Frontiers in Pharmacology最新文献

Introduction: As one of the most common complications of diabetes, diabetic cardiomyopathy (DCM) is the main cause of heart failure in patients with diabetes. However, the lack of effective treatments for DCM remains a clinical challenge. (Pro) renin receptor (PRR) is a member of renin angiotensin aldosterone system (RAAS). Here, we aim to determine whether PRR is involved in myocardial pyroptosis in diabetic cardiomyopathy.

Methods: We established diabetic rats model by intraperitoneal injection of streptozotocin (STZ). PRR overexpression adenovirus or PRR knockdown adenovirus was injected into the tail vein. Western blot, histopathology and immunohistochemistry staining, ELISA and Echocardiography were used to detect cardiac function changes and myocardial injury levels of DCM rats. Primary cardiomyocytes were stimulated with high glucose and PRR overexpression or PRR knockdown was achieved by adenovirus transfection, we also used the inhibitor of AMPK to decrease the activity of AMPK. Western blot, Real-time PCR, Immunofluorescence and ELISA were used to detect the level of PRR and pyroptosis in cardiomyocyte.

Results: We found that high glucose increased the expression of PRR in heart. After overexpression of PRR, the expression of the pyroptosis related proteins such as Caspase-1, IL-1β, IL-18, and NLRP3 was significantly increased, the phosphorylation level of AMPK was significantly decreased, and the fibrosis level was significantly increased, thus aggravating the cardiac function injury of DCM. On the contrary, PRR knockdown can alleviate the level of myocardial pyroptosis in DCM and improve cardiac function. The related mechanism was that PRR could inhibit AMPK phosphorylation and promote the activation of NLRP3 inflammasome.

Discussion: PRR aggravated pyroptosis of cardiomyocyte, increased the dysfunction of cardiomyocyte, and may be related to the decrease of AMPK phosphorylation and the overactivation of NLRP3. This may provide new ideas and targets for the treatment of DCM.

Introduction: Ferroptosis, induced by iron overload and an imbalance in redox homeostasis, promotes the generation of reactive oxygen species (ROS), leading to iron-dependent lipid peroxides (LPO) and oxidative stress. Lipid peroxidation induced by reactive oxygen species is essential for the progression of spermatogenesis. However, its imbalance can lead to reproductive system damage and oligoasthenospermia, a critical cause of oligoasthenospermia. Isatin (ISA) is a naturally occurring compound that is widely distributed in lobsters, crustaceans, shellfish and various plants. It exhibits significant antioxidant and anti-aging properties, suggesting its potential as a therapeutic agent for the treatment of oligoasthenospermia. This study aimed to investigate the effects and mechanisms of ISA on oligoasthenospermia and to elucidate the underlying molecular pathways.

Methods: All mice were divided into normal group, model group and treatment group. Both model group and treatment group received a single intraperitoneal injection of 30 mg/kg BUS to create the model of oligoasthenospermia. After 2 weeks, the treatment group received different doses of 25, 50 and 100 mg/kg ISA by gavage for 28 days, and then mice were sacrificed and tested.

Results: The results demonstrated that ISA effectively reversed busulfan-induced reproductive system damage in mice. This included the restoration of testicular histomorphology, improvement in sperm concentration and motility, regulation of serum sex hormone levels, and normalization of various oxidative indices in testicular tissue. Furthermore, ISA successfully reversed testicular ferroptosis by restraining the translocation of nuclear factor erythroid 2-related factor 2 (NRF2) into the nucleus and improved oligoasthenospermia through the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis.

Discussion: ISA was found to effectively ameliorate oligoasthenospermia in mice, presenting a potential therapeutic option for patients with this condition.

Objective: Biomaterials loaded with ingredients derived from traditional Chinese medicine (TCM) are viewed as a promising strategy for treating spinal cord injury (SCI). However, a comprehensive analysis of the existing literature on this topic has not yet been conducted. Therefore, this paper systematically reviews researches related to this approach, aiming to identify gaps and shortcomings in the field.

Methods: PubMed, EMBASE, Web of Science, Chinese Biomedical Literature, Wanfang, and China National Knowledge Infrastructure (CNKI) were searched for retrieving studies on biomaterials loaded with TCM ingredients published from their inception to October 2024. Two reviewers performed screening of search results, information extraction, and literature quality assessment independently.

