NEMO-Binding Domain/IKKγ Inhibitory Peptide Alleviates Neuronal Pyroptosis in Spinal Cord Injury by Inhibiting ASMase-Induced Lysosome Membrane Permeabilization.

A short peptide termed NEMO-binding domain (NBD) peptide has an inhibitory effect on nuclear factor kappa-B (NF-κB). Despite its efficacy in inhibiting inflammatory responses, the precise neuroprotective mechanisms of NBD peptide in spinal cord injury (SCI) remain unclear. This study aims to determine whether the pyroptosis-related aspects involved in the neuroprotective effects of NBD peptide post-SCI.

Chemoenzymatic Synthesis of DNP-Functionalized FGFR1-Binding Peptides as Novel Peptidomimetic Immunotherapeutics for Treating Lung Cancer.

Receptor-binding peptides are promising candidates for tumor target therapy. However, the inability to occupy "hot spots" on the PPI interface and rapid metabolic instability are significant limitations to their clinical application. We investigated a new strategy in which an FGFR1-binding peptide (Pep1) was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus.

Identification of potential PIM-2 inhibitors via ligand-based generative models, molecular docking and molecular dynamics simulations.

Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors.

Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps.

Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death.

Apoptotic Bodies Derived from Fibroblast-Like Cells in Subcutaneous Connective Tissue Inhibit Ferroptosis in Ischaemic Flaps via the miR-339-5p/KEAP1/Nrf2 Axis.

Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast-like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival.

Insight into the design of FGFR4 selective inhibitors in cancer therapy: Prospects and challenges.

Recently, FGFR4 has become a hot target for the treatment of cancer owing to its important role in cellular physiological processes. FGFR4 has been validated to be closely related to the occurrence of cancers, such as hepatocellular carcinoma, rhabdomyosarcoma, breast cancer and colorectal cancer. Hence, the development of FGFR4 small-molecule inhibitors is essential to further understanding the functions of FGFR4 in cancer and the treatment of FGFR4-dependent diseases.

A snake cathelicidin enhances transcription factor EB-mediated autophagy and alleviates ROS-induced pyroptosis after ischaemia-reperfusion injury of island skin flaps.

Background And Purpose: Ischaemia-reperfusion (I/R) injury is a major contributor to skin flap necrosis, which presents a challenge in achieving satisfactory therapeutic outcomes. Previous studies showed that cathelicidin-BF (BF-30) protects tissues from I/R injury. In this investigation, BF-30 was synthesized and its role and mechanism in promoting survival of I/R-injured skin flaps explored.

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A mediated lysosomal membrane permeabilization after spinal cord injury.

Background And Purpose: Autophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D-Ala , D-Leu ]-enkephalin) is a selective agonist for delta (δ) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI.

OTUB1 inhibits breast cancer by non-canonically stabilizing CCN6.

Background: CCN6 is a matricellular protein that critically regulates the tumourigenesis and progression of breast cancer. Although the tumour-suppressive function of CCN6 has been extensively studied, molecular mechanisms regulating protein levels of CCN6 remain largely unclear. This study aims to investigate the regulation of CCN6 by ubiquitination and deubiquitinating enzymes (DUBs) in breast cancer.

FGF-18 Protects the Injured Spinal cord in mice by Suppressing Pyroptosis and Promoting Autophagy via the AKT-mTOR-TRPML1 axis.

Spinal cord injury (SCI) is a severe medical condition with lasting effects. The efficacy of numerous clinical treatments is hampered by the intricate pathophysiological mechanism of SCI. Fibroblast growth factor 18 (FGF-18) has been found to exert neuroprotective effects after brain ischaemia, but its effect after SCI has not been well explored.

Cyclic helix B peptide alleviates proinflammatory cell death and improves functional recovery after traumatic spinal cord injury.

Background: Necroptosis and pyroptosis, two types of proinflammatory programmed cell death, were recently found to play important roles in spinal cord injury (SCI). Moreover, cyclic helix B peptide (CHBP) was designed to maintain erythropoietin (EPO) activity and protect tissue against the adverse effects of EPO. However, the protective mechanism of CHBP following SCI is still unknown.

