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In this study, we investigated the therapeutic potential of Berberine (BBR), an anti‐inflammatory agent capable of penetrating the blood–brain barrier, for mitigating postoperative cognitive dysfunction (POCD) in aged mice. BBR was administered at a dose of 10 mg/kg daily for 2 weeks and significantly improved cognitive impairments induced by surgical and anaesthesia‐related factors. Specifically, BBR markedly suppressed glial cell activation and reduced levels of pro‐inflammatory cytokines such as tumour necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β). Additionally, it alleviated oxidative stress markers and lipid accumulation. Using network pharmacology analysis, we demonstrated that BBR modulates neuroinflammation, oxidative processes and lipid metabolism by inhibiting the phosphorylation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway. Furthermore, extended research revealed that BBR upregulated the expression of PPAR‐γ mRNA, suggesting a neuroprotective mechanism via regulation of the PI3K‐Akt pathway. These findings support the potential application of BBR as a therapeutic agent for managing POCD in elderly populations.

Background Ibrutinib is a first‐line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. However, cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use. This study aimed to investigate the mechanism of ibrutinib‐induced cardiotoxicity and evaluate the protective role of metformin. Methods The study utilized male C57BL/6 J mice, which were administered ibrutinib at a dosage of 30 mg/kg/day via oral gavage for 4 weeks to induce cardiotoxicity. Metformin was administered orally at 200 mg/kg/day for 5 weeks, starting 1 week before ibrutinib treatment. Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail‐cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K‐AKT and AMPK pathways, along with apoptosis markers. Results C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib‐induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K‐AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K‐AKT activity, which contributed to the improvement of cardiac function. Conclusion The study concludes that metformin effectively mitigates ibrutinib‐induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K‐AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been associated with a significant increase in the risk of ventricular arrhythmias. In our present study, we aimed to investigate the cardiotoxicity of ibrutinib and explore the potential protective effects of metformin in ibrutinib‐treated mice. Our findings revealed that long‐term exposure to ibrutinib triggered ventricular myocardial apoptosis and fibrosis, leading to alterations in cardiac electrophysiological properties and an increased potential for ventricular arrhythmia. In this ibrutinib‐induced model of cardiac toxicity, metformin demonstrated the ability to upregulate the AMPK and PI3K/AKT signaling pathway, thereby mitigating the ibrutinib‐induced cardiotoxicity. As a result, we have demonstrated the protective effects of metformin in counteracting ibrutinib‐induced cardiotoxicity and propose it as a potential pharmaceutical therapeutic strategy for related diseases.

One of the most popular edible mushrooms in the world, Flammulina velutipes, has been shown to possess pharmacological properties such as anti-inflammatory and antioxidant properties. However, the potential activity of the brown strain of F. velutipes, a hybrid between the white and yellow strains, has not been thoroughly investigated. Numerous studies have been conducted in recent years to determine whether natural products can aid in improving or treating kidney diseases. In this study, we focused on the renoprotective effects of the brown strain of F. velutipes on cisplatin-induced acute kidney injury (AKI) in mice. Mice were pretreated with water extract from the brown strain of F. velutipes (WFV) from day 1 to day 10, with a single-dose intraperitoneal injection of cisplatin on day 7 to induce AKI. Our results demonstrated that WFV administration resulted in a reduction in weight loss and the amelioration of renal function and renal histological changes in mice with cisplatin-induced AKI. WFV improved antioxidative stress and anti-inflammatory capacity by increasing antioxidant enzymes and decreasing inflammatory factors. The expression of related proteins was determined via Western blot analysis, which showed that WFV could improve the expression of apoptosis and autophagy. We used the PI3K inhibitor Wortmannin and found that WFV achieved a protective effect by modulating the PI3K/AKT pathway and the expression of autophagy. Overall, WFV as a natural substance could be used as a new therapeutic agent for AKI.

