Pharmacology最新文献

Introduction: Neutrophils are a pivotal cell type in the K/BxN mouse model of rheumatoid arthritis and play an essential role in the progression of the arthritis. They are readily activated by immune complexes (ICs) via their FcγRs to release IL-1β in addition to other cytokines, which are inducing cartilage destruction. Neutrophils also release neutrophil-active chemokines to recruit themselves in an autocrine manner to perpetuate tissue destruction. FcγR-expression on neutrophils is of crucial importance for the recognition of ICs.

Methods: In this study, due to its high avidity for binding to FcγRs, we investigated the potential anti-inflammatory effect of a recombinant IgG1 Fc hexamer (rFc-µTP-L309C) on neutrophils in the K/BxN mouse model of endogenously generated chronic arthritis. 200 mg/kg rFc-µTP-L309C and human serum albumin (HSA), used as controls, were administered subcutaneously every other day. Mouse ankle joints were monitored daily to generate a clinical score. Immunohistology was used to evaluate neutrophil infiltration and TUNEL to assess apoptosis. ELISA was used to measure IL-1β.

Results: Treatment with rFc-µTP-L309C, but not HSA, was able to significantly ameliorate the arthritis in the K/BxN mice. Significant neutrophil infiltration into the ankle joint was found, but treatment with rFc-µTP-L309C resulted in significantly less neutrophil infiltration. There was no significant influence of rFc-µTP-L309C on neutrophil death or apoptosis. Less neutrophil infiltration could not be correlated to chemokine-mediated migration. Significantly less IL-1β was measured in mice treated with rFc-µTP-L309C.

Conclusion: In the endogenous K/BxN mouse model of rheumatoid arthritis, amelioration can be explained in part by inhibition of neutrophil infiltration into the joints as well as inhibition of IL-1β production. Given the observed inhibitory properties on neutrophils, rFc-µTP-L309C may be a potential therapeutic candidate to treat autoimmune and inflammatory conditions in which neutrophils are the predominant cell type involved in pathogenesis.

Introduction: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN.

Methods: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration.

Results: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively.

Conclusion: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

Introduction: Oxidative stress and inflammation are major factors contributing to the progressive death of dopaminergic neurons in Parkinson's disease (PD). Recent studies have demonstrated that morphine's biosynthetic pathway, coupled with nitric oxide (NO) release, is evolutionarily conserved throughout animals and humans. Moreover, dopamine is a key precursor for morphine biosynthesis.

Method: The present study evaluated a series of preclinical experiments to evaluate the effects of low-level morphine treatment upon neuro-immune tissues exposed to rotenone and 6-OHDA as models of PD, followed by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay and cell/tissue computer-assisted imaging analyses to assess cell/neuronal viability.

Results: Morphine at normal physiological concentrations (i.e., 10-6 M and 10-7 M) provided neuroprotection, as it significantly inhibited rotenone and 6-OHDA dopaminergic insults; thereby, reducing and/or forestalling cell death in invertebrate ganglia and human nerve cells. To ensure that morphine caused this neuroprotective effect, naloxone, a potent opiate receptor antagonist, was employed and the results showed that it blocked morphine's neuroprotective effects. Additionally, co-incubation of NO synthase inhibitor L-NAME also blocked morphine's neuroprotective effects against rotenone and 6-OHDA insults.

Conclusions: Taken together, the present preclinical study showed that while morphine can attenuate lipopolysaccharide-induced inflammation and cell death, both naloxone and L-NAME can abolish this effect. Preincubation of morphine precursors (i.e., L-3,4-dihydroxyphenylalanine, reticuline, and trihexyphenidyl [THP] at physiological concentrations) mimics the observed morphine effect. However, high concentrations of THP, a precursor of the morphine biosynthetic pathway, induced cell death, indicating the physiological importance of morphine biosynthesis in neural tissues. Thus, understanding the morphine biosynthetic pathway coupled with a NO signaling mechanism as a molecular target for neuroprotection against oxidative stress and inflammation in other preclinical models of PD is warranted.

Introduction: Bisphosphonates are widely used for the treatment of osteoporosis, which could cause osteonecrosis of the jaw (also known as bisphosphonate-related osteonecrosis of the jaw [BRONJ]). Currently, there is no effective treatment for BRONJ. Here, we investigated the role of human recombinant semaphorin 4D (Sema4D) in BRONJ in vitro.

Methods: MG-63 and RAW264.7 cells were used to determine the effects of Sema4D on BRONJ. Osteoclast and osteoblast were differentiated by treatment with 50 ng/mL RANKL for 7 days. In vitro BRONJ model was induced by treatment with ZOL (2.5 μm). The development of osteoclasts and osteoblasts was evaluated using ALP activity and ARS staining. qRT-PCR was used to measure the genes relative expression involved in the development of osteoclasts and osteoblasts. In addition, ZOL decreased TRAP-positive area; TRAP protein and mRNA expression were determined using Western blot and qTR-PCR.

Results: ZOL treatment remarkedly suppressed Sema4D expression in RAW264.7 cells. Moreover, ZOL reduced TRAP-positive area and TRAP protein and mRNA expression. In parallel, genes involved in osteoclast formation were reduced by ZOL treatment. In contrast, osteoclast apoptosis was increased by ZOL treatment. Recombinant human Sema4D significantly abolished these effects of ZOL. In addition, ALP activity was reduced by recombinant human Sema4D.

Discussions: Genes involved in osteoblast formation were decreased by recombinant human Sema4D in a dose-dependent manner. We demonstrated that ZOL treatment inhibited Sema4D expression in RAW264.7 cells.

Conclusion: Recombinant human Sema4D treatment can effectively alleviate ZOL-induced inhibition of osteoclast formation and apoptosis and promote osteoblast formation.

