBXO1 to E2Fs binding induced K48 ubiquitination and subsequent proteasomal degradation of E2Fs. Binding domain analysis indicated that the Arg (R)/Ile (I) and R/Val (V) motifs, which are located in the dimerization domain of E2Fs, of E2F 1 and 3a and E2F2, respectively, acted as degron motifs (DMs) for FBXO1. Notably, RI/AA or RV/AA mutation in the DMs reduced FBXO1-mediated ubiquitination and prolonged the half-lives of E2Fs. Importantly, the stabilities of E2Fs were affected by phosphorylation of threonine residues located near RI and RV residues of DMs. Phosphorylation prediction database analysis and specific inhibitor analysis revealed that MEK/ERK signaling molecules play key roles in FBXO1/E2Fs' interaction and modulate E2F protein turnover. Moreover, both elevated E2Fs protein levels by knockdown of FBXO1 and decreased E2Fs protein levels by sh-E2F3a delayed G1/S cell cycle transition, resulting in inhibition of cancer cell proliferation. These results demonstrated that FBXO1-E2Fs axis-mediated precise E2Fs stability regulation plays a key role in cell proliferation via G1/S cell cycle transition.

Posttranslational modifications (PTMs) are essential mechanisms that provide chemical diversity to proteins. The additional functional and structural elements can be introduced to exceed the primary amino acid composition. PTMs impact key biological and physiological processes including cell signaling, metabolism, protein degradation and influences interactions with other macromolecules. However, characterization of the structural and functional signatures of modified proteins has been historically limited. Since defects in PTMs are linked to numerous disorders and diseases, PTMs and their modifying enzymes are considered as potential drug targets. This has fueled new initiatives to determine how PTMs affect protein structure and function. In this review, I summarize some of the major, well-studied protein PTMs and related drug targets. Since PTMs are widely used for therapeutic targets or disease markers, highlighting structural changes after PTM provides new frontiers in understanding the detailed mechanism and related drug developments.

Numerous active compounds derived from ginseng exhibit various pharmacological and therapeutic effects in humans. Despite the benefits of ginsenosides, little is known about their influence on embryonic development, especially in human embryonic models. In this study, we evaluated the effect of two ginsenosides (Rg3 and Rh2) on human embryonic development, using embryoid bodies and three-dimensional (3D) aggregates of pluripotent stem cells. We exposed embryoid bodies to varying concentrations of Rg3 and Rh2 (5, 10, and 25μg/mL), and their embryotoxicity was evaluated by measuring the size of the embryoid body and the expression of epithelial-mesenchymal transition (EMT) markers. The growth rates of embryoid bodies were reduced upon treatment with a high concentration (25μg/mL) of Rg3 and Rh2. In addition, Rg3 induced E-cadherin expression while inhibiting N-cadherin and vimentin expression, which implies the inhibition of EMT. Such a change in E-cadherin expression was not observed after Rh2 treatment, but the inhibition of N-cadherin and vimentin expression was observed to be consistent with that observed on treatment with Rg3. Taken together, using the human embryoid model, we found that the two active ginsenosides, Rg3 and Rh2, induce aberrant embryoid body formation and ablate normal EMT.

Pralsetinib (PRL) is a selective Rearranged during Transfection (RET) inhibitor, developed by Blueprint Medicines Corporation for the treatment of RET fusion non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), and medullary thyroid carcinoma (MTC). RET is a known proto-oncogene found in NSCLC, PTC, and MTC. PRL was recently granted accelerated USFDA approval with the brand name GAVRETO™ on 4 September 2020 to treat metastatic RET fusion-positive NSCLC and was updated on 1 December 2020 with the addition of advanced and metastatic RET-altered MTC and PTC in the USA. On 19 November 2021, the European Commission granted conditional marketing authorization to PRL for use as a single agent in adult patients with RET fusion-positive advanced NSCLC. They were not previously treated with an RET inhibitor. This review article summarizes the milestones in the development of PRL, chemistry, chemical (synthesis) research and development, characterization and identification of PRL-resistant RET mutants, the structural basis of resistance to PRL, mechanism of action, pharmacokinetics, pharmacodynamic, adverse effects, and regulatory status, including ongoing clinical trial of PRL and other potential drug candidates, leading to this first approval of PRL for the treatment of various solid tumors (RET fusion NSCLC, MTC, and PTC).