Results: For this systematic review, 41 publications were included. Six TCM ingredients-paclitaxel, curcumin, tetramethylpyrazine, resveratrol, berberine, and tanshinone IIA were combined with biomaterials for treatment of SCI. Biomaterials were categorized into hydrogels, biodegradable scaffolds, nanoparticles, and microspheres according to the type of scaffold. These drug delivery systems exhibit commendable biocompatibility, drug-loading capacity, and drug-release capabilities, and in combination with TCM ingredients, synergistically contribute to anti-oxidative stress, anti-inflammatory, neuroprotective, and anti-apoptotic effects.

Conclusion: These studies demonstrated the efficacy of biomaterials loaded with TCM ingredients in facilitating motor function recovery and neuroprotection in SCI rats, providing evidence for future research. However, in the complex microenvironment of SCI, achieving the maximum drug loading capacity of TCM ingredients within biomaterials, along with sustained and controlled release to fully exert their pharmacological effects, remains a major challenge for future research.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42024505000.

The use of Bisphenol A (BPA) and its analogs in industries, as well as the products made from them, is becoming a significant concern for human health. Scientific studies have revealed that BPA functions as an endocrine disruptor. While some analogs of BPA (bisphenols) have been used for a longer time, it was later discovered that they are toxic, similar to BPA. Their widespread use ensures their presence in the environment, and thus, everyone is exposed to them. Scientific research has shown that BPA interacts with estrogen-related receptor gamma (ERRγ), affecting its normal function. ERRγ is involved in biological processes including energy metabolism and mitochondrial function. Therefore, continuous exposure to bisphenols increases the risk of various diseases. In our previous study, we observed that some analogs of BPA had a higher binding affinity to ERRγ compared to BPA itself and analyzed the amino acid residues involved in this interaction. We hypothesized that by antagonizing the interaction between bisphenols and ERRγ, we could neutralize their toxic effects. Taking into account the health benefits of millets and their toxin removal properties, virtual screening of millet-derived compounds was conducted along with prediction of their ADMET profiles. Top five candidates were prioritized for Density Functional Theory (DFT) calculations and further analyses. Long-term molecular dynamics simulation (1 µs) were utilized to evaluate their binding, stability, and antagonizing abilities. Furthermore, reevaluation of their binding energy was conducted using the MM-PBSA method. This study reports millet-derived compounds, namely, Tricin 7-rutinoside, Tricin 7-glucoside, Glucotricin, Kaempferol, and Setarin. These compounds are predicted to be potent competitive inhibitors that can antagonize the interactions between bisphenols and ERRγ. These compounds could potentially assist in the development of future therapeutics. They may also be considered for use as food supplements, although further investigations, including wet-lab experiments and clinical studies, are needed.

Postoperative pain management has consistently been a critical topic in the medical field, with patient-controlled intravenous analgesia (PCIA) being one of the most commonly utilized methods for postoperative analgesia. Currently, opioids remain the primary choice for PCIA in clinical practice. However, in recent years, an increasing number of studies have explored analgesic strategies aimed at reducing or eliminating the use of opioids in PCIA to mitigate the associated side effects and dependence. This article systematically reviews the progress of research on opioid-free analgesic strategies in PCIA through a comprehensive analysis of relevant literature.

Background and purpose: The damage or apoptosis of retinal ganglion cells (RGCs) is one of the leading causes of various blinding eye diseases, such as glaucoma, diabetic retinopathy, optic neuritis, and ischemic optic neuropathy. Oxidative stress is involved in RGCs death. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis, has various beneficial effects, including anti-inflammatory, anti-apoptotic, and antioxidant properties. However, the effects of baicalin on RGCs and the underlying mechanisms require further investigation.

Methods: In this study, a glutamate-induced oxidative stress damage model of R28 cells and a rat retinal injury model were established to investigate the effects of baicalin on oxidative stress damage to RGCs and try to elucidate the underlying mechanism.

