Biomedicine & Pharmacotherapy最新文献

Objective

Analyse the incidence, risk factors, antimicrobial susceptibility profile, and fatality in neonates infected with oxacillin-resistant Staphylococcus spp. (ORS).

Methods

In this retrospective observational descriptive cohort study, the medical records of neonates admitted to the Neonatal Intensive Care Unit (NICU) from January 2015 to June 2022 were analysed. Participants were monitored daily through the National Healthcare Safety Network.

Results

Among the 1610 neonates, 193 (12 %) developed ORS infections, primarily in the bloodstream (96.8 %). The incidence of these infections/patient-days decreased by 51.8 % between 2016 (8.3) and 2022 (4). The median age of affected neonates was 17.5 days (IQR:12–28.7). Pre-emptive prescription of fourth-generation cephalosporins (OR=14.36; P<0.01) emerged as a risk factor in the multivariate analysis. Staphylococcus epidermidis was the most prevalent species (60.1 %), with one isolate showing a “susceptible, increased exposure” profile to vancomycin. Additionally, 2 % of pathogens were extensively drug-resistant (XDR). ORS infections were associated with prolonged hospital stays (from 10 to 46 days) and increased mortality (from 10.2 % to 19.2 %). The median time between infection and the fatal outcome was 15 days (IQR:8–40), and Staphylococcus capitis was the most lethal species (26.7 %).

Conclusions

The high incidence of ORS infections was linked to extended hospitalisation and increased mortality, highlighting the complexity of this situation - a "perfect storm." This underscores the urgency of implementing effective interventions for managing and preventing ORS infections in the NICU.

Recently, increased attention has been focused on the regulatory mechanism and potential clinical application of ferroptosis in cancer cells, especially therapy-related ferroptosis. However, the mechanism of treatment-related ferroptosis and the application prospects and strategies for future treatment still require further clarification. This review highlights the molecular relationships between different clinical antitumour drugs, including commonly used chemotherapy drugs, radiation therapy and vitamins, and ferroptosis. This review also proposes strategies for future treatments that involve ferroptosis, with an aim to develop a new strategy for the transformative potential of the emerging field of ferroptosis to improve cancer therapy.

This study investigates the protective effects of propofol on the myocardium by inhibiting the expression of SLC16A13 through in vivo animal experiments, while also exploring its mechanism in ferroptosis to provide new strategies for preventing perioperative myocardial ischemia-reperfusion injury. We randomly divided 30 rats into three groups (n=10 each): sham surgery group, ischemia-reperfusion (I/R) group, and propofol pretreatment group. The results showed that compared with the sham surgery group, the I/R group had a significant decrease in cardiac function and an increase in infarct size. Propofol pretreatment effectively alleviated the damage caused by ischemia-reperfusion (I/R). In the next phase of the study, we administered the PPARα agonist GW7647 to artificially increase the expression of SLC16A13. Fifty rats were randomly divided into five groups (n=10 each), with the GW7647 pretreatment group and propofol+GW7647 pretreatment group added based on the previous three groups. Afterwards, we validated the in vivo results using H9C2 and further explored the mechanism by which propofol inhibits ferroptosis. The study found that L-lactic acid in myocardial tissue of the GW7647 group was further increased compared to the I/R group, and the degree of ferroptosis was aggravated. In addition, upregulation of SLC16A13 significantly inhibited the phosphorylation of AMPK, weakened the protective mechanism of AMPK, and exacerbated cardiac damage. However, propofol pretreatment can effectively inhibit the expression of SLC16A13, maintain normal myocardial cell morphology, and protect cardiac function. These results indicate that propofol inhibits the expression of SLC16A13, alleviates myocardial cell ferroptosis via the AMPK/GPX4 pathway, and reverses damage caused by myocardial ischemia-reperfusion.