Human placental mesenchymal stem cells (PMSCs) can prevent liver ischaemia–reperfusion injury (LIRI). However, their therapeutic effects are limited. Therefore, additional research is required to elucidate the mechanisms of PMSC‐mediated LIRI prevention and enhance the related therapeutic effects. This study aimed to examine the role of the Lin28 protein in the regulation of glucose metabolism in PMSCs. Further, it explored whether Lin28 could enhance the protective effects of PMSCs against LIRI and investigated the underlying mechanisms. Western blotting was performed to examine Lin28 expression in PMSCs under hypoxic conditions. A Lin28 overexpression construct was introduced into PMSCs, and the effect on glucose metabolism was examined using a glucose metabolism kit. Further, the expression of some proteins involved in glucose metabolism and the PI3K‐AKT pathway and the levels of microRNA Let‐7a–g were examined using western blots and real‐time quantitative PCR, respectively. To examine the relationship between Lin28 and the PI3K‐Akt pathway, the effects of AKT inhibitor treatment on the changes induced by Lin28 overexpression were examined. Subsequently, AML12 cells were co‐cultured with PMSCs to elucidate the mechanisms via which PMSCs prevent hypoxic injury in liver cells in vitro. Finally, C57BL/6J mice were used to establish a partial warm ischaemia–reperfusion model. The mice received intravenous injections containing PMSCs (control and Lin28‐overexpressing PMSCs). Finally, their serum transaminase levels and degree of liver injury were assessed using biochemical and histopathological methods, respectively. Lin28 was upregulated under hypoxic conditions in PMSCs. Lin28 exerted protective effects against hypoxia‐induced cell proliferation. Moreover, it increased the glycolytic capacity of PMSCs, allowing PMSCs to produce more energy under hypoxic conditions. Lin28 also activated the PI3K‐Akt signalling pathway under hypoxic conditions, and its effects were attenuated by AKT inhibition. Lin28 overexpression could protect cells against LIRI‐induced liver damage, inflammation and apoptosis and could also attenuate hypoxia‐induced hepatocyte injury. Lin28 enhances glucose metabolism under hypoxic conditions in PMSCs, thereby exerting protective effects against LIRI by activating the PI3K‐Akt signalling pathway. Our study is the first to report the potential of genetically modified PMSCs for LIRI treatment.

Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.

Drug resistance is a key factor underlying the failure of tumor chemotherapy. It enhances the stem-like cell properties of cancer cells, tumor metastasis and relapse. Luteolin is a natural flavonoid with strong anti-tumor effects. However, the mechanism(s) by which luteolin protects against paclitaxel (PTX)-resistant cancer cell remains to be elucidated. The inhibitory effect of luteolin on the proliferation of EC1/PTX and EC1 cells was detected by cell counting kit-8 assay. Colony formation and flow cytometry assays were used to assess clonogenic capacity, cell cycle and apoptosis. Wound healing and Transwell invasion tests were used to investigate the effects of luteolin on the migration and invasion of EC1/PTX cells. Western blotting was used to detect the protein levels of EMT-related proteins and stem cell markers after sphere formation. Parental cells and drug-resistant cells were screened by high-throughput sequencing to detect the differential expression of RNA and differential genes. ELISA and western blotting were used to verify the screened PI3K/Akt signaling pathway, key proteins of which were explored by molecular docking. Hematoxylin and eosin staining and TUNEL staining were used to observe tumor xenografts on morphology and apoptosis in nude mice. The present study found that luteolin inhibited tumor resistance (inhibited proliferation, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX-resistant esophageal squamous cell carcinoma (ESCC) cells. In addition, luteolin enhanced drug sensitivity and promoted the apoptosis of drug-resistant ESCC cells in combination with PTX. Mechanistically, luteolin may inhibit the PI3K/AKT signaling pathway by binding to the active sites of focal adhesion kinase (FAK), Src and AKT. Notably, luteolin lowered the tumorigenic potential of PTX-resistant ESCC cells but did not show significant toxicity in vivo. Luteolin enhanced drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in PTX-resistant ESCC and could be a promising agent for the treatment of PTX-resistant ESCC cancers.

Patterns of neuronal activity that induce synaptic plasticity and memory storage activate kinase cascades in neurons that are thought to be part of the mechanism for synaptic modification. One such cascade involves induction of phosphorylation of ribosomal protein S6 in neurons due to synaptic activation of AKT/mTOR and via a different pathway, activation of MAP kinase/ERK1/2. Here, we show that phosphorylation of ribosomal protein S6 can also be strongly activated by high frequency repetitive transcranial magnetic stimulation (hfrTMS). HfrTMS was delivered to lightly anesthetized rats using a stimulation protocol that is a standard for inducing LTP in the perforant path (trains of 8 pulses at 400 Hz repeated at intervals of 1/10 s). Stimulation produced stimulus-locked motor responses but did not elicit behavioral seizures either during or after stimulation. After as little as 10 min of hfrTMS, immunostaining using phospho-specific antibodies for the phosphorylated form of ribosomal protein S6 (rpS6) revealed robust induction of rpS6 phosphorylation in large numbers of neurons in the cortex, especially the piriform cortex, and also in thalamic relay nuclei. Quantification revealed that the extent of the increased immunostaining depended on the number of trains and stimulus intensity. Of note, immunostaining for the immediate early genes Arc and c-fos revealed strong induction of IEG expression in many of the same populations of neurons throughout the cortex, but not the thalamus. These results indicate that hfrTMS can robustly activate molecular pathways critical for plasticity, which may contribute to the beneficial effects of TMS on recovery following brain and spinal cord injury and symptom amelioration in human psychiatric disorders. These molecular processes may be a useful surrogate marker to allow optimization of TMS parameters for maximal therapeutic benefit.