Results: In vitro experiments demonstrated that the survival rate of R28 cells after glutamate treatment dropped to 33.4%, while 10 μM baicalin significantly inhibited glutamate-induced damage in RGCs (P < 0.001) and enhanced cell viability through decreasing ROS levels, increasing antioxidant enzyme activity, and suppressing the expression of inflammatory factors iNOS, TNF-α, IL-6, and IL-1β (P < 0.001). In vivo, baicalin effectively mitigated structural damage to retinal tissue and RGCs morphology induced by glutamate, increasing the thickness of the retinal ganglion cell layer, improving RGCs density, and reducing overall retinal thinning in rats (P < 0.001) in a time- and dose-dependent effects. Mechanistic studies revealed that glutamate evaluated the phosphorylation levels of JAK/STAT, while baicalin effectively inhibited the activation of the JAK/STAT signaling pathway.

Conclusion: This study confirmed that baicalin protects against glutamate-induced oxidative stress damage in RGCs. It effectively alleviates oxidative stress and inflammatory responses, reduces cell apoptosis, and improves the pathological changes in the retina of rat models of RGCs damage, thereby decreasing RGCs death. Further exploration of its mechanism revealed that baicalin effectively inhibits the JAK/STAT signaling pathway, protecting RGCs from oxidative stress damage. This provides an experimental basis for the application of baicalin in the treatment of RGCs damage.

Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic ossification of the ligamentum flavum in the thoracic spine and is considered the main cause of thoracic spinal stenosis and spinal cord disease. Osteoblast specific transcription factor Osterix (Osx) is required for bone formation, and there is no bone formation or ossification without Osx. Surgical intervention is recognized as the only effective method for TOLF treatment with set of complications. However, underlying mechanisms of TOLF are not well understood. This paper summarizes the pathogenesis of TOLF. Some relevant factors have been discussed, such as mechanical stress, genetic susceptibility genes, endocrine and trace element metabolism abnormalities, which may associate with TOLF. More recent studies using proteomics technology and RNA sequencing approach have discovered that some new factors participate in TOLF by upregulation of Osx gene expression including inflammatory factors. TOLF is a unique disease involving multiple factors. On the other hand, studies on TOLF pathogenic mechanism may provide new ideas for finding possible upstream regulatory factors of Osx and further developing novel drugs to stimulate new bone formation to treat osteoporosis.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide, with no effective treatment currently available. In recent decades, various traditional Chinese medicines (TCMs) and their active ingredients have shown the potential to attenuate the pathogenesis of AD in cellular and animal models. However, the effects of TCM formulas, which are typically administered in practice, have been less studied. This study aims to investigate the therapeutic effects of several formulas consisting of 4 components herbal components: catalpol, puerarin, gastrodin, and borneol, on streptozotocin (STZ)-induced AD models in cells and rats. The new object recognition (NOR), elevated plus maze (EMP), and Morris water maze (MWM) tests were used to evaluate the cognitive functions of rats. Golgi staining, Haematoxylin and Eosin (HE) staining, and Nissl staining analyses were employed assess the physiology of hippocampal tissues. Gene expression profiles were analyzed used transcriptomics and reverse transcription quantitative polymerase chain reaction analysis, while protein expression levels were determined using immunoblotting, immunohistochemical, and immunofluorescence. The production of cytokines was evaluated with enzyme-linked immunosorbent assay. The results demonstrated that the combined administration of these 4 components (CPGB) had superior mitigating effects on AD cell model, as evidenced by the reduced pro-inflammatory cytokine production and decreased deposition of Aβ protein. Further in vivo and in vitro experiments confirmed that varying doses of CPGB formula effectively ameliorated STZ-induced cognitive deficits, as shown by NOR, MWM, and EMP tests, as well as pathological changes in hippocampal tissues and a 3-dimensional brain neurovascular unit (3D-NVU) model, including decreased deposition of Aβ protein and formation of plaques. Transcriptome sequencing and analysis identified 35 genes with significantly altered expression levels due to STZ and CPGB treatment in hippocampal tissues, which were enriched in the Tlr4/Myd88/NF-κB signaling pathway. Interference with this pathway significantly influenced the therapeutic effects of CPGB in the 3D-NVU model. Collectively, these findings suggest that the combined administration of catalpol, puerarin, gastrodin, and borneol offers superior therapeutic effects on AD by modulating the Tlr4/Myd88/NF-κB signaling pathway. This study strengthens the theoretical foundation for using TCMs to treat AD, proving new insights and references for alleviating and treating AD.