Rosemary (Rosmarinus officinalis L.) is a rich source of dietary bioactive compounds such as rosmarinic acid and carnosol with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. In the present study, we investigated rosemary as a potential new therapeutic agent for cognitive function and other symptoms of aging. In this present study, we have aimed to investigate the effects of oral administration of rosemary extract (RME) on learning and memory in the context of other biomarkers-related cognitive function and neurotransmitter levels in senescent accelerated prone 8 (SAMP8) mouse, a model of accelerating aging and Alzheimer’s disease. The Morris water maze (MWM) test showed improved spatial learning and memory behavior in RME treated SAMP8 mouse. Moreover, RME decreased Aβ₄₂ and inflammatory cytokine levels and increased BDNF, Sirt1, and neurotransmitter levels in SAMP8 mouse. Whole-genome microarray analysis revealed that RME significantly increased gene expression related to oligodendrocyte differentiation, myelination, and ATP production in the hippocampus and decreased gene expression related to stress, neuroinflammation, and apoptosis. Also, in the SAMP8 hippocampus, RME significantly increased Olig1 and Olig2 expression. Altogether, our study is the first to report improvement of spatial learning and memory of RME, modulation of genes important for oligodendrogenesis, and Anti-neuroinflammatory effect by suppressing Aβ₄₂ levels in mouse brain and thus highlights the prospects of RME in the treatment of cognitive dysfunction and aging.

Osteoarthritis (OA) is the most common degenerative joint disease. Multiple tissues are altered during the development of OA, resulting in joint pain and permanent damage to the osteoarticular joints. Current research has demonstrated that non-apoptotic cell death plays a crucial role in OA. With the continuous development of targeted therapies, non-apoptotic cell death has shown great potential in the prevention and treatment of OA. We systematically reviewed research progress on the role of non-apoptotic cell death in the pathogenesis, development, and outcome of OA, including autophagy, pyroptosis, ferroptosis, necroptosis, immunogenic cell death, and parthanatos. This article reviews the mechanism of non-apoptotic cell death in OA and provides a theoretical basis for the identification of new targets for OA treatment.

Metabolic diseases (MetD) such as diabetes mellitus, obesity, and hyperlipidemia have become global health challenges. As a naturally occurring plant component, puerarin has been verified to possess a wide range of pharmacological effects including lowering blood glucose, improving insulin resistance, and regulating lipid metabolism, which has attracted extensive attention in recent years, and its potential in the treatment of MetD has been highly acclaimed. In addition, puerarin has exhibited antioxidant, anti-inflammatory, and cardiovascular protective effects, which are of great significance in the prevention and treatment of MetD. This article comprehensively summarizes the research progress of puerarin in the treatment of MetD and explores its pharmacological mechanisms, clinical applications, and future perspectives. More importantly, this review provided a list of the involved molecular mechanims in treating MetD of puerarin. Taking into account these conclusions, it may provide a strong foundation for the optimized use of puerarin in the treatment of patients suffering from MetD.

Increased blood-brain barrier (BBB) permeability can lead to cerebral vasogenic edema and hemorrhagic transformation (HT) after reperfusion with tissue plasminogen activator (tPA), the only United States Food and Drug Administration (FDA)-approved treatment for acute ischemia stroke (AIS). The therapeutic benefits of tPA after AIS are partially outweighed by a more than a six-fold increase in the risk of symptomatic intracerebral hemorrhage. Therefore, strategies to protect the integrity of BBB are urgently needed to reduce HT and vasogenic edema after tPA thrombolysis or endovascular thrombectomy. Interestingly, an NIH study showed that smokers treated with tPA had a significantly lower prevalence of brain hemorrhage than nonsmokers, suggesting that cigarette smoking may protect patients treated with tPA from the side effects of cerebral hemorrhage. Importantly, we recently showed that treatment with nicotine reduces AIS-induced BBB damage and that modulating α7nAChR by modulation could reduce ischemia/reperfusion-induced BBB damage, suggesting that α7nAChR could be a potential target to reduce BBB after AIS. In this review, we first provide an overview of stroke and the impact of α7nAChR activation on BBB damage. Next, we discuss the features and mechanism of BBB destruction after AIS. We then discuss the effect of nicotine effect on BBB integrity as well as the mechanism underlying those effects. Finally, we discuss the side effects and potential strategies for modulating α7nAChR to reduce AIS-induced BBB damage.

