Clinical and Experimental Pharmacology and Physiology最新文献

Excessive oxidative stress and apoptosis of ovarian granulosa cells lead to severe ovarian dysfunctions and even premature ovarian insufficiency (POI). Stachydrine (STA), the main active component of Leonurus japonicas, possesses antioxidant and anti-apoptotic actions. However, the effects of STA on POI remain unknown. This work aimed to investigate STA's role in cyclophosphamide (CP)-induced POI. CP was intraperitoneally injected into rats for 14 days (200 mg/kg for day 1, 8 mg/kg for day 2–14) to establish a POI model, and STA (20 or 40 mg/kg/d) was orally given to rats for three weeks after CP treatment. We found that STA treatment (40 mg/kg) alleviated the estrous cycle disorder and the imbalance of serum sex hormone levels in CP-treated rats. Further, STA administration (40 mg/kg) inhibited oxidative stress and apoptosis of ovarian granulosa cells. Subsequently, human granulosa-like cells (KGN) were treated with CP (250 μM) for 48 h, followed by STA administration (1 μM) for 24 h to investigate the in vitro effects of STA. Consistently, STA treatment prevented KGN cells from CP-induced cell damage. In detail, STA treatment activated the Nrf2/HO-1 signalling pathway, thereby inhibiting the oxidative stress and cell apoptosis of CP-injured KGN cells. In conclusion, STA exerted a protective role in CP-induced POI by alleviating oxidative stress and apoptosis through activating the Nrf2/HO-1 signalling pathway, providing a new insight into POI treatment.

Bone cement implantation syndrome is a critical complication of orthopaedic surgery, characterised by hypotension and hypoxemia. This syndrome is hypothesised to result from obstruction caused by fat droplets and the biochemical release of histamine caused by bone cement components. This study aimed to elucidate the histamine release mechanism, focusing on Mas-related G protein-coupled receptor X2 expressed on mast cells, which is hypothesised to be activated by bone cement components. Using a mast cell-deficient mouse femur fracture model, we examined bone cement's effect on serum histamine. Rat basophil-like cells expressing Mas-related G protein-coupled receptor X2 were exposed to monomethyl methacrylate, a bone cement component, to assess degranulation via β-hexosaminidase release. Our findings demonstrated that histamine levels significantly increased in wild-type mice post-cement application, from 27.7 ± 11.1 to 35.3 ± 12.9 ng/mL (p = 0.016). Furthermore, Mas-related G protein-coupled receptor X2 expressing cells showed a marked increase in β-hexosaminidase release upon monomethyl methacrylate stimulation (p = 4.30 × 10⁻⁵). These results support the hypothesis that activating Mas-related G protein-coupled receptor X2 by monomethyl methacrylate contributes to bone cement implantation syndrome via histamine release. Bone cement implantation syndrome can manifest as a condition involving either peripheral vascular embolism, the release of chemical mediators, or a combination of both. Our research elucidates the role of chemical mediators, particularly histamine-induced vasodilation, in the pathophysiology of bone cement implantation syndrome, providing valuable insights that pave the way for targeted interventions to mitigate this severe complication during orthopaedic surgery.

Sepsis is a life-threatening disease caused by the dysregulation of the immune response. It is important to identify influential genes modulating the immune response in sepsis. In this study, we used P-NET, a biologically informed explainable artificial intelligence model, to evaluate the gene importance for sepsis. About 688 important genes were identified, and these genes were enriched in pathways involved in inflammation and immune regulation, such as the PI3K-Akt signalling pathway, necroptosis and the NF-κB signalling pathway. We further selected differentially expressed genes both at bulk and single-cell levels and found TIMP1, GSTO1 and MYL6 exhibited significant different expressions in multiple cell types. Moreover, the expression levels of these 3 genes were correlated with the abundance of important immune cells, such as M-MDSC cells. Further analysis demonstrated that these three genes were highly expressed in sepsis patients with worse outcomes, such as severe, non-survived and shock sepsis patients. Using a drug repositioning strategy, we found navitoclax, curcumin and rotenone could down-regulate and bind to these genes. In conclusion, TIMP1, GSTO1 and MYL6 may serve as promising biomarkers and targets for sepsis treatment.

The study by An et al. provides valuable insights into rocuronium pharmacodynamics in patients with high body fat percentages (PBF). However, the lack of normalisation for acceleromyographic train-of-four (TOF) ratios raises concerns about the validity of endpoints. Due to the acceleromygraph's inherent “inverse fade” artefact, non-normalised TOF ratios may mask clinically significant residual paralysis. For example, a reported TOF of 0.9 could correspond to a true ratio of 0.75 (assuming a baseline of 1.2), overestimating recovery. This methodological gap weakens the study's conclusion on fat-free mass-based dosing advantages in high-PBF patients. Future studies should adopt TOF normalisation or electromyography (EMG)-based monitoring to improve accuracy and patient safety. Addressing this limitation would strengthen the clinical applicability of individualised neuromuscular blocking strategies.

