Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition.

COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC50 = 1.53 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.

Synthesis and anti-inflammatory activity of novel firocoxib analogues with balanced COX inhibition.

The adverse effects caused by nonselective and selective cyclooxygenase-2 (COX-2) inhibitors remain a challenge for current anti-inflammatory medications. A balanced inhibition of COX-1/-2 represents a promising strategy for the development of novel COX-2 inhibitors. In this study, we present the design and synthesis of a novel series of firocoxib analogues incorporating an amide bond to facilitate essential hydrogen bonding with amino residues in COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX-1 and COX-2 enzymes. Among them, compound 9d demonstrated potent and balanced inhibition. Inhibition of COX enzymes by 9d in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages resulted in the suppression of the NF-κB signaling pathway to reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, nitric oxide (NO), and reactive oxygen species (ROS). The remarkable in vitro anti-inflammatory activity exhibited by 9d positions it as a promising candidate for further development as a novel lead compound for inflammation treatment.

Exploring peptides from toad venom for source identification by LC-MS/MS using MRM method.

Toad venom is a traditional Chinese medicine (TCM) with various sources and wide-ranging preparations. Previous quality assessment studies primarily concentrated on small molecular compounds like toad dienolactones and indole alkaloids, studies on macromolecular peptides and proteins as quality assessment standards remained at the qualitative stage, lacking the development of practical and convenient quantitative methods. In this study, to explore the peptides from toad venom as a new method for identifying and evaluating its source, a complete scan of the water extract of peptides from toad venom was conducted using HPLC-Quadrupole Time-of-Flight Mass Spectrometer (Q-TOF) 5600, leading to the identification of peptides based on mass spectrometry data. Subsequently, HPLC- Quadrupole-Linear Ion Trap Mass Spectrometer (Q-Trap) 5500 employing Multiple Reaction Monitoring (MRM) mode was utilized to quantitatively analyze peptides in various sources of toad venom, followed by Partial Least Squares Discriminant Analysis (PLS-DA) to further analyze the data and evaluate the effectiveness. This study highlights the importance of exploring macromolecular substance in natural products research and provides a foundation for further studies on toad venom.

Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years.

Cyclooxygenases play a vital role in inflammation and are responsible for the production of prostaglandins. Two cyclooxygenases are described, the constitutive cyclooxygenase-1 and the inducible cyclooxygenase-2, for which the target inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins are a class of lipid compounds that mediate acute and chronic inflammation. NSAIDs are the most frequent choices for treatment of inflammation. Nevertheless, currently used anti-inflammatory drugs have become associated with a variety of adverse effects which lead to diminished output even market withdrawal. Recently, more studies have been carried out on searching novel selective COX-2 inhibitors with safety profiles. In this review, we highlight the various structural classes of organic and natural scaffolds with efficient COX-2 inhibitory activity reported during 2011-2021. It will be valuable for pharmaceutical scientists to read up on the current chemicals to pave the way for subsequent research.

Three-dimensional trabecular alignment model.

Trabecular alignment theory has been used to quantify Wolff's Law of bone remodeling. A three-dimensional finite element scheme was developed to analyze the bone remodeling phenomenon. The mathematical model proposed by Mullender et al. and later modified by Smith et al. was adopted to simulate the surface-based trabecular resorption and formation processes. Enhancements incorporated into the previous model include: mapping into three-dimensions, controlling the remodeling signal's passage through marrow, controlling the finite distance the signal may pass through the bone matrix, and including non-bone material in the finite element model. After the model is explained and thoroughly studied, three-dimensional implant surface geometries are simulated.