Application of cell therapy in rheumatoid Arthritis: Focusing on the immunomodulatory strategies of Mesenchymal stem cells.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease that primarily affects the joints, leading to synovial inflammation and hyperplasia, which subsequently causes joint pain, swelling, and damage. The microenvironment of RA is characterized by hypoxia, high reactive oxygen species (ROS), low pH, and levels of high inflammatory factors. Traditional treatments only partially alleviate symptoms and often cause various adverse reactions with long-term use.

Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity.

Undue central nervous system (CNS) side effects including dysphoria and sedation remain to be a challenge for the development of κ opioid receptor (KOR) agonists as effective and safe analgesics. On the basis of our previous work on morphinan-based KOR agonists, a series of 7α-methyl-7β-substituted northebaine derivatives were designed, synthesized, and biologically assayed. Among others, compound () has been identified as a highly selective and potent KOR agonist both and , and its molecular basis was also examined and discussed.

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging.

κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides.

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from -Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept.

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of -cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound , SLL-039) as a highly selective and potent κ opioid agonist (κ, = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays and antinociceptive assays .

7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues.

Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib.

A series of structurally novel proteasome inhibitors 1-12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC = 9.7 nM) to bortezomib (IC = 8.

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands.

The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable.

Major Depressive Disorder and Kappa Opioid Receptor Antagonists.

Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitor (SNRIs) for this condition have been widely accepted, but they were challenged by unacceptable side-effects, potential drug-drug interactions (DDIs) or slow onset/lack of efficacy. The endogenous opioid system is involved in stress and emotion regulatory processes and its role in MDD has been implicated.

Nanodomain Formation of Ganglioside GM1 in Lipid Membrane: Effects of Cholera Toxin-Mediated Cross-Linking.

Cross-linking of specific lipid components by proteins mediates transmembrane signaling and material transport. In this work, we conducted coarse-grained simulation to investigate the interactions of binding units of chorela toxin (CTB) with mixed ganglioside GM1 and dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. We determine that the binding of CTB pentamers cross-links GM1 molecules into protein-sized nanodomains that have distinct lipid order compared with the bulk.

A novel colorimetric potassium sensor based on the substitution of lead from G-quadruplex.

Potassium ions play diverse roles in biological processes, and abnormal K(+) levels are the hallmarks of diseases. However, the potential clinical application of the developed DNA-based K(+) sensors remains a challenge due to the presence of Pb(2+) in blood samples. In this contribution, a novel colorimetric potassium sensing assay that functions in the presence of Pb(2+) is reported.