Background: Heliox shows protective effects against acute focal ischemia-reperfusion injury in the brain. However, further research is needed to unveil the intricate molecular mechanisms involved. Determining how heliox affects ferroptosis caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells as well as the underlying mechanism was the goal of the current work. Methods: With the use of 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA), JC-1, and methyl thiazolyl tetrazolium, we assessed the survival, reactive oxygen species (ROS), and mitochondrial membrane potential in SH-SY5Y cells after they had been exposed to OGD/R and heliox. The expression of molecules associated with ferroptosis and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed using quantitative polymerase chain reaction (PCR) and immunoblotting, while malondialdehyde (MDA), oxidized glutathione disulfide (GSSG), ferrous ion (Fe2+), and reduced glutathione (GSH) levels were evaluated using biochemical kits. Results: OGD/R treatment reduced the GSH to GSSG ratio; the potential of the mitochondrial membrane; the expression of the proteins GSH, SLC7A11, and glutathione peroxidase 4 (GPX4); and the ability of SH-SY5Y cells to survive. In contrast, OGD/R treatment increased the expression of cyclooxygenase-2 (COX2), ACSL4, and ferritin heavy chain 1 (FTH1) proteins, the production of MDA and GSSG, and the levels of ROS and Fe2+. However, heliox effectively mitigated all these OGD/R-induced effects. Furthermore, in OGD/R-treated SH-SY5Y cells, heliox administration stimulated the PI3K/AKT pathway while suppressing the nuclear factor-κB (NF-κB) pathway. When MK-2206, an AKT inhibitor, was applied concurrently to the cells, these outcomes were reversed. Conclusions: Heliox prevents OGD/R from causing ferroptosis in SH-SY5Y cells by activating the PI3K/AKT pathway. This suggests a promising therapeutic potential for heliox use in the management of ischemia/reperfusion injury.

Phloretin has pleiotropic effects, including glucose transporter (GLUT) inhibition. We previously showed that phloretin promoted adipogenesis of bone marrow stromal cell (BMSC) line ST2 independently of GLUT1 inhibition. This study investigated the effect of phloretin on osteoblastogenesis of ST2 cells and osteoblastic MC3T3-E1 cells. Treatment with 10 to 100 µM phloretin suppressed mineralization and expression of osteoblast differentiation markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), type 1 collagen, runt-related transcription factor 2 (Runx2), and osterix (Osx), while increased adipogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid-binding protein 4, and adiponectin. Phloretin also inhibited mineralization and decreased osteoblast differentiation markers of MC3T3-E1 cells. Phloretin suppressed phosphorylation of Akt in ST2 cells. In addition, treatment with a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, suppressed the mineralization and the expression of osteoblast differentiation markers other than ALP. GLUT1 silencing by siRNA did not affect mineralization, although it decreased the expression of OCN and increased the expression of ALP, Runx2, and Osx. The effects of GLUT1 silencing on osteoblast differentiation markers and mineralization were inconsistent with those of phloretin. Taken together, these findings suggest that phloretin suppressed osteoblastogenesis of ST2 and MC3T3-E1 cells by inhibiting the PI3K/Akt pathway, suggesting that the effects of phloretin may not be associated with glucose uptake inhibition.

Breast cancer ranks as the leading cause of cancer-related mortality in females worldwide. It has been proven that microRNAs (miRNAs or miRs), a type of non-coding RNA, are involved in tumorigenesis. An increasing number of studies has confirmed the critical role of miR-214 in certain types of cancer. Nevertheless, the biological function of miR-214, as well as its underlying mechanisms of action in breast cancer remain largely unknown. In the present study, the expression of miR-214 was found to be upregulated in four human breast cancer cell lines in contrast to its expression level in the non-malignant breast epithelial cell line, MCF-10A. Moreover, the overexpression of miR-214 markedly increased cell viability and abrogated the apoptosis triggered by serum starvation, indicating that miR-214 plays a pivotal role in breast cancer cell growth. Further analysis suggested that the upregulation of miR-214 markedly induced the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, which largely accounted for the protective effects of miR-124 on cancer cell growth. This was further confimed by pre-treatment with the PI3K/Akt inhibitor, LY294002, which markedly attenuated the miR-214-induced increase in cell viability and resistance to apoptosis. Furthermore, the expression of phosphatase and tensin homolog (PTEN) was decreased following transfection wtih miR-214 mimics and PTEN was confirmed as the direct target of miR-214 by bioinformatics analysis and a dual-firefly luciferase reporter assay. Importantly, the introduction of PTEN cDNA lacking the 3′ untranslated region (3′UTR) significantly inhibited the miR-214-induced activation of the PI3K/Akt signaling pathway, and abrogated the protetive effects of miR-214 on cell survival and resistance to apoptosis. Taken together, these findings suggest that miR-214 possesses oncogenic activity and that its effects are mediated through the promotion of cell growth by targeting the PTEN-PI3K/Akt pathway. Thus, pharmaceutical interventions targeting miR-124 may provide a promising therapeutic strategy for the treatment of breast cancer.