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The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.NOD-like receptors (NLRs), as a part of intracellular pattern recognition receptors (PRR), are important regulators in innate immune system. The NLRP3 inflammasome which is a member of NLRs has been linked to several human inflammatory diseases. Gouty arthritis is triggered when the deposition of monosodium urate (MSU) crystals in joints induces acute inflammation characterized by the recruitment of macrophages and neutrophils. In this study, we explored the curcumin analogue AI-44 alleviated the gouty arthritis in mice via suppressing MSU engaging NLRP3 inflammasome activation. Furthermore, we demonstrated that AI-44 inhibited the interaction of cathepsin B and NLRP3 to prevent the activation of NLRP3 inflammasome. Moreover, we found AI-44 inhibited the enzyme activity of cathepsin B and bound to the key residue E122 in cytoplasm but not in lysosome. Collectively, these data suggest that AI-44 is a novel drug candidate for the treatment of gouty arthritis through targeting cathepsin B and inhibiting NLRP3 inflammasome activation.

Cerebral ischemia-reperfusion injury (CIRI) is the leading cause of poor neurological prognosis after cardiopulmonary resuscitation (CPR). We previously reported that the extracellular signal-regulated kinase (ERK) activation mediates CIRI. TBOPP purchase Here, we explored the potential ERK/calpain-2 pathway role in CIRI using a rat model of cardiac arrest (CA).

Adult male Sprague-Dawley rats suffered from CA/CPR-induced CIRI, received saline, DMSO, PD98059 (ERK1/2 inhibitor, 0.3mg/kg), or MDL28170 (calpain inhibitor, 3.0mg/kg) after spontaneous circulation recovery. The survival rate and the neurological deficit score (NDS) were utilized to assess the brain function. Hematoxylin stain, Nissl staining, and transmission electron microscopy were used to evaluate the neuron injury. The expression levels of p-ERK, ERK, calpain-2, neuroinflammation-related markers (GFAP, Iba1, IL-1β, TNF-α), and necroptosis proteins (TNFR1, RIPK1, RIPK3, p-MLKL, and MLKL) in the brain tissues were determined by western blotting and immunohisoptosis after CIRI in the CA model rats.Sodium glucose cotransporter-2 (SGLT-2) inhibitor has been reported to exert a glucose-lowering effect in the peritoneum exposed to peritoneal dialysis solution. However, whether SGLT-2 inhibitors can regulate peritoneal fibrosis by suppressing TGF-β/Smad signaling is unclear. We aimed to (i) examine the effect of the SGLT-2 inhibitor empagliflozin in reducing inflammatory reaction and preventing peritoneal dialysis solution-induced peritoneal fibrosis and (ii) elucidate the underlying mechanisms. High-glucose peritoneal dialysis solution or transforming growth factor β1 (TGF-β1) was used to induce peritoneal fibrosis in vivo, in a mouse peritoneal dialysis model (C57BL/6 mice) and in human peritoneal mesothelial cells in vitro, to stimulate extracellular matrix accumulation. The effects of empagliflozin and adeno-associated virus-RNAi, which is used to suppress SGLT-2 activity, on peritoneal fibrosis and extracellular matrix were evaluated. The mice that received chronic peritoneal dialysis solution infusions showed typical features of peritoneal fibrosis, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and upregulated α-smooth muscle actin and collagen I expression. Empagliflozin treatment or downregulation of SGLT-2 expression significantly ameliorated these pathological changes. Inflammatory cytokines (TNF-α, IL-1β, IL-6) and TGF-β/Smad signaling-associated proteins, such as TGF-β1 and phosphorylated Smad (p-Smad3), decreased in the empagliflozin-treated and SGLT-2 downregulated groups. In addition, empagliflozin treatment and downregulation of SGLT-2 expression reduced the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), TGF-β1, α-smooth muscle actin, collagen I, and p-Smad3 accumulation in human peritoneal mesothelial cells. Collectively, these results indicated that empagliflozin exerted a clear protective effect on high-glucose peritoneal dialysis-induced peritoneal fibrosis via suppressing TGF-β/Smad signaling.Fear renewal occurs when the context changes after fear extinction; however, whether avoidance is also influenced by context changes following fear extinction is untested. Forty-two participants performed an avoidance task within a typical fear renewal procedure. During Pavlovian conditioning, two stimuli (CS+) were associated with an aversive electrical stimulus (US), while a third stimulus was not (CS-). During subsequent avoidance learning, clicking a button canceled the delivery of the US during one but not the other CS+. Fear-related levels were then reduced by removing the US and the button in a new context (fear extinction with response prevention [Ext-RP]). Next, persistence of avoidance was tested in the extinction context B (group ABB) or the original conditioning context A (group ABA). We also tested whether ratings of relief pleasantness (based on both the CS- and the avoided CS+) during avoidance and Ext-RP predicted individual levels of persistent avoidance. Results showed that persistent avoidance was higher in conditioning context A than in extinction context B, and was predicted by higher relief pleasantness during avoidance conditioning. We conclude that persistent avoidance poses a threat to the long-term success of Ext-RP, and we propose that interventions aimed at mitigating the influence of context and relief levels might prove beneficial in this regard.