Cu-Catalyzed Regioselective C-H Amination of 2-Indazoles for the Synthesis of Indazole-Containing Indazol-3(2)-ones.

A copper-catalyzed C3 amination of 2-indazoles with 2-indazoles and indazol-3(2)-ones under mild conditions was developed. A series of indazole-containing indazol-3(2)-one derivatives were produced in moderate to excellent yields. The mechanistic studies suggest that the reactions probably proceed through a radical pathway.

Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux.

Increasing evidence suggests that acute traumatic spinal cord injury (SCI)-induced defects in autophagy and autophagy-lysosomal pathway (ALP) may contribute to endothelial barrier disruption following injury. Recently, Kruppel-like factor 2 (KLF2) was reported as a key molecular switch on regulating autophagy. Whether KLF2 coordinates endothelial endothelial ALP in SCI is not known.

3,4-Dimethoxychalcone, a caloric restriction mimetic, enhances TFEB-mediated autophagy and alleviates pyroptosis and necroptosis after spinal cord injury.

Caloric restriction mimetics (CRMs) mimic the favourable effects of caloric restriction (CR) and have been shown to have therapeutic effects in neuroinflammatory disease. However, whether CRMs improve the functional recovery from spinal cord injury (SCI) and the underlying mechanism of action remain unclear. In this study, we used the CRMs 3,4-dimethoxychalcone (3,4-DC) to evaluate the therapeutic value of CRMs for SCI.

4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry.

The 4-Aminopyrazolopyrimidine scaffold has been an interesting pharmacophore since the disclosure of the intimate connection between small-molecule inhibitors and the treatment of diseases. Modification of the 4-aminopyrazolopyrimidine scaffold according to different targets, especially tyrosine kinase and serine/threonine kinase, has resulted in a variety of small-molecule inhibitors. Kinase inhibitors with 4-aminopyrazolopyrimidine derivatives as scaffolds have been widely applied in the treatment of diseases.

TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis.

Mitochondrial dynamics, including mitochondrial fission and fusion, are critical for maintaining mitochondrial functions. Evidence shows that TANK-binding kinase 1 (TBK1) regulates mitochondrial fusion and fission and then mitophagy. Since a previous study demonstrates a strong correlation between mitophagy and osteoarthritis (OA), we herein investigated the potential role of TBK1 in OA process and mitochondrial functions.

The novel FGFR inhibitor F1-7 induces DNA damage and cell death in colon cells.

Background: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients.

Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury.

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both and Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization.

Cyclic helix B peptide promotes random-pattern skin flap survival via TFE3-mediated enhancement of autophagy and reduction of ROS levels.

Background And Purpose: Necrosis of random-pattern skin flaps limits their clinical application. Helix B surface peptide (HBSP) protects tissues from ischaemia-reperfusion injury but its short plasma half-life limits its applications. Here, we have synthesized cyclic helix B peptide (CHBP) and investigated its role in flap survival and the underlying mechanisms.

Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer.

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner.

Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells.

Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant L.

Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression.

Fibroblast growth factor (FGF) receptor 4 (FGFR4) belongs to a family of tyrosine kinase receptor. FGFR4 is highly activated in certain types of cancer and its activation is closely associated with its specific ligand, FGF19. Indeed, FGF19-FGFR4 signaling is implicated in many cellular processes including cell proliferation, migration, metabolism, and differentiation.

The discovery of potent and stable short peptide FGFR1 antagonist for cancer therapy.

Fibroblast growth factor receptor 1 (FGFR1) is one of the attractive pharmaceutical targets for cancer therapy. The FGFR1 targeting antagonist peptides, especially of the short peptides harbouring only coding amino acid might highlights promising aspects for their higher affinity, specificity and lower adverse reactions. However, most of peptides inhibitors remain in preclinical research, likely associating with their instability and short half-life.