Pharmacology最新文献

Introduction: The aim of the study was to investigate the role of D-cycloserine (DCS) in the adaptation process and maintenance of motion sickness (MS).

Methods: In experiment 1, 120 SD rats were used to study the promoting effect of DCS on the adaptation process of MS in rats. They were randomly divided into four groups, DCS-rotation (DCS-Rot), DCS-static, saline-rotation (Sal-Rot), and saline-static, and further divided into three subgroups according to the adaptation time (4 days, 7 days, and 10 days) in each group. After being given DCS (0.5 mg/kg) or 0.9% saline, they were rotated or kept static according to the group. Their fecal granules, total distance, and total activity of spontaneous activity were recorded and analyzed. In experiment 2, other 120 rats were used. The experimental grouping and specific experimental method were the same as experiment 1. According to the grouping of the adaptive maintenance duration, the animals of 14 days, 17 days, and 21 days groups were measured on the corresponding date of the changes in the animals' exploratory behavior.

Results: In experiment 1, the fecal granules, total distance, and total activity of spontaneous activity of Sal-Rot returned to the control level on 9 days, and the DCS-Rot group returned to the control level on 6 days, indicating that DCS could shorten the adaptation time of MS rats from 9 days to 6 days. In experiment 2, the Sal-Rot could not maintain the adaptive state after 14 days' absence from the seasickness environment. The fecal granules of DCS-Rot increased significantly, and total distance and total activity of spontaneous activity of DCS-Rot decreased significantly from 17 days. These illustrate that DCS can prolong the adaptive maintenance time from within 14 days to 17 days in MS rats.

Conclusion: 0.5 mg/kg DCS injected intraperitoneally can shorten the MS adaptation process and extend the maintenance time of adaptation of SD rats.

Introduction: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β).

Methods: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo.

Results: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545.

Conclusion: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.

Introduction: Inappropriate prescribing is common in patients with end-stage kidney disease, especially in those over 65 years of age. Our study aimed to reveal potentially inappropriate drug prescribing in patients on peritoneal dialysis (PD) and explore factors associated with this phenomenon.

Methods: The research was designed as an observational, cross-sectional study on a convenient sample of 145 consecutive patients with PD who attended the four tertiary-care hospitals in Serbia. The main outcome was the extent of inappropriate prescribing, as assessed by the medication appropriateness index, and potential predictors were tested by multiple linear regression.

Results: Inappropriate prescribing was a widespread phenomenon among patients on PD. The main factors that promote inappropriate prescribing in this subgroup of patients on kidney replacement therapy are comorbidities (p = 0.000), increased body weight (p = 0.022), a number of prescribed drugs (p = 0.000), and arterial hypertension on examination (p = 0.030). On the other hand, drinking alcohol and higher systolic blood pressure were associated with a lower inappropriate prescribing.

Conclusion: In order to prevent the occurrence of inappropriate prescribing and its severe health or economic consequences, clinicians should pay special attention when prescribing new drugs to high-risk patients.

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.