Scutellarin (Scu), a flavonoid from herbal Erigeron breviscapus (Vaniot) Hand-Mazz, exerts neuroprotective effects against cerebral ischemia. However, whether the effects of Scu are related to mitochondrial protection needs further investigation. In this study, we aimed to clarify the mechanisms of Scu against HT22 cells injury caused by oxygen-glucose deprivation and reperfusion (OGD/R). Our results proved that Scu significantly reduced the overload of intracellular reactive oxygen species (cellar ROS) and mitochondria reactive oxygen species (mito-ROS), ameliorating oxidative stress damage. TUNEL positive rate, Caspase-3 activity, and Cytochrome c (Cyto-c) expression remarkably decreased following Scu treatment. Meanwhile, Scu could maintain mitochondrial morphology and reverse ultrastructure changes. And mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), adenosine triphosphate (ATP) production and Na⁺/K⁺-ATPase activity were obviously promoted. Additionally, Scu was found to stimulate mitophagy level by increasing the expression of LC3, Beclin1, PINK1 and Parkin proteins, as well as promoting the degradation of p62. More importantly, the regulatory effects of Scu on mito-ROS, MMP, ATP, Na⁺/K⁺-ATPase, cell viability and lactate dehydrogenase (LDH) were markedly limited by Mdivi-1 (a mitophagy inhibitor). Of note, the inhibitor also reversed Scu-mediated apoptosis suppression, evidenced by the diminished apoptosis rate, the down-regulated expression activities of Cyto-c, Bax and cleaved Caspase-3, as well as the elevated level of Bcl-2 protein. Collectively, Scu could improve mitochondrial dysfunction and inhibit apoptosis by stimulating mitophagy, thereby attenuating OGD/R-induced HT22 cells injury.

Trigonelline (TRIG) is a natural compound in an alkaloid family found in diverse plants. This compound exerts anti-inflammatory, anti-allergic, anti-oxidative and anti-fibrotic activities in several disease models. However, its beneficial role in endothelial injury, especially induced by diabetes, is unclear. We, therefore, evaluated the effects of TRIG on the cellular proteome of human endothelial (EA.hy926) cells followed by functional validation in high-glucose (HG)-induced endothelial deteriorations. Label-free quantification using nanoLC-ESI-Qq-TOF MS/MS revealed 40 downregulated and 29 upregulated proteins induced by TRIG. Functional enrichment analysis using DAVID and REVIGO tools suggested the involvement of these altered proteins in several biological processes and molecular functions, particularly cell-cell adhesion, ATP metabolic process, cell redox homeostasis, cadherin binding, and ATP hydrolysis activity. Experimental validation showed that HG triggered endothelial-to-mesenchymal transition (EndMT) (as demonstrated by increased spindle index and mesenchymal markers, i.e., fibronectin and vimentin, and decreased endothelial markers, i.e., PECAM-1 and VE-cadherin), increased oxidized proteins, and reduced intracellular ATP, active mitochondria, endothelial tube/mesh formation and VEGF secretion. However, TRIG successfully abolished all these defects induced by HG. These data indicate that TRIG prevents HG-induced EndMT, oxidative stress, mitochondrial dysfunction, and impaired angiogenic activity in human endothelial cells.

Background

Atopic dermatitis is a common chronic inflammatory skin disease characterized by relapsing eczema and intense itch. DGT is a novel synthetic heterocyclic diterpenoid derived from plants. Its therapeutic potential and mechanism(s) of action are poorly understood.

Objectives

We investigated the potent therapeutic effect of DGT on atopic dermatitis, exploring the underlying mechanisms and determining whether DGT is a safe and well-tolerated topical treatment.

Methods

We observed anti-inflammatory effects of DGT on tumor necrosis factor-α/interferon-γ–treated human keratinocytes, and anti-allergic effects on immunoglobulin E–sensitized bone marrow–derived mast cells. In vivo, DGT was topically applied to two experimental mouse models of atopic dermatitis: oxazolone-induced sensitization and topically applied calcipotriol. Then the therapeutic effects of DGT were evaluated physiologically and morphologically. Moreover, we performed nonclinical toxicology and safety pharmacology research, including general toxicity, pharmacokinetics, and safety pharmacology on the cardiovascular, respiratory, and central nervous systems.

Results

In keratinocytes, DGT reduced the expression of inflammatory factors, promoting the expression of barrier functional proteins and tight junctions and maintaining the steady state of barrier function. DGT also inhibited the activation and degranulation of mast cells induced by immunoglobulin E. Moreover, we found that interleukin-4 receptor-α was the possible target of DGT. Meanwhile, DGT had therapeutic effects on oxazolone/calcipotriol-treated mice. Notably, our pharmacology results demonstrated that DGT was safe and nontoxic in our studies.

Conclusion

DGT’s potent anti-inflammatory effects and good safety profile suggest that it is a potential candidate for the treatment of atopic dermatitis.