Introduction: Acid-related inflammatory damage to the esophageal epithelium is a key component in the development of gastroesophageal reflux disease. Melatonin (MT) is considered as a potential therapeutic agent, but its molecular mechanism is unknown.

Methods: The expression of HIF-1α and pyroptosis-related genes (NLRP3, caspase-1, IL-1β, and IL-18) was analyzed using bioinformatics methods in GSE63401 and validated using quantitative real-time polymerase chain reaction and Western blot in an HEEC inflammation model induced by deoxycholic acid (DCA). Hoechst 33342/PI double staining was used to assess the level of pyroptosis, and the effect of MT treatment was observed. The miRDB, TarBase, miRcode, miRNet, and ENCORI databases were used to predict the long non-coding RNA (lncRNA) targeting HIF-1α and the RNA-binding protein interacting with the lncRNA.

Results: The expressions of Moloney leukemia virus 10 (MOV10), lncRNA NEAT1, HIF-1α, and pyroptosis-related genes were upregulated, while the expression of miR-138-5p was downregulated in acidic DCA-induced HEEC inflammation. MOV10 may bind to lncRNA NEAT1 and stabilize its expression, while lncRNA NEAT1 upregulates the expression of HIF-1α by adsorbing miR-138-5p to activate the NLRP3 inflammasome. However, MT pretreatment can significantly inhibit these processes.

Conclusions: MOV10-lncRNA NEAT1/miR-138-5p/HIF-1α/NLRP3 axis plays a crucial role in acid-related esophageal epithelial inflammatory injury, and MT may exert an esophageal protective effect by inhibiting the pathway.

Introduction: Myeloid differentiation protein 1 (MD1), a negative regulator of toll-like receptor 4 (TLR4), is widely expressed in the heart. Recent studies have shown that MD1 plays an important role in cardiac remodelling. However, the effects and potential mechanisms underlying MD1-mediated atrial remodelling in diabetic cardiomyopathy (DCM) remain unclear. Therefore, this study was designed to explore the role of MD1 in DCM-related atrial remodelling.

Methods: MD1 knockout (MD1-KO) mice and wild-type (WT) littermates were injected with streptozotocin (STZ) to establish a diabetic mouse model. These mice were then used to evaluate MD1 expression and its effects on atrial remodelling in vivo.

Results: MD1 expression was significantly decreased in STZ-induced diabetic mice. The loss of MD1 aggravated atrial fibrosis, inflammation, and apoptosis in DCM mice and promoted atrial remodelling. MD1-KO diabetic mice also showed higher susceptibility to atrial fibrillation (AF) and worse cardiac function. Mechanistically, the deletion of MD1 promoted the activation of the TLR4/NF-κB signalling pathway, resulting in atrial remodelling in DCM mice via increased p65 phosphorylation.

Conclusions: The deletion of MD1 plays an important role in inflammatory and apoptotic atrial remodelling and increases susceptibility to AF in DCM mice, providing a new target for the preventive treatment of DCM-related atrial remodelling.

Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of generally reported lung cancer patients.

Objectives: This is a systematic review of the clinical efficacy and safety of osimertinib in treating epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC.

Methods: A network search was completed for clinical research literature (from inception of each database to May 30, 2020) on osimertinib for EGFR mutation-positive advanced NSCLC. Strict inclusion and exclusion criteria were formulated to screen the literature. After data extraction, RevMan 5.3 software was utilized for quality evaluation and meta-analysis. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events of grades 3 and 4.

Results: Finally, 6 eligible articles and a total of 1,848 patients containing 1,123 in experimental groups and 725 in control groups were included. Meta-analysis indicated that ORR (odds ratio [OR] = 3.40, 95% CI 1.64∼7.01, p = 0.0009), DCR (OR = 4.36, 95% CI 3.09∼6.15, p < 0.00001), PFS (HR = 0.36, 95% CI 0.27∼0.47, p < 0.00001), and OS (OR = 0.58, 95% CI 0.46∼0.72, p < 0.00001) of the experimental group were prominently better than the control group. Adverse events of grades 3 and 4 mainly incorporated decreased nausea, rash, stomatitis, and vomiting, which were dramatically relieved compared with the control group.

Conclusion: Osimertinib is currently an appreciably effective and well-tolerated therapeutic avenue for EGFR mutation-positive advanced NSCLC.

Introduction: Hepatocellular carcinoma (HCC) is the most deadly cancer. Many signal pathways are implicated in HCC development, including sonic hedgehog (SHH). Propofol is an anesthetic commonly used in surgery. Recent studies have reported that propofol inhibits tumorigenesis and the development of HCC in a dose-dependent manner. The study aimed to identify the mechanism of how the propofol-mediated SHH-signaling molecule works in HCC.

Methods: Cell proliferation, apoptosis, and invasion were examined, respectively, through colony formation, TUNEL, caspase-3 activity, and transwell assays. Protein levels of SHH, Ptch1, Smo, and Gli1 were determined via Western blot.

Results: Propofol could inhibit cell proliferation, migration, and invasion and induce apoptosis via suppression on SHH to inactivate the SHH pathway. By mechanistic assays, miR-340-5p was identified to target SHH and negatively regulate SHH. Long intergenic non-protein coding RNA 475 (LINC00475) was the endogenous sponge of miR-340-5p to upregulate SHH. Finally, the rescue assays were implemented. The activator of the SHH pathway completely rescued the effects of LINC00475 and SHH in propofol-induced HCC cells.

Conclusion: Propofol inhibits HCC cell malignant behaviors via repressing LINC00475 to suppress SHH, thus inactivating the SHH pathway. These new findings might contribute to the understanding and application of propofol in HCC.