Instances of drug-resistant tuberculosis (TB), particularly multidrug- and extensive drug-resistant TB, are escalating worldwide; therefore, there is an urgent need to explore suitable treatment strategies. This study assessed the precision of matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF MS) in detecting drug-resistant TB. We developed a multiplex MALDI-TOF MS detection assay that concurrently identifies 51 gene mutations for six commonly used medications: rifampicin (RFP), isoniazid (INH), levofloxacin (LVX), moxifloxacin (MOX), capreomycin (CPM) and amikacin (AMK). Subsequently, we evaluated the accuracy of the system by testing clinical sputum samples with known (n = 45) and unknown (n = 254) minimum inhibitory concentrations (MICs), using Sanger-sequenced genes as references. The detection system exhibited a minimum sensitivity of 88.00% and a specificity of 95.24% for the 45 known isolates. Similarly, for the 254 unknown samples, the detection system demonstrated sensitivity and specificity for mutations associated with each medication as follows: RFP—sensitivity: 98.97%, specificity: 99.36%; INH—sensitivity: 97.80%, specificity: 100.00%; LVX and MOX—sensitivity: 97.14%, specificity: 100.00%; AMK and CPM—sensitivity: 100.00%, specificity: 100.00%. The unknown samples also displayed favourable sensitivity and specificity values in the MIC validation as follows: RFP—sensitivity: 92.39%, specificity: 92.59%; INH—sensitivity: 75.21%, specificity: 99.27%; LVX—sensitivity: 75.28%, specificity: 99.39%; MOX—sensitivity: 73.24%, specificity: 91.26%; AMK—sensitivity: 94.87%, specificity: 96.74%; CPM—sensitivity: 89.47%, specificity: 95.83%. Meanwhile, our study allows for the identification of the Mycobacterium tuberculosis complex (MTBC). The MALDI-TOF MS exhibited remarkable accuracy in the detection of drug-resistant TB, making it a potential alternative approach for clinical TB diagnosis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by dopaminergic neuronal loss and chronic neuroinflammation, leading to significant motor and non-motor deficits. This study explores the therapeutic potential of alpha-linolenic acid (ALA), a known antioxidant and anti-inflammatory agent, in a lipopolysaccharide (LPS)-induced murine model of PD. Male Balb-C mice were divided into control, LPS-treated, LPS + ALA-treated and ALA-only groups. Behavioural assessments, including the pole test, rotarod test and open field test, revealed significant motor impairments in LPS-treated mice. Co-treatment with ALA partially ameliorated motor deficits in LPS-treated mice compared to the healthy control group. However, no direct comparison was made with standard PD treatments such as levodopa. Immunohistochemistry analysis showed a 68% reduction in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra pars compacta (SNpc) of LPS-treated mice. Notably, ALA co-treatment preserved dopaminergic neurons, demonstrating its neuroprotective effects. Western blotting and ELISA revealed heightened expression of inflammatory mediators, including TNF-α, IL-1β and NF-κB, in LPS-treated mice. ALA treatment significantly reduced these markers, indicating its capacity to mitigate neuroinflammation. Molecular docking analysis revealed moderate binding affinities of ALA to NF-κB (−5.1 kcal/mol), TNF-α (−5.7 kcal/mol) and IL-1β (−3.9 kcal/mol), suggesting possible interactions with key inflammatory pathways. These interactions were comparable to known inhibitors, indicating ALA's potential for neuroprotection. This study highlights the neuroprotective and anti-inflammatory effects of ALA in reducing dopaminergic neuronal loss and mitigating neuroinflammation in an LPS-induced PD model. Although behavioural improvements were moderate, these findings underscore ALA's potential as an adjunct therapeutic candidate for PD and other neurodegenerative diseases. Further research is warranted to explore its translational applications in clinical settings.

The seminal work by Fink et al. on sex steroid regulation of mood, cognition, and memory has profound implications for understanding sex differences in psychiatric disorders and addiction treatment. Their findings that estradiol upregulates serotonin transporter (SERT) and 5-HT2A receptor expression, along with testosterone's reliance on aromatisation for its serotonergic effects, highlight key neurobiological mechanisms underlying psychiatric conditions. These insights are particularly relevant to addiction medicine, given serotonin's modulatory role in reward pathways and substance use disorders. Recent research by Gu et al. has demonstrated that estradiol reduces serotonin reuptake by downregulating the plasma membrane monoamine transporter (PMAT) through oestrogen receptor beta (ERβ) and MAPK/ERK signalling pathways, further elucidating the neurochemical underpinnings of mood disorders. Additionally, testosterone's effects on serotonergic regulation are dependent on its conversion to estradiol via aromatase, which influences the expression of SERT and 5-HT2A receptors in critical brain regions. This process may explain sex differences in psychiatric disorders and treatment responses, particularly in mood disorders and substance use disorders. From a clinical perspective, understanding aromatase activity's role in modulating serotonergic pathways may aid in predicting treatment responses, particularly for male patients undergoing testosterone replacement therapy. Furthermore, targeting ERβ as a potential treatment strategy could provide novel therapeutic avenues for managing depression and substance use disorders in women experiencing hormonal fluctuations. These findings underscore the importance of sex-specific considerations in psychiatric and addiction treatment paradigms.