For decades, the use of secondary metabolites of various herbs has been an attractive strategy in combating human diseases. Rosmarinic acid (RA) is a bioactive phenolic compound commonly found in plants of Lamiaceae and Boraginaceae families. RA is biosynthesized using amino acids tyrosine and phenylalanine via enzyme-catalyzed reactions. However, the chemical synthesis of RA involves an esterification reaction between caffeic acid and 3,4-dihydroxy phenyl lactic acid contributing two phenolic rings to the structure of RA. Several studies have ascertained multiple therapeutic benefits of RA in various diseases, including cancer, diabetes, inflammatory disorders, neurodegenerative disorders, and liver diseases. Many previous scientific papers indicate that RA can be used as an anti-plasmodic, anti-viral and anti-bacterial drug. In addition, due to its high anti-oxidant capacity, this natural polyphenol has recently gained attention for its possible application as a nutraceutical compound in the food industry. Here we provide state-of-the-art, flexible therapeutic potential and biomedical features of RA, its implications and multiple uses. Along with various valuable applications in safeguarding human health, this review further summarizes the therapeutic advantages of RA in various human diseases, including cancer, diabetes, neurodegenerative diseases. Furthermore, the challenges associated with the clinical applicability of RA have also been discussed.

The blood-brain barrier (BBB) is composed of specific tight junction proteins and transporters expressed on the lining of endothelial cells of the vasculature in the brain. The structural and functional integrity of the BBB is one of the most critical factors for maintaining brain homeostasis and is mainly regulated by complex interactions between various cell types, such as endothelial cells, pericytes, and astrocytes, which are shaped by their differential responses to changes in microenvironments. Alterations in these cellular components have been implicated in neurodegenerative disorders. Although it has long been considered that BBB dysfunction is a mere ramification of pathological phenomena, emerging evidence supports its critical role in the pathogenesis of various disorders. In epilepsy, heightened BBB permeability has been found to be associated with increased occurrence of spontaneous seizures. Additionally, exaggerated inflammatory responses significantly correlate with increased BBB permeability during healthy aging. Furthermore, it has been previously reported that BBB disruption can be an early marker for predicting cognitive impairment in the progression of Alzheimer's disease. We herein review a potential role of the major cellular components of the BBB, with a focus on the contribution of BBB disruption, in neurodegenerative disease progression.

Ginkgo biloba (Ginkgoaceae), commonly known as "ginkgo", is called a living fossil, and it has been cultivated early in human history for various uses in traditional medicine and as a source of food. As part of ongoing research to explore the chemical diversity and biologically active compounds from natural resources, two new coumaric acid-aliphatic alcohol hybrids, ginkwanghols A (1) and B (2) were isolated from the leaves of G. biloba. The coumaric acid-aliphatic alcohol hybrids of natural products have rarely been reported. The structures of the new compounds were determined by extensive NMR spectroscopic analysis, HRESI-MS, and quantum chemical ECD calculations, and by comparing the experimental HRESI-MS/MS spectrum of chemically transformed compound 1a with the predicted HRESI-MS/MS spectra proposed from CFM-ID 3.0, a software tool for MS/MS spectral prediction and MS-based compound identification. Ginkwanghols A (1) and B (2) increased alkaline phosphatase (ALP) production in C3H10T1/2, a mouse mesenchymal stem cell line, in a dose-dependent manner. In addition, ginkwanghols A and B mediated the promotion of osteogenic differentiation as indicated by the induction of the mRNA expression of the osteogenic markers ALP and osteopontin (OPN).

The role of advanced glycation end products (AGEs) is not limited to diabetes and diabetes-related complications. There are multiple modulators, including the receptor for advanced glycation end products, high mobility group box 1, glyoxalase 1, nuclear factor-kappa B, tumor necrosis factor-α, chronic unpredictable stress, reactive oxygen species, and inflammatory cytokines, which interact with AGE signaling and control diabetes, modulating these interacting modulators. The progression of diabetes, as well as related complications, can be controlled and treated. Natural products rich in bioactive constituents can interact with AGEs and their related mediators through various signaling cascades, thereby controlling and preventing the progression of diabetes. This review provides a deeper assessment of the signaling pathway, interactions between phytochemicals and AGEs, and its mediators, to develop a multifold therapeutic approach to prevent and treat diabetes and its related complications.

Canonical transient receptor potential channels (TRPCs) are nonselective, high calcium permeability cationic channels. The TRPCs family includes TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7. These channels are widely expressed in the cardiovascular and nervous systems and exist in many other human tissues and cell types, playing several crucial roles in the human physiological and pathological processes. Hence, the emergence of TRPCs modulators can help investigate these channels’ applications in health and disease. It is worth noting that the TRPCs subfamilies have structural and functional similarities, which presents a significant difficulty in screening and discovering of TRPCs modulators. In the past few years, only a limited number of selective modulators of TRPCs were detected; thus, additional research on more potent and more selective TRPCs modulators is needed. The present review focuses on the striking desired therapeutic effects of TRPCs modulators, which provides intel on the structural modification of TRPCs modulators and further pharmacological research. Importantly, TRPCs modulators can significantly facilitate future studies of TRPCs and TRPCs related diseases.