Clinical and Experimental Pharmacology and Physiology最新文献

Psoriasis is a complex inflammatory autoimmune skin illness that causes epidermal keratinocyte hyperproliferation and dedifferentiation. In a previous study we did in the lab, we found that treating human keratinocytes (HaCaT) with PUVA increased the expression of hsa-miR-718 compared to control. In this study, an imiquimod (IMQ)-induced mouse model and HaCaT were used to look at how overexpressing miR-718 could help treat psoriasis and its causes. To gain more understanding, the in vivo study used the JAK1/3 inhibitor tofacitinib. We observed that miR-718 overexpression leads to the inhibition of JAK–STAT signalling, as evidenced by the reduced expression of STAT1, JAK proteins, and their phosphorylated forms, both in vitro and in vivo. Luciferase assay demonstrated the direct inhibition of STAT1 due to miR-718 overexpression. Additionally, in vitro experiments showed downregulation of STAT2 and STAT3. Inhibition of basal miR-718 in HaCaT overactivates JAK–STAT signalling proteins. In psoriatic mice, ectopic miR-718 reduces NF-kB, a key mediator of inflammation. IHC shows lower acanthosis and parakeratosis in IMQ-induced psoriatic mice. In the skin of mice that had been miR-718 transfected, there was less VEGF, MMP7 and MMP9. Understanding how miR-718 improves psoriasis not only provides new information but also inspires hope for its potential use as a psoriasis treatment.

Sepsis is the leading cause of acute lung injury (ALI), and kaempferol has a protective effect against ALI. However, the underlying mechanisms have not been fully elucidated. This study aimed to investigate the role of kaempferol in sepsis-induced ALI and its underlying molecular mechanism, particularly the involvement of succinylation. Human pulmonary microvascular endothelial cells were treated with lipopolysaccharide to induce injury. Cell apoptosis and inflammation were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Succinylation was analysed using immunoblotting, co-immunoprecipitation and protein stability assay. The results showed that kaempferol inhibited apoptosis and inflammation response in LPS-treated HPMVECs and attenuated lung damage in septic mice. Moreover, kaempferol enhanced succinylation levels and reduced SIRT5 protein levels. SIRT5 suppressed the succinylation of SRPK1 at lysine (K) 588 site and facilitated SRPK1 degradation. Overexpression of SIRT5 or knockdown of SRPK1 reversed the inhibitory effects of kaempferol or SIRT5 knockdown on cellular biological behaviours, respectively. In conclusion, kaempferol attenuates sepsis-induced lung injury by inhibiting HPMVEC apoptosis and inflammation. Mechanistically, kaempferol suppresses SIRT5-mediated desuccinylation of SRPK1, thereby promoting SRPK1 protein stability. The findings suggest the important role of SRPK1 succinylation in ALI and kaempferol may be used for the treatment of the disease.

Whole blood hydroxychloroquine (WBHCQ) levels were found to correlate with cutaneous lupus (CLE) disease severity. Studies have shown HCQ to be highly variable in blood concentrations and clinical response among patients; however, the exact cause of this variation is not well understood. Genetic polymorphism of CYP450 enzymes was suspected to be a possible contributing factor. This study aimed to determine the effects of genetic polymorphism of CYP450 enzymes on clinical response to HCQ among Malaysians with CLE and its association with blood [HCQ], [DHCQ] or [HCQ]: [DHCQ] ratio. This study was a multicentre cohort study targeting CLE subjects on HCQ, recruited from five main hospitals in Malaysia. A total of 33 subjects were recruited from 1 September 2021 to 30 November 2023. Blood [HCQ], [DHCQ] or its concentration ratio and clinical response to HCQ were the outcome variables determined. Statistical Analysis showed that CYP2D6*10 was significantly associated with blood [HCQ] (p < 0.05), while CYP3A5*3 was shown to be significantly associated with [DHCQ]: [HCQ] ratio (p < 0.05). However, a statistically significant association was not observed between identified SNPs and clinical response to HCQ (OR: 4.444, CI: 0.770, 25.654, p = 0.095). These findings are aligned with those reported previously on blood HCQ and CYP polymorphism; however, clinical response to HCQ and CYP polymorphism is still debatable, as we did not observe any significant association. CYP450 genetic polymorphism significantly affects levels of HCQ in patients. Thus, individual genotypes of CYP450 enzymes may be considered for the optimum use of HCQ among CLE subjects.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved cancer outcomes but can induce immune-related adverse events, including mycobacterial infections. This study retrospectively analysed pulmonary nontuberculous mycobacteria (NTM) infection in 91 patients with pre-existing stage II–IV lung cancer at Shanghai Pulmonary Hospital between June 2015 and June 2024. Among these patients, 78.0% [71/91] were male, and 16.5% [15/91] were receiving ICIs monotherapy at the time of initial pulmonary NTM infection diagnosis (ICIs group). Compared with the non-ICIs group, ICIs-treated patients developed pulmonary NTM infection earlier (median time: 12 months [IQR, 6–18] vs. 21.5 months [IQR, 13–30]; p = 0.004), and had a higher proportion of rapid-growing NTM isolates (73.3% [11/15] vs. 30.3% [23/76]; p = 0.003), predominantly Mycobacterium abscessus complex (40.0% [6/15]). In contrast, Mycobacterium avium complex was the predominant NTM species in the non-ICIs group (71.1% [54/76]). During 12 months of anti-NTM therapy, the ICIs group showed a lower cumulative sputum culture conversion rate (36.4% [4/11] vs. 59.6% [31/52]; p = 0.19) and a longer median time to initial sputum culture conversion (12 months vs. 6 months; p = 0.13), though these differences were not statistically significant. The most commonly administered ICIs drugs were tislelizumab (40.0% [6/15]) and sintilimab (26.7% [4/15]). These findings suggest that ICIs may be associated with earlier development of pulmonary NTM infection in lung cancer patients. Future prospective studies with larger sample sizes are needed to validate this conclusion.

The prevalence of parkinsonism is increasing worldwide, not only in age groups but now becoming a favourite of adults. As the onset is increasing in developed and underdeveloped countries, the current therapy lacks a permanent cure. Therefore, the research has used the gold-containing compound auranofin (AUF) in its neuroprotective form. The research was conducted to decipher the neuroprotective potential of AUF hybrid nanoparticles (AUFHNPs) using the in silico and in vivo 6-OHDA models. The in silico study was performed using CDOCKER software and the binding affinity of AUF with PI3K (5DXT), AKT (1UNQ), GSK-3β (1Q41), Nrf2 (2DYH), and HO-1 (1N45) were assessed. Then, intra-striatal unilateral injection of 6-OHDA (10 μg/2 μL) was given to rats with the help of stereotaxic surgery. After performing the amphetamine challenge test, rodents were treated with AUF (10 mg/kg) and AUFHNPs (5 and 10 mg/kg) for 21 days. All the behaviour parameters were performed on the last 2 days, and animals were sacrificed; brains were isolated for oxidative stress, neuroinflammatory, apoptotic, histological, and molecular marker analysis. In the docking study, AUF offered the highest binding score of −61.1231 with GSK-3β. In vivo administration of AUF and AUFHNPs significantly restored motor and behaviour alterations observed in open field tests, narrow beam walks, and grip strength meter. It also restored morphological changes and increased expression of pPI3K/pAKT, followed by inhibition of GSK-3β. Thus, the AUFHNPs were more significant than AUF alone and exerted neuroprotection via modulation of PI3K/AKT/GSK-3β signalling pathways.