Current Issue : July-September Volume : 2022 Issue Number : 3 Articles : 5 Articles
Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT1A autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 (also known as F15599) is a selective biased agonist which exhibits preferred activation of cortical over brain stem 5-HT1A receptors. Here, we used behavioral, neurochemical and molecular methods to examine the antidepressant-like effects in rats of a single dose of NLX-101 (0.16 mg/kg, i.p.). NLX-101 reduced immobility in the forced swim test when measured 30 min but not 24 h after drug administration. NLX-101 increased extracellular concentrations of glutamate and dopamine in the medial prefrontal cortex, but no changes were detected in the efflux of noradrenaline or 5-HT. NLX-101 also produced an increase in the activation of pmTOR, pERK1/2 and pAkt, and the expression of PSD95 and GluA1, which may contribute to its rapid antidepressant action....
Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-N-(5-(tertbutyl)- 2-hydroxyphenyl)butanamides (1, 2, and 3), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers’ expression and A549 cells’ migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1, 2, and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells....
The non-canonical Wnt signalling receptor ROR1 is aberrantly expressed in numerous cancers, including ovarian and endometrial cancer. We previously reported that silencing ROR1 could inhibit the proliferation and metastatic potential of ovarian and endometrial cancer cells in vitro. Zilovertamab is an ROR1-targeting humanised monoclonal antibody, with demonstrated safety and efficacy in clinical trials of several ROR1-related malignancies. The aim of this study was to investigate the potential of zilovertamab alone, or in combination with commonly utilised gynaecological cancer therapies (cisplatin, paclitaxel and the PARP inhibitor—Olaparib) on highgrade serous ovarian cancer (HGSOC), including models of platinum resistance and homologous recombination deficiency (CaOV3, CaOV3CisR, PEO1 and PEO4) and endometrial cancer (EC) cell lines (Ishikawa and KLE). The effect of zilovertamab (at 25 g/mL or 50 g/mL) +/ agents was investigated using the IncuCyte S3 Live Cell imaging system. Zilovertamab alone inhibited the proliferation of HGSOC and EC cells in vitro, including in models of platinum resistance and homologous recombination deficiency. In general, the addition of commonly used chemotherapies to a fixed dose of zilovertamab did not enhance the observed anti-proliferative activity. This study supports the potential of zilovertamab, or other ROR1-targeting therapies, for treating women with HGSOC and EC....
The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar adult male rats were randomly arranged into four groups. Group 1: the control group; given only the vehicle for 14 days, then given a saline i.p. injection from the 10th to the 14th day. Group 2: the FEB group; rats received FEB (10 mg/kg) once daily po for 14 days before receiving a saline i.p. injection from the 10th to the 14th day. Group 3: the 5-FU group; from the 10th to the 14th day, rats received an intraperitoneal injection of 5-FU (35 mg/kg/day). Group 4: the FEB/5-FU group; rats were pre-treated with FEB po for 14 days before receiving 5-FU i.p injections for five consecutive days from the 10th to the 14th day. Parotid gland damage was detected histologically and biochemically by the evaluation of oxidative stress markers (malondialdehyde (MDA) and nitric oxide levels (NOx)), oxidant defences (reduced glutathione (GSH) and superoxide dismutase (SOD)), inflammatory markers (tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β)), and transient receptor potential canonical1 (TRCP1) and C/EBP homologous protein (CHOP). FEB pre-treatment reduced MDA, TNF-, and IL-1 while increasing SOD, GSH, and NOx. FEB also significantly increased TRPC1 and decreased CHOP in parotid gland tissue. In conclusion, FEB pre-treatment reduced 5-FU-induced parotid salivary gland damage not only through its powerful anti-inflammatory and antioxidant effects, but also through its effect on the TRPC1/CHOP signalling pathway....
The administration of zoledronic acid (ZA) to patients who received cementless total hip arthroplasty (THA) has been reported to reduce bone turnover markers (BTMs) and increase bone mineral density (BMD). The effects of two-dose ZA versus placebo on cementless THA patients were analyzed in this five-year extension study. Alkaline phosphatase (ALP), osteocalcin (OC), procollagen 1 intact N-terminal propeptide (P1NP), serum calcium, renal function, radiological findings, and functional outcomes were compared in 49 patients, and the periprosthetic BMD of seven Gruen zones were compared in 19 patients. All the patients had normal renal function and calcium levels at their final follow-up. The mean ALP level in the ZA group was significantly lower at the fifth year, mean OC levels were significantly lower at the second and fifth year, and mean P1NP levels were significantly lower from 6 weeks to 5 years as compared with the control group. Fifth-year BMD levels were not found to be different between the ZA and control groups. The BMD Change Ratios in the ZA group were significantly increased in Gruen zone 6 at 1, 2, and 5 years. Our study results suggest that short-term ZA treatment with a subsequent 4-year drug holiday may inhibit serum BTMs and provide periprosthetic bone preservation at five years without adverse events....
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